SAMJ Vol 104, No 4 (2014) by HMPG

APRIL 2014

VOL. 104 NO. 4

The Teddy Bear Clinic Constitutional Court case

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Dangers of children swallowing magnetic beads

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Safety of osteoporosis medication

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Neurological manifestations of the acute porphyrias SciELO (SA) â&#x20AC;&#x201C; enhancing visibility of SA research CME: Spina bifida

283, 285 287 310-318

Neurology: • New Targets for Stress • Calcium signalling in brain diseases • Optimizing anti-epilepsy drug discovery • The addictive brain through different receptor subtypes • New approaches for Non-neuronal brain diseases • Rethinking mood therapeutics – novel pharmacological approaches for anxiety and depression • Pharmacotherapy of neurodegenerative diseases • The nitric oxide-cGMP pathway in neuropsychiatric illness: an update • Combination medications as novel treatments for stimulant addiction • New drug research and development for Alzheimer’s disease

World Congress of Pharmacology is coming to Cape Town Pharmacology - the multi-disciplinary science, essential for effective patient care and outcomes. Be sure to attend WCP2014 to become updated on the latest developments and advancements in treatment.

NOBEL LAUREATE TO OPEN WCP 2014 Dr. Robert Lefkowitz, Professor at Duke University Medical Center, Nobel Laureate of Chemistry in 2012, has been involved for more than three decades in G protein-coupled receptors. He has made numerous discoveries in his field directed at the molecular properties and regulatory mechanisms that control the function of plasma membrane receptors for hormones and drugs under normal and pathological circumstances. His contributions greatly assisted our understanding and development of new therapeutic strategies for several disease areas. Dr. Lefkowitz has amongst other isolated eight of nine subtypes of adrenergic receptors and determined their complete amino acid sequences. The Beta-adrenergic receptors are among the most common G protein-coupled receptors.

Do not miss the opportunity to hear the following speakers:

Oncology: • Therapeutic monoclonal antibodies in oncology • Targeted small molecule therapy in oncology • TGFB in Radiation biology and therapy • DNA repair and topoisomerase inhibitors in oncology • Sarcoma genetics and targeted therapeutics Infectious Diseases: • Pharmacology of tuberculosis regimens • Antibiotic resistance • New therapeutic strategies in HIV • Pharmacogenetics in infectious diseases • Recent advancements in malaria treatment • Advances in antiviral therapy • Vaccine development Immunology: • Inflammation and allergy: new therapeutic avenues • Immunopharmacology of the systemic inflammatory response syndrome • Immunobiologicals and chronic inflammatory diseases Lifestyle and Non-Communicable Diseases: • Obesity • New challenges of diabetes mellitus • Epigentic mechanisms in cell- and drug-based heart failure therapies

Prof R. Richard Neubig: Signal transduction in therapeutics Prof Bruce McEwen: Neurobiological effects of stress Our scientific programme includes a diverse array of themes and topics pertaining to basic and clinical pharmacology, which include more than 90 sessions on: • Pharmacology of Infectious Diseases and Immunology • Drugs of the Brain • Pharmacology of Chronic Diseases of Lifestyle • Drugs in Oncology d edite • Regulatory and Translational Pharmacology Accr • Fundamental Pharmacology

CPD

Gastro-Intestinal: • Manipulation of gut microbiome as a treatment strategy for gastrointestinal & metabolic disorders • Neuroendocrine regulation of GI protection: Central and peripheral pathways • Hydrogen sulphide in GI health and disease • Advances in GI pharmacology: new approaches to upper and lower GI ulcers and inflammation Pain: • Aspirin the wonder drug • Targeting the TRPA1 channel for pain treatment

FEATURED SYMPOSIUM IATDMCT Symposium – Frontiers in Therapeutic Drug Management Monday, 14 July – 17:00 – 19:00 Objectives of Symposium: 1. To describe the use of Bayesian adaptive feedback for optimized dosing of drugs in tuberculosis, HIV and transplantation. 2. Exploring biomarker supported management strategies in transplantation 3. To demonstrate an electronic medical record (EMR) integrated decision support tool for application of pharmacometrics to manage individual therapy in the clinical and research settings.

Targeted Sessions and Symposia The Scientific Programme Committee has compiled a comprehensive scientific programme with all the latest developments in medicine, which include:

For more information contact Scatterlings Conferences and events: Carolyn Ackermann – project manager – caro@soafrica.com Carina du Plessis – registration manager – carina@soafrica.com Lauren Gleeson – sponsorship and exhibition – lauren@soafrica.com Janice Candlish – abstracts and programme – Janice@soafrica.com

The full programme is available at: http://www.wcp2014.org/index.php/programme/scientific-programme Clinicians have the opportunity of registering for the full congress, single day or for an individual session. Registration fees as follows: Full Congress Day Registration Single Session

– R 8,000 – R 2,500 – R 625

APRIL 2014

GUEST EDITORIAL

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Neurosurgery in South Africa G Fieggen

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EDITOR’S CHOICE

VOL. 104 NO. 4

EDITOR Janet Seggie, BSc (Hons), MD (Birm), FRCP (Lond), FCP (SA) EDITOR EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG MD (Hon), FCM (Hon)

CORRESPONDENCE 256

Hereditary haemorrhagic telangiectasia in North African and sub-Saharan patients C Canzonieri, F Ornati, E Matti, F Chu, G Manfredi, C Olivieri, E Buscarini, F Pagella

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Physician, heal thyself: Creative writing as a tool for self-care and enhancing care of others D Garisch

258 The neglected triple disease burden and interaction of helminths, HIV and tuberculosis: An opportunity for integrated action in South Africa Z L Mkhize-Kwitshana, M L H Mabaso 259

Palliative care: Definition of euthanasia D J J Muckart, D Gopalan, T Hardcastle, E Hodgson, response from D J McQuoid-Mason

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Palliative care: Preventing misconceptions L Gwyther, response from D J McQuoid-Mason

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WHIDMT: Rossouw and Howard blatantly miss the point T D Noakes

EDITORIAL SYSTEMS MANAGER Melissa Raemaekers, BSc (Hons), PhD SCIENTIFIC EDITOR Kerry Gordon, MSc, PhD TECHNICAL EDITORS Paula van der Bijl, BA, HDipLib Emma Buchanan, BA NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za

PRODUCTION ASSISTANT Neesha Hassan ART DIRECTOR Brent Meder

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Community service doctors ‘slaves to the State’ – court challenge E Cape health officials nearly turn TB victims into cash cows Quack remedy cast – ‘We were pawns, not told, didn’t know, won’t say, don’t care’

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OBITUARIES/HULDEBLYKE Ivan James Nurick Hessel Utian

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BOOK REVIEW A School of Struggle: Durban’s Medical School and the Education of Black Doctors

FORUM

DTP & DESIGN Anelia du Plessis | Carl Sampson ONLINE MANAGER Gertrude Fani DISTRIBUTION MANAGER Edward Macdonald | Tel. 021-681-7085

CLINICAL PRACTICE 273 Diagnosis and management of Pompe disease L Bhengu, A Davidson, P du Toit, C Els, T Gerntholtz, K Govendrageloo, B Henderson, L Mubaiwa, S Varughese MEDICINE AND THE LAW 275 The Teddy Bear Clinic Constitutional Court case: Sexual conduct between adolescent consenting children aged under 16 years decriminalised and a moratorium on the reporting duties of doctors and others D J McQuoid-Mason CLINICAL PRACTICE The risks of gastrointestinal injury due to ingested magnetic beads S Cox, R Brown, A Millar, A Numanoglu, A Alexander, A Theron

279 The safety of osteoporosis medication F S Hough, S L Brown, B Cassim, M R Davey, W de Lange, T J de Villiers, G C Ellis, S Lipschitz, M Lukhele, J M Pettifor, for the National Osteoporosis Foundation of South Africa 283

Acute intermittent porphyria presenting as progressive muscular atrophy in a young black man C H Albertyn, M Sonderup, A Bryer, A Corrigall, P Meissner, J M Heckmann

EDITORIALS

285

DEPUTY EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB

HEAD OF PUBLISHING Robert Arendse

IZINDABA

277

CONSULTING EDITOR JP de V van Niekerk, MD, FRCR

The neurological manifestations of the acute porphyrias M W Sonderup, R J Hift

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April 2014, Vol. 104, No. 4

HEAD OF SALES AND MARKETING Diane Smith | Tel. 012-481-2069 Email: dianes@samedical.org PROFESSIONAL ADVERTISING Bronlyne Granger | Tel. 021-681-7000 E-mail: bronlyne.granger@hmpg.co.za HMPG BOARD OF DIRECTORS Prof. M G Veller (Chair), Prof. M Lukhele, Dr M Mbokota, Prof. A A Stulting, Dr M R Abbas, Dr G Wolvaardt ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman ISSN 0256-9574 Publisher website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za

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Increased visibility and discoverability of South African health-related research S Veldsman, W Gevers

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CONTENTS LISTED IN Index Medicus (Medline) Excerpta Medica (EMBASE) Web of Knowledge Biological Abstracts (BIOSIS) Science Citation Index (SciSearch) Current Contents/Clinical Medicine

288

High prevalence of cisplatin-induced ototoxicity in Cape Town, South Africa H Whitehorn, M Sibanda, M Lacerda, T Spracklen, L Ramma, S Dalvie, R Ramesar

292

Angiotensin converting enzyme inhibitors v. angiotensin receptor blockers in the management of hypertension: A funder’s perspective J L Makkink, O B W Greeﬀ

SAMJ SUBSCRIPTION RATES Local subscriptions R1 144.00 p.a. Foreign subscriptions R2 580.00 p.a. Single copies R95.00

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Mammographic screening for breast cancer in a resource-restricted environment J P Apﬀelstaedt, L Dalmayer, K Baatjes

Members of SAMA receive the SAMJ only on request, as part of their membership benefit.

297

Results of a pilot programme of mammographic breast cancer screening in the Western Cape J P Apﬀelstaedt, R Hattingh, K Baatjes, N Wessels

Subscriptions: Tel. 012-481-2071 E-mail: members@samedical.org

299

Community v. non-community assault among adults in Khayelitsha, Western Cape, South Africa: A case count and comparison of injury severity S Forgus, W Delva, C Hauptfleisch, S Govender, J Blitz

The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA.

302

Self-induction of abortion among women accessing second-trimester abortion services in the public sector, Western Cape Province, South Africa: An exploratory study D Constant, D Grossman, N Lince, J Harries

305

Clinicians ignore best practice guidelines: Prospective audit of cardiac injury marker ordering in patients with chest pain U Bellbhudder, J C Stanfliet

307

Hepatitis B and HIV co-infection in pregnant women: Indication for routine antenatal hepatitis B virus screening in a high HIV prevalence setting N V Thumbiran, D Moodley, R Parboosing, P Moodley

CONTINUING MEDICAL EDUCATION 310

314

REVIEW Transition from child- to adult-orientated care for children with long-term health conditions: A process, not an event A Westwood, N Langerak, G Fieggen ARTICLES The orthopaedic management of myelomeningocele A Horn, S Dix-Peek, S Mears, E B Hoﬀman

315

Hydrocephalus in spina bifida T Morgado, A Figaji

316

Occult spinal dysraphism N Mankahla, A Figaji

317

Beyond the operating theatre: Long-term quality of life in spina bifida Z Toefy

318

The International Federation for Spina Bifida and Hydrocephalus: Priorities in developing countries L Bauwens

28 Main Road (Cnr Devonshire Hill Road), Rondebosch, 7700 Tel. 021-681-7200. E-mail: publishing@hmpg.co.za Website: www.hmpg.co.za Please submit all letters and articles for publication online at www.samj.org.za © Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of SAMA Use of editorial material is subject to Creative Commons Attribution – Noncommercial Works License 3.0. http://creativecommons. org/licenses/by-nc/3.0

Plagiarism is defined as the use of another’s work, words or ideas without attribution or permission, and representation of them as one’s own original work. Manuscripts containing plagiarism will not be considered for publication in the SAMJ. For more information on our plagiarism policy, please visit http://www.samj.org.za/index. php/samj/about/editorialPolicies Printed by Creda Communications

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The Milky Way reflected in a dam in the Western Cape, South Africa. Photo and text: Eric Nathan Email: eric@ericnathan.com

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FIRST PUBLISHED IN 1884

Neurosurgery in South Africa Deeply rooted in clinical neurology, neurosurgery emerged as a special branch of surgery early in the 20th century and evolved swiftly with developments in anaesthesia, critical care, imaging and a host of surgical innovations. Today, the treatment of patients with diseases of the nervous system is one of the most rapidly advancing areas of medical practice and neurosurgery remains at the forefront, with new insights and advances transforming the management of diseases such as subarachnoid haemorrhage, traumatic brain injury, degenerative disc disease and hydrocephalus. This is an exciting time to be a neurosurgeon. The educational component of this issue of the SAMJ concludes a two-part series on the management of spina bifida, a neurosurgical condition that requires multidisciplinary management to ensure an optimal outcome. Given the sophistication of modern neurosurgery, it is easy to forget that we treat a wide range of common conditions ranging from congenital malformations through to trauma, stroke and meningitis, underscoring the relevance of teaching neurosurgical principles in the undergraduate curriculum. In a sense, the spectrum of cases presenting to the neurosurgeon reflects the adequacy of primary healthcare in a society as earlier diagnosis and treatment of conditions such as tuberculous meningitis and sinusitis would go a long way to preventing their neurosurgical complications. Spina bifida is potentially one of the most preventable of all longterm health conditions. While the administration of folate prior to conception has significantly reduced the incidence (and our National Department of Health is to be commended on being among the first to introduce food fortification legislation more than a decade ago), we need to do more by ensuring people are aware of the need for folate, promoting antenatal diagnosis and delivering appropriate care to any baby born with the condition. Another example of a successful public health intervention has been the introduction of gun control legislation, which has seen a fall in the number of gunshot injuries treated by neurosurgeons across our country, but we still have a long way to go in combating the scourge of neurotrauma due to assault and motor vehicle accidents. As neurosurgery has flourished, a number of new challenges have emerged, perhaps the greatest of which is the burgeoning number of subspecialties. The American Association of Neurological Surgeons now has seven major subspecialty sections, including spine and peripheral nerve, neurotrauma and critical care, stereotactic and functional, pain, cerebrovascular, tumour and paediatric neurosurgery. This is an issue for academic centres striving to ensure that they keep abreast of developments in all these areas so that the next generation can be properly prepared for a fast-paced and everchanging practice environment. It is clear that we have to train more neurosurgeons, and train them for longer than 4 years, to meet the needs of our country. We need surgeons with a wide range of skills encompassing microsurgery, spinal instrumentation, stereotactic and endoscopic surgery among others, and who are flexible enough to be able to gain expertise in areas as yet undiscovered.

254

Although spinal surgery is the core business of private practice, a number of practitioners have gained world-class expertise in other fields, but it is just not possible to achieve mastery of all. We will need innovative and effective continuing education programmes to ensure practitioners stay abreast of the evolution of our specialty. Although industry has an important role to play, such education must be unbiased – the response to the recently initiated African paediatric neurosurgery course, supported by the European Society for Pediatric Neurosurgery, the International Society for Pediatric Neurosurgery (ISPN) and the Society of Neurosurgeons of South Africa (SNSA), shows how much interest there is in education of this kind. An allied issue is the worsening medico-legal climate with dramatically rising malpractice insurance costs. We have to work with all stakeholders – government, insurers, professional groups and the public – to identify the reasons for this and bring it under control. This is a looming crisis that needs urgent attention. Neurosurgery was established in South Africa by an impressive founder generation and we face the future with a number of strengths. For the first time ever, all training centres are actively represented in the College of Neurosurgeons, and the SNSA enjoys dynamic leadership, which is addressing many of the challenges already mentioned. Although research output has been inadequate over the past decade, the requirement that registrars embark on research offers an opportunity to reverse this decline. On the international front, South African neurosurgeons have long played a leadership role in the World Federation of Neurosurgical Societies and the ISPN and are now contributing to organisations ranging from the World Federation of Interventional and Therapeutic Neuroradiology to the International Neurotrauma Society. We have also played an important role in the emergence of the Continental Association of African Neurosurgical Societies, a broadly supported organisation representing neurosurgery in Africa. Through training neurosurgeons from elsewhere in Africa, we have a real opportunity to grow our specialty in a sustainable way across our continent. As with all specialties in South Africa, we face challenges in the distribution of expertise and resources across some parts of our country. As a country, we are able to offer the most appropriate management to many patients, but not all. We need to find ways to meet the needs of those who don’t always receive the care they need. We can and must do better. Graham Fieggen

Division of Neurosurgery, University of Cape Town and Spina Bifida Clinic, Red Cross War Memorial Children's Hospital, Cape Town, South Africa graham.fieggen@uct.ac.za

S Afr Med J 2014;104(4):254. DOI:10.7196/SAMJ.8213

April 2014, Vol. 104, No. 4

EDITOR’S CHOICE

CME: Spina bifida

This month’s education component continues to advise on the management of children born with spina bifida/myelomeningocele and securing long-term quality of life for these children. This is dependent on the challenges of their disability being recognised, met and overcome, so that handicap is minimised, ensuring social integration, education, employment and independence.

ACEIs v. ARBs: A cost-benefit analysis

Hypertension poses a financial risk to any funder/medical aid scheme, not least because, according to the annual report of the South African Council for Medical Schemes for 2010 - 2011, hypertension is the most prevalent chronic disease among medical aid members, affecting 11.7%. The medical aid industry has >8 million beneficiaries, of whom ~1 million members will require treatment for hypertension. The most up-to-date South African Hypertension Guideline states that the choice of therapy for either an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) should be based on cost and tolerability. A health economic analysis[1] reveals that it is more cost beneficial to treat chronic hypertensive patients with an ACEI than with ARBs to prevent cardiovascular-related complications. Managed-care companies should continue to recommend ACEIs rather than ARBs in the treatment of their hypertensive patients.

Cisplatin-induced ototoxicity

Cisplatin is administered as the first-line treatment of soft-tissue cancers and has a reported cure rate of up to 85%. However, ototoxicity, characterised by irreversible bilateral hearing loss, affects 23 - 50% of adults and up to 60% of children. Such ototoxicity has been shown to be dependent on age at initiation of treatment, with those under 5 years and those over 40 years of age being most susceptible. An incidence of cisplatin-induced ototoxicity (55.1%) was observed in an adult population in South Africa (SA) studied by Whitehorn et al.,[2] of whom 62.7% experienced bilateral hearing loss. This study highlights the importance of regular audiological monitoring of patients receiving high-dose cisplatin. Adequate knowledge of the complication of ototoxicity on the part of clinicians may facilitate the prevention or amelioration of further ototoxic damage through administration of otoprotective agents, or a change of chemotherapeutic drugs. The authors call for further research aimed at understanding other risk factors, particularly genetic predictors of cisplatin-induced ototoxicity in the uniquely diverse SA population.

Acute porphyria: Unusual presentation

Acute intermittent porphyria (AIP) is the most common porphyria affecting the nervous system. Albertyn et al.[3] describe an unusual presentation in a young man with AIP, a reminder that acute forms of porphyria should never be forgotten when confronted with a patient with unexplained motor neuropathy, whether or not the characteristic features of the acute attack are present. This patient was fortunate in being referred to a neurology unit where exclusion of porphyria is a standard practice for patients with unexplained neuropathy, given the very high prevalence of porphyria in the SA population. He, unusually, improved rapidly in response to definitive therapy for porphyria with haem arginate, even though neurophysiological studies confirmed the presence of axonal necrosis. For those with a research interest in neuropathophysiology, this example is an invitation[4] to explore the interplay of disordered haem synthesis and neuronal function.

255

Breast cancer screening in SA

Breast cancer is a growing healthcare burden especially in the developing world and is the most common female cancer, accounting for 20% of all cancers in women in SA. The experience of breast cancer screening at the Tygerberg Academic Hospital, a tertiary referral hospital in Western Cape Province, SA,[5] indicates a high breast-cancer load in this urbanised population. The authors point out that the well documented shortage of radiologists, specifically breast radiologists, must not prevent the urgent establishment of breast centres to cater for the rapidly rising disease burden of breast cancer in our country while there are experienced trained surgeons, with a special interest in breast health, available to interpret breast imaging.

Risks associated with magnetic bead ingestion

Paediatric surgeons, Cox et al.,[6] draw attention to the risks of gastrointestinal (GI) injury due to ingested magnetic beads. They are freely available at many large retail stores and sold as an executive stress toy. If several are ingested, the magnets conglomerate in different segments of bowel, causing pressure necrosis, perforation and/or fistula formation anywhere along the GI tract. Symptoms do not occur until complications have developed, and even then, unless magnetic ingestion is suspected, treatment may initially be mistakenly expectant, as with any other foreign body. The authors reproduced the likely sequence of events in a laboratory setting using fresh, post-mortem porcine bowel as an animal model. Pressureinduced perforation appeared extremely rapidly, replicating the operative findings in their cases. If magnet ingestion is suspected, early endoscopic or surgical retrieval is mandatory. Appropriate, rapid, surgical intervention is indicated, laparoscopy offering a minimally invasive therapeutic option.

SciELO (SA): Enhancing SA research

I recently joined editors, publishers and researchers in São Paulo, Brazil, to celebrate the 15th anniversary of the Scientific Electronic Library Online (SciELO), which was joined by SciELO SA as its first African extension in 2009. SciELO SA was established by the Academy of Science of South Africa and is funded by the Department of Science and Technology. Two Health and Medical Publishing Group journals, the SAMJ and the South African Journal of Surgery, have already been accepted onto the platform.[7] Thomson Reuters: Intellectual Property and Science announced recently that it is now collaborating with the SciELO Network Portal to integrate the SciELO Citation Index into the Web of Knowledge. This initiative will bring even greater visibility and improved access to research from emerging countries like SA. JS 1. Makkink JL, Greeff OBW. Angiotensin converting enzyme inhibitors v. angiotensin receptor blockers in the management of hypertension: A funder’s perspective. S Afr Med J 2014;104(4):292-293. [http:// dx.doi.org/10.7196/SAM.7593] 2. Whitehorn H, Sibanda M, Lacerda M, et al. High prevalence of cisplatin-induced ototoxicity in Cape Town, South Africa. S Afr Med J 2014;104(4):288-291. [http://dx.doi.org/10.7196/SAMJ.7389] 3. Albertyn CH, Sonderup M, Bryer A, Corrigall A, Meissner P, Heckmann JM. Acute intermittent porphyria presenting as progressive muscular atrophy in a young African man. S Afr Med J 2014;104(4):283-285. [http://dx.doi.org/10.7196/SAMJ.7785] 4. Sonderup MW, Hift RJ. The neurological manifestations of the acute porphyrias. S Afr Med J 2014;104(4):285-286. [http://dx.doi.org/10.7196/SAMJ.7782] 5. Apffelstaedt JP, Dalmayer L, Baatjes K. Mammographic screening for breast cancer in a resourcerestricted environment. S Afr Med J 2014;104(4):294-296. [http://dx.doi.org/10.7196/SAMJ.7246] 6. Cox S, Brown R, Millar A, Numanoglu A, Alexander A, Theron A. The risks of gastrointestinal injury due to ingested magnetic beads. S Afr Med J 2014;104(4):277-278. [http://dx.doi.org/10.7196/ SAMJ.7500] 7. Veldsman S, Gevers W. Increased visibility and discoverability of South African health-related research. S Afr Med J 2014;104(4):287. [http://dx.doi.org/10.7196/SAMJ.7934]

April 2014, Vol. 104, No. 4

Air Liquide Southern Africa Tel: +27 (0)11 389 7262, Celeste Gopaul (Executive Healthcare Assistant) Fax: +27 (0)11 389 7394 www.airliquide.co.za

CORRESPONDENCE

Hereditary haemorrhagic telangiectasia in North African and sub-Saharan patients

To the Editor: Hereditary haemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu disease is an autosomal-dominant inherited vascular disease, characterised by the presence of mucocutaneous telangiectasia and visceral arteriovenous malformations (AVMs). Three main causative genes are known: ENG, ACVRL1 and SMAD4. BMP9 has also been shown to be involved in a small number of cases. We report two cases of HHT in North African and subSaharan patients. HHT is a vascular dysplasia that affects approximately 1 in 5 000 8 000 individuals,[1] with regional differences due to founder effects. [2,3] The clinical diagnosis of HHT is based on the Curaçao criteria,[1] including: spontaneous and recurrent nosebleeds; mucocutaneous telangiectasia at characteristic sites (nose, lips, oral cavity, fingertips and gastrointestinal mucosa); AVMs in lungs, liver, gastrointestinal tract, brain and spinal cord; and a first-degree relative with HHT.

SCORE

10 9 8 7 6 5 4 3 2 1

Nova-1 Nova-1 SRp30c Nova-1

ETR-3 ETR-3 SRp40 SRp30c

Nova-1

Sam68

ggguggcacaaccuauacaaaucugacuggacugugugugucucuccucugugucccccagGGCCCGUUACAGCUGGAGCUGACUCUCCAGGCAUCCAAGCAAAAUGGCACCUGCCC

| 10 -1 -2 -3 -4 -5 -6 -7 -8 -9 hnRNP P (TLS) -10

SCORE

10 9 8 7 6 5 4 3 2 1

SF2/ASF SRp40

YB-1

ETR-3 ETR-3 ETR-3 ETR-3

Approximately 85% of HHT patients[3] have a mutation identiﬁed in either ENG (OMIM#187300, HHT1)[4] or ACVRL1 (OMIM#600376, HHT2);[5] and 2% of the HHT families have a mutation identified in the SMAD4 gene, present in HHT in association with juvenile polyposis (OMIM #175050, JPHT).[6] For both ENG and ACVRL1, many mutations have been reported by independent groups in different countries, in most cases without any evidence of a founder effect, which could be suspected only in a limited number of cases.[2,7] As is known, HHT in people of black African descent is a rarity. To date, only one paper reports a mutation (exon 7 of ACVRL1: c.818T>C, p.L273P) in an HHT black adult patient born in Kenya,[8] as Westermann et al.[9] discuss in their letter. The other cases in literature were published before the identification of the two disease-related genes.[2] A December 2012 census showed that the number of immigrants from North Africa and sub-Saharan countries, residing regularly in Italy, for whom the public healthcare service is fully available, is 760 500 and 350 000, respectively. However, a high number of non-registered immigrants are certainly

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hnRNP DL

CUG-BP1 CUG-BP1 CUG-BP1 CUG-BP1 hnRNP F hnRNP A1 hnRNP I (PTB) CUG-BP1 Fox-1 hnRNP H1 hnRNP H2 Fox-2 CUG-BP1 hnRNP I (PTB) CUG-BP1 hnRNP H3 CUG-BP1 CUG-BP1 TDP43 TDP43 TDP43

B SF2/ASF SRp40

YB-1

ETR-3 ETR-3 ETR-3 ETR-3

Nova-1 1 Nova-1 SRp300c Nova-1

ETR-3 ETR-3 SRp40

SRp40 SRp30c

Nova-1 1

Sam68

ggguggcacaaccuauacaaaucugacuggacugugugugucucuccucugugucccccacGGCCCGUCACAGCUGGAGCUGACUCUCCAGGCAUCCAAGCAAAAUGGCACCUGGCCC

| 10 -1 -2 -3 -4 -5 -6 -7 -8 -9 hnRNP P (TLS) -10

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CUG-BP1 CUG-BP1 CUG-BP1 CUG-BP1 hnRNP A1 CUG-BP1 hnRNP I (PTB) CUG-BP1 Fox-1 CUG-BP1 hnRNP I (PTB) Fox-2 CUG-BP1 CUG-BP1 CUG-BP1 TDP43 TDP43 TDP43

hnRNP DL

Fig. 1. SpliceAid analysis of ENG mutation (c. 220-1G>C, splice defect). (A) hnRNP exonic splicing silencer (ESS) in wild-type sequence of intron2/exon3 of ENG (circled); (B) SRp40 exonic splicing enhancer (ESE) in mutated sequence of intron2/exon3 of ENG (circled).

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ADVERTORIAL

CORRESPONDENCE

present. The countries of origin of the two patients are those with the highest number of immigrants to Italy from North African or subSaharan areas – Morocco and Senegal. We wish to report our observation on two patients among the ~500 index cases, collected by the centres caring for HHT in northern Italy, in Pavia and Crema. The HHT diagnosis was arrived at according to Curaçao criteria. The first case is a patient born in Morocco (regular immigrants: ~501 600) with a ‘possible’ diagnosis of HHT (2/4 Curaçao criteria). The second patient was born in Senegal (regular immigrants: ~81 000) with a ‘definite’ diagnosis of HHT (3/4 Curaçao criteria). Molecular analysis of ENG and ACVRL1, according to Olivieri et al.,[10] disclosed a mutation in intron 2 of ENG (c.220-1G>C, splice defect) and a mutation in exon 8 of ACVRL1 (c.1232G>A, p.R411Q), respectively. Analysis of exon 3 of ENG, including intron-exon boundaries, covers 20% of the mutations identified in this gene in our lab. The mutation observed is yet unpublished. Analysis of splice sites with SpliceAid (http://www.introni.it/) (Fig. 1) and Human Splicing Finder (http://www.umd.be/HSF/), bioinformatics tools useful for predicting the effect of splicing mutations, shows the replacement of an exonic splicing silencer (ESS) with an exonic splicing enhancer (ESE). Overall, bioinformatics tests suggest that the mutation is pathogenetic. Exon 8 of the ACVRL1 gene carries 24% of the mutations identified in this gene in our lab. We observed the same mutation in 5/38 index cases from unrelated families and it has also been reported several times in the HHT mutation database (http://arup.utah.edu/database/hht/) in patients from different ethnic origins. Overall, these data support the observation by Westermann et al.[9] regarding the rarity of HHT in patients from Africa. We are aware of the limitations associated with reporting single cases, but we feel a short report of this observation is relevant as data are totally lacking regarding the incidence and prevalence of HHT, and the relative involvement of ENG or ACVRL1 in the African population. Cecilia Canzonieri Federica Ornati

General Biology and Medical Genetics, Department of Molecular Medicine, University of Pavia, Italy cecilia.canzonieri@gmail.com

Elina Matti Francesco Chu

Department of Otorhinolaryngology, Foundation IRCCS, San Matteo Polyclinic, Pavia, Italy

Guido Manfredi

Department of Gastroenterology, Maggiore Hospital, Crema, Italy

Carla Olivieri

General Biology and Medical Genetics, Department of Molecular Medicine, University of Pavia, Italy

Elisabetta Buscarini

Department of Gastroenterology, Maggiore Hospital, Crema, Italy

Fabio Pagella

Department of Otorhinolaryngology, Foundation IRCCS, San Matteo Polyclinic, Pavia, Italy 1. Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet 2011;48(2):73-87. [http://dx.doi. org/10.1136/jmg.2009.069013]

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2. Westermann CJ, Rosina AF, de Vries V, de Coteau PA. The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: A family screening. Am J Med Genet A 2003;116A(4):324-328. [http://dx.doi.org/10.1002/ajmg.a.10002] 3. Lesca G, Plauchu H, Coulet F, et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat 2004;23(4):289-299. [http://dx.doi. org/10.1002/humu.20017] 4. McAllister KA, Baldwin MA, Thukkani AK, et al. Six novel mutations in the endoglin gene in hereditary hemorrhagic telangiectasia type 1 suggest a dominant-negative effect of receptor function. Hum Mol Genet 1995;4(10):1983-1985. 5. Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13(2):189-195. [http://dx.doi. org/10.1038/ng0696-189] 6. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004;363(9412):852-859. [http://dx.doi.org/10.1016/S0140-6736(04)15732-2] 7. Lesca G, Olivieri C, Burnichon N, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: Data from the French-Italian HHT network. Genet Med 2007;9(1):14-22. [http://dx.doi. org/10.1097/GIM.0b013e31802d8373] 8. Kitonyi GW, Wambugu PM, Oburra HO, Ireri JM. Hereditary haemorrhagic telangiectasia in a black adult male: Case report. East Afr Med J 2008;85(8):412-416. 9. Westermann CJ, Kitonyi GW, Letteboer TG. Is hereditary haemorrhagic telangiectasia rare in the black race? The first sub-Saharan mutation. Haemophilia 2011;17(1):e244. [http://dx.doi.org/10.1111/ j.1365-2516.2010.02353.x] 10. Olivieri C, Pagella F, Semino L, et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet 2007;52(10):820-829. [http://dx.doi.org/10.1007/s10038-007-0187-5]

S Afr Med J 2014;104(4):256-257. DOI:10.7196/SAMJ.7816

Physician, heal thyself: Creative writing as a tool for self-care and enhancing care of others I was afraid that … conforming to the modes of behaviour expected of a doctor would distort my sense of self and my passion for art. – AS (second-year medical student) To the Editor: In his recent article in the SAMJ,[1] Prof. Steve Reid questions whether inclusion of art and humanities in the medical curriculum can improve the flexibility and skill of a graduate. As a writer and a general practitioner, I have struggled with the split between my artistic life and that of working with the ill, the injured and the emotionally hurt. As a student, I developed a chronic condition; although medication helped limit morbidity, it was my practise of taking emotional difficulty to the page that helped me manage stressors that adversely impacted on my health. Wishing to pass on tools that helped me look after myself, I run workshops in memoir writing, and wrote a book titled Eloquent Body.[2] Recently, I was invited to mentor four medical students in a writing project. Since 2011, Prof. Reid has offered groups of second-year University of Cape Town medical students the option to research the relationship between art and medicine during a one-month special studies module (SSM). An accomplished musician, Prof. Reid knows the life-enhancing benefits of artistic practice, and was concerned that medicine excluded this valuable component of health. The four components of the ‘writing and health’ SSM were: selfexploration through writing; noticing how language and the patient’s narrative are controlled in medical settings; a literature search on creative writing and its effects on health; and a visit to hospitalised patients, comparing strengths and weaknesses of medical historytaking with an open-ended conversation where patients used their own language to frame their experience. Scientists use objective measurement to determine what constitutes illness, and which interventions are effective. Most artists work intuitively from a subjective space, distilling the essence of experience that reflects on the human condition. The students wrote: AS: ‘I thought I would be told what to do, as in the rest of medical studies. I didn’t realise that I would have to find my own way,

April 2014, Vol. 104, No. 4

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following my interests, and that it would be about me. Finding out about myself is going to make me a better doctor.’ PN: ‘Since becoming a medical student, I don’t have time to write, and it is starting to make me feel ill. … We are taught to put our own thoughts and emotions aside as if there is no place for them. As a result I lost sight of the human aspect within medicine.’ Is there evidence supporting art as a serious component in medical education? Many disciplines jostle for more time on the academic calendar. To deliver appropriate care, we need to develop skills such as empathy that are difficult to teach. My medical education was filled with incidents where patients received quality treatment but were badly treated. ZW: ‘Reflective writing requires retreating into the subconscious, allowing for self-awareness,[3] thus facilitating the inspection of beliefs and values, internal conflicts and dealing with strong emotions.[4] … Writing slows down the whirlwind of medical education and allows students to make sense of their experience on their own terms.’ Writing a memoir is a form of debriefing and reflection. Taking circumstances that are troubling, whether an interaction with an infuriating colleague or patient, a personal loss or an illness, and giving the feelings a shape through words or other art forms has many tangential and unexpected benefits for both self-care and relationships. I recommend The Artist’s Way[5] to depressed patients; a colleague sends her stressed patients off to art or dance classes. Art is a way back to ourselves, a way of paying attention to what is going on below the radar of the mind, and a way of managing anxiety and stress. PN: ‘[Creative writing] may not be part of my assessments, but it increases the quality of my life. It helps me to cope with my experiences in order to prevent the cynicism and disillusionment found to plague medical students.’[6] Dawn Garisch

Author, workshop facilitator and part-time general practitioner dawn.garisch@gmail.com 1. Reid S. The ‘medical humanities’ in health science education in South Africa. S Afr Med J 2014;104(2):109-110. [http://dx.doi.org/10.7196/SAMJ.7928] 2. Garisch D. Eloquent Body. Cape Town: Modjaji Books, 2012. 3. Shapiro J, Shafer A, Kasman D. Words and Wards: A model of reflective writing and development of reflective capacity in medical education. J Gen Intern Med 2010;25(7):746-749. [http://dx.doi. org/10.1007/s11606-010-1347-4] 4. Hatem D, Ferrara E. Becoming a doctor: Fostering humane caregivers through creative writing. Patient Educ Couns 2001;45(1):13-22. [http://dx.doi.org/10.1016/S0738-3991(01)00135-5] 5. Cameron J. The Artist’s Way: A Course in Discovering and Recovering Your Creative Self. London: Pan Macmillan, 1995. 6. Shapiro J, Rucker L. Can poetry make better doctors? Teaching humanities and arts to medical students and residents at the University of California. Acad Med 2003;78(10):953-957. [http://dx.doi. org/10.1097/00001888-200310000-00002]

S Afr Med J 2014;104(4):257-258. DOI:10.7196/SAMJ.8063

The neglected triple disease burden and interaction of helminths, HIV and tuberculosis: An opportunity for integrated action in South Africa

To the Editor: The convergent distribution of HIV/AIDS and neglected tropical diseases (NTDs), particularly helminthiasis, in subSaharan Africa has been described and associated with accelerated HIV/AIDS and tuberculosis (TB) epidemics in the region.[1] South Africa (SA) suffers from the highest burden of HIV/AIDS and TB, especially in poor communities where helminth infection is endemic. The international NTD community is calling for integration

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of helminth control programmes into HIV/AIDS, TB and malaria control activities in developing countries.[2] SA has integrated TB and HIV/AIDS services and plans to initiate a national helminth control programme,[3] though how this might be integrated into HIV/AIDS and TB services is not clear. In SA, the most common NTDs include infection with the soil-transmitted helminths – Ascaris lumbricoides, Trichuris trichiura, Necator americanus, Enterobius vermicularis – and the less prevalent but common Strongyloides and Taenia spp. and Schistosoma haematobium and S. mansoni. These pathogens, owing to the undramatic symptoms they typically cause, have largely been neglected globally and in SA, despite their detrimental impact on nutritional status, child development, pregnancy outcome and worker productivity. Under conditions of poverty, overcrowding and limited access to water and sanitation, children and adults are commonly infested by helminths, as shown in Limpopo[4] and KwaZulu-Natal provinces,[5,6] and in Cape Town.[7] When the association of helminth infections with AIDS and TB became recognised from the 1990s onwards,[1] a greater interest was shown in the triple disease burden borne by the 36.4% of the SA population living below the poverty line.[8] Epidemiological and immunological studies have provided plausible evidence to suggest that the transmission of HIV and accelerated progression to full-blown AIDS are driven in part by the endemic presence of NTDs, especially in developing countries.[1] Similarly, chronic infection with NTDs results in impaired immune responses to TB, compromised BCG vaccination[1] and a poor clinical response to TB therapy.[9] While studies of helminth co-infection with HIV/TB and their deleterious effects are lacking in SA, elsewhere on the African continent there is accumulating evidence that prevention of helminthiasis might be part of the solution to the pandemics of HIV/AIDS and TB.[1] Great strides have been taken in SA to control the dual epidemic of HIV/TB by integrating HIV and TB services with the ‘onestop shop under one roof for two diseases, one patient and one folder’ approach.[10] A recent evaluation of this service integration reported success in both rural and urban settings.[11] Deworming and preventive chemotherapy can be incorporated into these integrated HIV/TB services to achieve a sustainable reduction of worm burden and control of co-morbidities. Screening for, and treatment of, helminth infections is relatively simple and inexpensive, and treatment of helminth infections alongside treatment of HIV/AIDS can be implemented at various levels of the SA healthcare system including: HIV counselling and testing programmes, targeting the general population; HIV prevention of mother-to-child transmission, targeting pregnant women; medical male circumcision campaigns at primary healthcare level, targeting youth and young adults; school health programmes, targeting learners; and TB and HIV healthcare facilities, targeting these patient populations. Such an integrated intervention package could also include appropriate education of communities on the modes of transmission of helminths and the importance of effective sanitation, a supply of clean water, and general hygiene as preventive measures. Alternatively, mass treatment of all high-risk populations in regions of the country with a high prevalence of helminth infection, using the preventive chemotherapy approach recommended by the World Health Organization,[12] could be adopted. All vulnerable individuals in the general adult population, and particularly pregnant women, children, youth and young adults, could be targeted. Depending on the group being targeted, some helminth control programmes might be school-based and others community-based.

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The potential benefits of integrating helminth control programmes into existing HIV and TB services warrant consideration. Such efforts should be supported by operational research to evaluate the impact of helminth control on HIV/AIDS and TB disease progression. Epidemiological and immunological research is also essential to understand the complexities of immunity during co-infections with helminths, HIV and TB. Z L Mkhize-Kwitshana

School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, South Africa kwitshana@ukzn.ac.za

M L H Mabaso

HIV/AIDS, STI and TB (HAST), Human Sciences Research Council, Durban, South Africa 1. Borkow G, Bentwich Z. Chronic immune activation associated with chronic helminthic and human immunodeficiency virus infections: Role of hyporesponsiveness and anergy. Clin Microbiol Rev 2004;17(4):1012-1030. [http://dx.doi.org/10.1128/CMR.17.4.1012-1030.2004] 2. Hotez PJ, Mistry N, Rubinstein J, Sachs JD. Integrating neglected tropical diseases into AIDS, tuberculosis, and malaria control. N Engl J Med 2011;364:2086-2089. [http://dx.doi.org/10.1056/ NEJMp1014637] 3. National Department of Health. Draft Policy Guidelines for Control of Schistosomiasis and Soil Transmitted Helminths. Pretoria: NDoH, 2005. http://www.health.gov.za/policies.php (accessed 22 January 2014). 4. Samie A, Nchachi DJ, Obi CL, Igumbor EO. Prevalence and temporal distribution of Schistosoma haematobium infections in the Vhembe district, Limpopo Province, South Africa. Afr J Biotechnol 2010;9:7157-7164. 5. Sumad AF, Anderson CB, Jackson TFHG. Impact of environmental conditions on the prevalence of intestinal parasites in the Durban metropolitan area. J S Afr Vet Assoc 2003;75(1):61-71. 6. Kwitshana ZL, Tsoka JM, Mabaso MLH. Intestinal parasitic infections in adult patients in KwaZuluNatal. S Afr Med J 2008;98(9):709-711. 7. Mkhize-Kwitshana ZL, Taylor M, Jooste P, Mabaso MHL, Walzl G. The influence of different helminth infection phenotypes on immune responses against HIV in co-infected adults in South Africa. BMC Infect Dis 2011;11:273. [http://dx.doi.org/10.1186/1471-2334-11-273] 8. Statistics South Africa. Living Conditions Survey 2008/09. Poverty Profile of South Africa: Application of the Poverty Lines on the LCS 2008/2009. Pretoria: StatsSA, 2012. http://www.statssa.gov.za/ publications/Report-03-10-03/Report-03-10-032009.pdf (accessed 25 August 2013). 9. Resende Co T, Hirsch CS, Toossi Z, Dietze R, Ribeiro-Rodrigues R. Intestinal helminth co-infection has a negative impact on both anti-Mycobacterium tuberculosis immunity and clinical response to tuberculosis therapy. Clin Exp Immunol 2007;147(1):45-52. [http://dx.doi.org/10.1111/j.13652249.2006.03247.x] 10. National Department of Health. A Practical Guide for TB and HIV Service Integration at Primary Health Care Facilities. Pretoria: NDoH, 2010. http://www.inpracticeafrica.com/~/media/Guidelines/ Practical_Guide_TBHIV.pdf (accessed 24 February 2014). 11. Scott VE, Sanders D. Evaluation of how integrated HIV and TB programs are implemented in South Africa and the implications for rural-urban equity. Rural Remote Health 2013;13(2):2165. 12. World Health Organization. Preventive Chemotherapy in Human Helminthiasis. Coordinated use of Anthelminthic Drugs in Control Interventions: A Manual for Health Professionals and Programme Managers. Geneva: WHO, 2006. http://whqlibdoc.who.int/publications/2006/9241547103_eng.pdf (accessed 18 December 2013).

S Afr Med J 2014;104(4):258-259. DOI:10.7196/SAMJ.7947

Palliative care: Definition of euthanasia

To the Editor: Euthanasia is defined as ‘conduct that brings about an easy and painless death for persons suffering from an incurable or painful disease or condition’.[1] Active euthanasia is the intentional killing of a person suffering from an incurable disease, and fulfils the legal criteria for murder. There is intent, causation, a human is the victim, and the act, whether by omission or commission, is unlawful. Motive, albeit the altruistic desire to relieve unnecessary suffering in the face of futility, is irrelevant to criminal intent.[2] The term passive euthanasia includes withholding extreme medical measures or removing life support in the presence of futile or non-beneficial treatment. McQuoid-Mason[2] outlines the reason why, in the eyes of the law, passive euthanasia is not a criminal offence, and withholding or withdrawing life-sustaining treatment or administering sufficient analgesia and sedation during the latter cannot be construed as murder. Of the four legal prerequisites for the definition of murder, namely intent, causation, a human victim and contravention of the

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law, only the last-mentioned is not fulfilled and spares the doctor from a conviction. Although reassuring to those working in critical care, where withholding or withdrawing support is a fact of life (or death), the fact that only one component of the legal definition spares us from being labelled criminals is somewhat disconcerting. We would argue that in addition to the lack of unlawfulness, neither intent nor causation applies, and furthermore that the term ‘passive euthanasia’ is an oxymoron and should be abandoned. In the situation of withholding or withdrawing treatment, which hastens death, the legal concept of eventual intent applies whereby the perpetrator does not mean to kill the person but does foresee death as a consequence.[2] We contend that death arises directly as a consequence of the underlying disease process and the inability of the patient to maintain homeostasis, and indirectly as the result of withdrawal of support. In fact McQuoid-Mason[1] defines passive euthanasia as ‘aiming at preventing the prolonging of death by allowing an irreversible fatal underlying illness to kill the patient through withholding or withdrawing treatment’, implying thereby that the disease and not the actions of the doctor causes death. There is a major difference between intentional killing, albeit out of altruism, and allowing death to occur as a direct consequence of the inciting disease or injury in the presence of non-beneficial treatment. The same argument pertains to causation, where legally the underlying disease is not considered as a new intervening cause and the cause of death is regarded as the final event, such as withholding or withdrawing therapy. According to McQuoid-Mason’s definition of passive euthanasia, it is the underlying illness that is responsible for death. Furthermore, part 1 of paragraph 77 in Section G1 of the Notice of Death/Still Birth clearly specifies that the immediate cause of death must be documented as the final disease or condition resulting in death. This is in direct conflict with legal causation if treatment has been withheld or withdrawn. Must we therefore complete the immediate cause of death as withdrawal of therapy and conditions leading to the immediate cause as non-beneficial treatment? That the legal stance of causation is contentious is illustrated by the following not uncommon scenario in South Africa. Consider two patients with traumatic brain injury and a large extradural haematoma, one in a remote rural area and the other with immediate access to a neurosurgical unit. The former dies before transfer to definitive care, and the latter after a craniotomy and evacuation but when further treatment is deemed non-beneficial and support is therefore withdrawn. Both die as a direct consequence of their injury. Why therefore is the act of withdrawal regarded as causation, thereby changing the entire legal perspective? Murder cannot be defined in active or passive terms and, if synonymous by definition, neither can euthanasia. The term passive euthanasia is paradoxical, serves only to confuse, and should be abandoned. In the presence of futility, withholding or withdrawing therapy and administering sufficient doses of analgesia and sedation to ensure comfort is humane and acceptable practice.[3] We propose that there should be only a single definition of euthanasia, namely an act of omission or commission remote from the normal standard of care with the specific intent of causing death. D J J Muckart

Department of Surgery, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa davidmuc@ialch.co.za

Dean Gopalan

Department of Anaesthesiology, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

April 2014, Vol. 104, No. 4

CORRESPONDENCE

Timothy Hardcastle

Department of Surgery, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

Eric Hodgson

Department of Anaesthesiology, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 1. McQuoid-Mason DJ. Emergency medical treatment and ‘do not resuscitate’ orders: When can they be used? S Afr Med J 2013;103(4):223-225 [http://dx.doi.org/10.7196/SAMJ.6672] 2. McQuoid-Mason DJ. Withholding or withdrawing treatment and palliative treatment hastening death: The real reason why doctors are not held liable for murder. S Afr Med J 2014;104(2):102-103. [http:// dx.doi.org/10.7196/SAMJ.7405] 3. Truog RD, Campbell ML, Curtis JR, et al. Recommendations for end-of-life care in the intensive care unit: A consensus statement by the American Academy of Critical Care Medicine. Crit Care Med 2008;36(3):953-963. [http://dx.doi.org/10.1097/CCM.0B013E3181659096]

Prof. McQuoid-Mason responds: I can understand the somewhat emotional response to my article, illustrated by the sentence ‘that only one component of the legal definition spares us from being labelled criminals’. The real reason doctors are not held legally liable for murder when they withdraw or withhold treatment in futile cases, or hasten death through the prescription of certain drugs, is because their conduct is not unlawful – not because they do not intend the patient to die or did not cause the death of the patient. As I said in my article,[1] all four elements for murder (the element referring to a human being is not usually in dispute) have to be satisfied – if the unlawfulness element is missing, there is no crime. This is not unusual for other areas of medical practice. For instance, cutting a person open during an operation is a serious assault (the surgeon causes injury to the patient’s body), but it is not unlawful if the patient consented to the procedure, or it if it is an emergency situation where the patient is unable to give consent. Muckart et al.’s contention that ‘in addition to the lack of unlawfulness, neither intent nor causation applies’ does not hold in terms of the law. Surely a doctor who orders that life support treatment is withheld or withdrawn, or prescribes a drug that lessens a person’s life expectancy, knows that their omission or conduct will hasten the patient’s death? Legally this knowledge amounts to eventual intention. Likewise, death will follow either immediately or later, the underlying illness or injury taking over, and the conduct of the doctor contributes to the death of the patient by allowing such condition to take over. This satisfies the legal requirement of causation for the reasons set out in the article. The suggestion that there ‘is a major difference between intentional killing, albeit out of altruism, and allowing death to occur as a direct consequence of the inciting disease or injury in the presence of nonbeneficial treatment’ is recognised by the law, which states that such conduct is not unlawful – even though the other elements of murder may be present. The concern about part 1 of paragraph 77 in Section G of the Notice of Death/Still Birth could be met by adopting what was quoted from Mason and McCall Smith at the end of my article: ‘Lawful withdrawal of life support systems which were necessitated by [the disease]’.[2] This would be the technically accurate manner of recording the death – with suitable adjustments for the nature of the injury or illness. However, it may be that the current practice is acceptable to the Registrar of Births and Deaths and the other relevant authorities. The example of the two cases of patients with traumatic brain injury and a large extradural haematoma ‘compares apples with oranges’. The death of the patient in the remote rural area ‘before transfer to definitive care’ may be directly due to the injuries without any intervention by healthcare professionals, unless the death was due to some negligent act or omission by them, so the latter did not cause the death. In the case

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of the patient who is given ‘immediate access to a neurosurgical unit’, the healthcare professionals concerned have placed the patient on life support to keep him/her alive. When they withdraw the support they hasten the death of the patient because further treatment is futile, but their conduct is not unlawful. The ‘legal perspective’ does not change, because in both situations the death may be lawful. I agree that ‘passive euthanasia’ is an oxymoron, for the reasons set out in the article, but it is a widely used term for lawful euthanasia. The definition of euthanasia suggested by Muckart et al. fails to deal with the question of causation and the objectives aimed at ending pain or suffering. However, there is some merit in adopting an amended version of the current definition of ‘active euthanasia’ as a definition of ‘euthanasia’ proper, without subdividing it into ‘active’ and ‘passive’. Thus, the definition could read: ‘Euthanasia occurs where a person with the actual intention to kill unlawfully causes the death of a terminally ill patient to end pain or suffering.’ This definition is consistent with that of murder, in that it includes intention, unlawfulness and causation, but is modified to include the elements of ‘actual intention’, which excludes ‘eventual intention’, and the objective ‘to end pain and suffering’ that is associated with euthanasia. D J McQuoid-Mason

Centre for Socio-Legal Studies, University of KwaZulu-Natal, Durban, South Africa mcquoidm@ukzn.ac.za 1. McQuoid-Mason DJ. Withholding or withdrawing treatment and palliative treatment hastening death: The real reason why doctors are not held liable for murder. S Afr Med J 2014;104(2):102-103. [http:// dx.doi.org/10.7196/SAMJ.7405] 2. Mason JK, Laurie GT. Mason and McCall Smith’s Law and Medical Ethics. 8th ed. Oxford: Oxford University Press, 2011:573-574.

S Afr Med J 2014;104(4):259-260. DOI:10.7196/SAMJ.8016

Palliative care: Preventing misconceptions

To the Editor: McQuoid-Mason’s statement that ‘Doctors who hasten the termination of the lives of their patients by withholding or withdrawing treatment or prescribing a potentially fatal palliative dose of medication satisfy the elements of intention and causation of a charge of murder against them’[1] is of great concern. It highlights a disconnect between the professions of law and medicine and misconceptions regarding the practice of palliative care. Such statements influence professional and public perceptions and create barriers to patient and family access to quality end-of-life care that focuses on relief of suffering and improving quality of life. The World Health Organization definition of palliative care includes affirming life, regards dying as a normal process, and intends neither to hasten nor postpone death. The palliative care approach aims to improve quality of life and assist patients to live as actively as possible. It may aim to prolong life where there is expectation of fair quality of life, but not to prolong dying. Clinical skill and experience assist the doctor and the palliative care team in identifying where quality of life can be improved and when patients are dying without likelihood of improvement. Excluding those who die suddenly, many people are under medical care when they die. Doctors do not cause the death, which results from the disease process. When treatment is futile, is refused or has no benefit, it should not be given just because treatment is available. ‘Consideration of withholding or withdrawing treatment as a sound clinical decision developed as a consequence of the availability of advanced medical technology and the resultant ability to prolong life that in some cases is in fact unwanted prolongation of the dying process.’[2]

April 2014, Vol. 104, No. 4

CORRESPONDENCE

Focusing on death, which is common to end-of-life care and to euthanasia, is ‘a reductionist philosophy that does not reflect clinical reality’.[3] Euthanasia is an active intervention intending to cause the person’s death. Palliative care advises that the decision to withhold or withdraw treatment should only be taken after careful consideration by the care team and discussion with the patient (if competent) and the family. Withholding or withdrawing treatment is a sound clinical decision under these circumstances. The statement that the doctor ‘legally has the eventual intention to kill the patient’[1] highlights the disconnect between the legal and medical professions on this point, and lack of understanding of clinical reality. It is a misconception that ‘prescribing a potentially fatal palliative dose of medication’[1] is part of medical practice, in particular palliative care. Responsible prescribing of medicine by doctors is reinforced in palliative medicine training, where doctors use sedatives and analgesics, titrating the dose to the patient’s response so that the symptoms are controlled without threatening the patient’s life. This misconception stems from the ‘Doctrine of Double Effect’ first described by Thomas Aquinas in the 13th century. Advances in medical knowledge and skill enable doctors to provide quality care without shortening life. Palliative care integrated into cancer care can increase life expectancy.[4] That using opioids or sedatives may shorten life is a myth; ‘there is no evidence that the use of opioids or sedatives in palliative care requires the doctrine of double effect as a defence’, and ‘although the doctrine is a valid ethical device, it is, for the most part, irrelevant to symptom control at the end of life. To exaggerate its involvement perpetuates a myth that satisfactory symptom control at the end of life is inevitably associated with hastening death. The result can be reluctance to use medication to secure comfort and failure to provide adequate relief to a deeply vulnerable group of patients.’[5] The Hospice Palliative Care Association of South Africa urges doctors to improve their knowledge and skills in palliative care and pain management, and to refer patients to hospice, or to a palliative care or pain service if they lack the knowledge and skills to address their patient’s suffering. Legal and ethics specialists must also update their understanding of palliative care and not perpetuate misconceptions that deprive patients of quality palliative care. Liz Gwyther

Hospice Palliative Care Association of South Africa liz@hpca.co.za 1. McQuoid-Mason DJ. Withholding or withdrawing treatment and palliative treatment hastening death: The real reason why doctors are not held liable for murder. S Afr Med J 2014;104(2):102-103. [http:// dx.doi.org/10.7196/SAMJ.7405] 2. Gwyther E. Withholding and withdrawing treatment: Practical applications of ethical principles in end-of-life care. South African Journal of Bioethics and Law 2008;1(1):24-26. 3. Finlay I. ‘Assisted suicide’: Is this what we really want? Br J Gen Pract 2005;55(518):720-721. 4. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363(8):733-742. [http://dx.doi.org/10.1056/NEJMoa1000678] 5. Sykes N, Thorns A. The use of opioids and sedatives at the end of life. Lancet Oncol 2003;4(5):312-318. [http://dx.doi.org/10.1016/S1470-2045(03)01079-9]

Prof. McQuoid-Mason responds: Gwyther’s ‘great concern’ about the fact that two of the four elements necessary for a charge of murder may be satisfied is understandable, but unfounded. The law is clear – unless all four elements are satisfied there is no question of a crime or a civil wrong being perpetrated (see my example in ‘Definition of euthanasia’ above, concerning surgeons in the operating theatre). I do not understand the statement that ‘Such statements influence professional and public perceptions and create barriers to patient and family access to quality end-of-life care that focuses on relief of suffering and improving quality of life.’ Surely doctors explain to patients and their families that when treatment is withheld or

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withdrawn in cases of futility, it will hasten the patient’s death and not prolong their dying? The doctors know that their act or omission will allow the underlying condition to cause death, but that they are protected by the law because their conduct is regarded as lawful; they may have what the law calls ‘eventual intention’, but their conduct is not unlawful. This is because the law recognises that, in Gwyther’s words, ‘When treatment is futile, is refused or has no benefit, it should not be given just because treatment is available.’ There is no disconnect between the law and medicine on this point, as the law regards such conduct as lawful. I stand corrected if it is a ‘misconception’ that the drugs used in palliative may reduce a patient’s life expectancy, and in Gwyther’s words, that ‘symptoms are controlled without threatening the patient’s life’. However, the principle regarding the hastening death might apply in other situations – unless such treatment is also no longer practised. Presumably, in the past, when certain drugs did reduce a patient’s life expectancy this was fully explained to patients (and to their families) to ensure that such conduct was lawful. I agree with Gwyther’s statement that ‘Legal and ethics specialists must also update their understanding of palliative care and not perpetuate misconceptions that deprive patients of quality palliative care.’ I also agree with the statement by Mason and McCall Smith that prompted me to write the article and is quoted at the end: ‘When, however, a treatment is discontinued solely by reason of its futility, there is nothing to be lost – and much to be gained by intellectual honesty – in attributing death, correctly, to “Lawful withdrawal of life support systems which were necessitated by [the disease]”.’[1] D J McQuoid-Mason

Centre for Socio-Legal Studies, University of KwaZulu-Natal, Durban, South Africa mcquoidm@ukzn.ac.za 1. Mason JK, Laurie GT. Mason and McCall Smith’s Law and Medical Ethics. 8th ed. Oxford: Oxford University Press, 2011:573-574.

S Afr Med J 2014;104(4):260-261. DOI:10.7196/SAMJ.8093

WHIDMT: Rossouw and Howard blatantly miss the point

To the Editor: Rossouw and Howard’s response[1] to my article[2] confirms that it is they and not I who miss the point. My key focus[2] was not whether the Women’s Health Initiative Dietary Modification Trial (WHIDMT) supports the use of carbohydrate-restricted diets. Nor did my key points focus ‘on subgroup findings rather than the robust overall findings’ of the study. By introducing these arguments, Rossouw and Howard[1] neatly sidestep the single most important question I raised. I wished to understand why these authors have yet to communicate the sole significant finding of the WHIDMT, which is that women with established heart disease at the start of the trial fared worse if they changed to the low-fat ‘prudent’ diet than did those equally ill women who continued to eat a supposedly unhealthy diet. I also showed that the key finding in their Fig. 3[3] is unintelligible because an essential line of text is missing, and furthermore that no reference is made to Fig. 3 in their response.[1] Instead they dismiss the only significant finding in their study as ‘likely to be a chance finding’ because ‘there is no biologic basis for expecting a different outcome in this [ill] subgroup, as shown in cholesterol-lowering trials of women with prior disease’.[1] An inconvenient outcome is therefore ignored because of their certainty that this adverse result has no (currently known) biological basis.

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There are a number of reasons why this explanation is scientifically unacceptable. First, the meta-analysis of the ‘cholesterol-lowering trials’ Rossouw and Howard cite[4] was published in 2012, 6 years after their paper[3] was published in 2006. Second, ‘cholesterol-lowering trials’ use medications, not diet, to lower blood cholesterol concentrations and hence provide an invalid comparison. Their inability to find a single study showing that dietaryinduced cholesterol lowering improves long-term outcomes is the conclusive admission by these experts that no such evidence exists. Third, the meta-analysis that Rossouw and Howard cite[4] has been subject to independent re-analysis.[5] The new conclusion is that drug-induced cholesterol lowering in a population at low risk of heart disease, as was the WHIDMT cohort, produced ‘no significant effect on overall mortality’, whereas ‘140 low risk persons would need to be treated with statins for 5 years to prevent one major coronary event or stroke [but] without any reduction in all-cause mortality’.[5] The finding that drug-induced cholesterol lowering provides a marginal benefit to only 1 of 140 treated subjects cannot support their argument that any negative outcomes caused by dietary-induced cholesterol lowering can safely be ignored because they are not biologically plausible.[1] It is important to note that the WHI prudent diet reduced the mean blood low-density lipoprotein cholesterol concentration by just 0.18 mmol/l at 3 years,[3] proving that the most expensive low-fat dietary intervention yet undertaken was essentially ineffective in reversing hypercholesterolaemia. Fourth, they make no reference to the Estrogenic Replacement and Atherosclerosis (ERA) Trial,[6] which found that coronary atherosclerosis progressed significantly more rapidly over a 3-year period in postmenopausal women eating the equivalent of the WHIDMT lowfat prudent diet than it did in those eating a diet high in saturated fats and low in carbohydrates and polyunsaturated fats. Rossouw and Howard concede[1] that the WHIDMT was not designed as a trial of the diet-heart hypothesis. This is obvious from the experimental design in which the intervention group also received an ‘intensive behavioural modification program’ comprising 18 group sessions in the first year followed by quarterly maintenance sessions for the next 7 years. The control group received only a copy of Dietary Guidelines for Americans. This renders mute any conclusions that any positive outcomes can be ascribed purely to dietary change. Yet they are not discouraged from continuing to conclude that ‘the lower fat diet ... led to less weight gain, improved insulin resistance (at 1 year), and no increased risk of diabetes risk compared with the control diet’.[1] But once more Rossouw and Howard are economical with the truth, because at the finish of the 8-year trial, there were no biologically important differences between groups in body weight (~500 g) (Fig. 2[7]), in blood glucose or insulin concentrations, or in other measures of insulin resistance including homeostatic model

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assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) (Table 2[8]). In fact, so disappointing were these findings that the authors were forced to conclude not that the dietary intervention produced positive outcomes, but that there were ‘no significant adverse effects’ (my italics) on insulin sensitivity,[8] a quite different conclusion from that which they aim to project in their letter.[1] Similarly, the only ‘robust’ conclusion of the total study was that a ‘low fat dietary pattern ... showed no evidence of reducing diabetes risk after 8.1 years’.[9] In fact, as early as within the first year of the trial, glucose control worsened significantly in those postmenopausal women with type 2 diabetes mellitus who reduced their fat intake on the high-carbohydrate prudent diet (Table 4[8]). Eight-year follow-up data have yet to be reported. Now is perhaps the time for its two senior authors finally to concede that the WHIDMT proved that a low-fat diet with or without an ‘intensive behavioural modification program’ is likely to be detrimental to the health of postmenopausal women with established heart disease or type 2 diabetes, and that mechanisms well described in the literature can readily explain these adverse outcomes. These findings have important implications for dietary advice to women with either established coronary artery disease or type 2 diabetes mellitus, and could have wider connotations. T D Noakes

Department of Human Biology, Faculty of Health Sciences, University of Cape Town, South Africa timothy.noakes@uct.ac.za 1. Rossouw JE, Howard BV. Noakes misses the point. S Afr Med J 2013;103(12):882. [http://dx.doi. org/10.7196/SAMJ.7709] 2. Noakes TD. Low-carbohydrate and high-fat intake can manage obesity and associated conditions: Occasional survey. S Afr Med J 2013;103(11):826-830. [http://dx.doi.org/10.7196/SAMJ.7302] 3. Howard BV, Van HL, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: The Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006;295(6):655666. [http://dx.doi.org/10.1001/jama.295.6.655] 4. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. Lancet 2012;380(9841):581-590. [http://dx.doi.org/10.1016/S0140-6736(12)60367-5] 5. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123. [http://dx.doi.org/10.1136/bmj.f6123] 6. Mozaffarian D, Rimm EB, Herrington DM. Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women. Am J Clin Nutr 2004;80(5):1175-1184. 7. Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: The Women’s Health Initiative Dietary Modification Trial. JAMA 2006;295(1):39-49. [http://dx.doi. org/10.1001/jama.295.1.39] 8. Shikany JM, Margolis KL, Pettinger M, et al. Effects of a low-fat dietary intervention on glucose, insulin, and insulin resistance in the Women’s Health Initiative (WHI) Dietary Modification trial. Am J Clin Nutr 2011;94(1):75-85. [http://dx.doi.org/10.3945/ajcn.110.010843] 9. Tinker LF, Bonds DE, Margolis KL, et al. Low-fat dietary pattern and risk of treated diabetes mellitus in postmenopausal women: The Women’s Health Initiative randomized controlled dietary modification trial. Arch Intern Med 2008;168(14):1500-1511. [http://dx.doi.org/10.1001/archinte.168.14.1500]

This correspondence is now closed. – Editor S Afr Med J 2014;104(4):261-262. DOI:10.7196/SAMJ.8041

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Community service doctors ‘slaves to the State’ – court challenge A Constitutional Court (ConCourt) challenge to South Africa’s health authorities by a communityservice doctor conscript, outraged by his ‘slave-like’ working conditions (including excessive overtime and arbitrary posting), has been turned down amid strong, and mixed, collegial emotion. Miguel Desroches, a Wits-educated and former Tygerberg Hospital medical intern, hit a raw empathic nerve in complaining to the ConCourt about provincially dysfunctional administrations and dismal working conditions under which he and his peers struggle daily. Most expert healthcare system observers agree that this combination contributes to a downward spiral that results in 70% of new doctors exiting the critically overburdened public sector, abandoning their thinly spread colleagues to a healthcare load representing more than 80% of the population. Desroches, citing National Health Minister, Dr Aaron Motsoaledi, and the Health Professions Council of South Africa (HPCSA) as respondents, wanted the ConCourt to rule the Community Service Regulations in Section 24A of the Health Professions Act (1974)[1] as unconstitutional. However, his application to be heard directly was dismissed by the judges who said it was ‘not in the interests of justice to hear it at this stage’ – leaving his puzzled lawyer scratching her head. Said filing attorney, Nicolette Erasmus, ‘I’m not sure they’re obliged to provide more detailed reasons, but I’d love to know. The final words are most odd … I don’t know what they mean … is it [do they mean] “at this stage in our democracy?” – I can only speculate.’ She revealed that the South African Human Rights Commission turned down her 2012 request to probe the issue, claiming it was a labour dispute. The Public Protector, however, is still probing the matter. Erasmus said that when the issue of excessive hours of work without pay was put to the National Health Department by the Public Protector, it denied this was happening. However, the department did admit that if junior doctors did not comply with orders to work all overtime allocated to them, they would face disciplinary

Miguel Desroches. Picture: Chris Bateman

action. The Public Protector subsequently put these responses to Erasmus, who at the time of going to print was collecting evidence of abusive overtime rosters from junior doctors. Desroches’ objection to the community service statutory one-year geographical posting won less sympathy than his employer-abuse complaints. Web and blog site postings (mainly anonymous) pulsated with young medics supporting ‘giving back’ to disadvantaged communities (often in the most deprived deep rural areas), saying this is a valid quid pro quo for the huge State subsidy they receive to qualify as healthcare workers, not to mention the rich and varied hands-on exposure to an almost globally unparalleled disease and trauma profile. One doctor, Karen Milford, wrote, ‘The Department of Health is not asking doctors to give up their lives and move to a remote jungle to slave away for no remuneration until they die. They’re asking them to take a short break from their life of privilege, to go and serve a community that desperately needs their help.’ Recommended almost universally by medics joining the debate was ‘playing’ the community service deployment system by carefully doing your homework and selecting the best alternatives listed under your ‘hospital-of-first choice’ to reduce the chances of 12 months in a ‘hospital from hell’. Desroches told Izindaba that he had wanted to stay on and do his community

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service in the Cape because he had an aunt with breast cancer in Groote Schuur Hospital and a great grandmother (who has since died) living in Cape Town. The rest of his family had emigrated to Australia and he now plans to follow them. He began agitating for a local community service posting in April 2013, before most interns had ‘even thought of doing so,’ but got consigned to rural choices in the Eastern Cape and KwaZulu-Natal. His subsequent multiple attempts to change this exposed what he believes is an ‘inflexible and nontransparent’ process. In the Western Cape, priority for placement is given to the province’s own bursars and to Muslim women (for religious reasons). Desroches said he firmly believes in ‘giving back’ to society, especially to underprivileged communities. ‘Of course it’s true that doctors gain invaluable experience in rural areas, but there are certain drawbacks often not considered. How many of those doctors would trust their relatives into the hands of a junior, inexperienced doctor who often is working without supervision, and is often the highest authority in a remote area? I’m not saying we don’t get good medical experience at these places, but it is a violation of our patients’ human rights to turn them into “practice dummies”. We took an oath to protect those lives and it encompasses the core of our practice as caregivers, which is to “first do no harm”.’

‘Forced labour violates my rights and freedoms’ – Desroches

Desroches wanted the ConCourt to decide whether legislation governing the rights and freedoms of health practitioners compelled to perform community service is justifiable. He also wanted to know what the human rights norms and standards should be ‘for determining forced labour, slavery and cruel and degrading treatment in the workforce in relation to community service’. The litany of woes that interns (two years of mainly hands-on learning and service) and ‘comserves’ (one year, service-orientated), plus regular medical officers and more die-hard State veterans, face are well documented. They range from dismal accommodation, living for months without payment, dysfunctional and/ or vindictive management, lack of proper

April 2014, Vol. 104, No. 4

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(or any) supervision, non-maintenance or non-existence of vital life-saving equipment, insufficient basic protective tools (masks, gloves), sometimes gut-wrenching ablution facilities and inadequate security measures (incidents of healthcare worker murder, assault and rape all made headlines last year). In a hard-hitting article entitled ‘Slaves of the State,’ published in the SAMJ in August 2012, Nicolette Erasmus, an attorney with a PhD in corporate law, baldly laid out what she calls ‘the professionally selective discrimination and exploitation’ of junior doctors. Openly declaring her ‘conflict of interest’ in coming from an extended family of nine medical practitioners and three nursing sisters, her research exposed sleepdeprived medical interns and communityservice doctors working up to 200 hours of overtime per month under the State’s commuted overtime policy. ‘Nurses moonlight in circumvention of the Basic Conditions of Employment Act. For trainee doctors, overtime in excess of 80 hours (per month) remains unpaid, rendered involuntarily under threat of not qualifying to practice medicine in South Africa (HPCSA rules). As forced labour, and sleep deprivation amounting to cruel and degrading treatment, this is outlawed in international law. No other professional group in the country is subjected to such levels of exploitation and discrimination by the State. These abuses should be challenged under the Constitution.’ Her solutions include the installation of electronic time-recording in State hospitals, putting a stop to unpaid overtime – limiting medical intern shifts to a maximum of 16 hours, and an investigation by the Human Rights Commission of South Africa. Desroches calls the forced overtime requirement ‘cruel and degrading,’ adding that married couples were being forced to separate due to placements. He says the working hours are so draining that many doctors have accidents on the way home – and stand a greater chance of making lifethreatening mistakes on duty. ‘Just because I can work a 36-hour shift without sleep or rest does not make it a good idea. It might make us tougher, but at what cost to ourselves and to our patients? The literature abounds with discussions of mistakes being made mostly after hours!’

SAMA fires broadside

The disgruntled young medics’ opening legal salvo drew unprecedented vitriol against the HPCSA by Dr Phophi Ramathuba, chairperson of the South African Medical

Nicolette Erasmus. Picture: Chris Bateman

Association (SAMA)’s Public Sector Committee. Known for her colourful and often abrasive language, Ramathuba outdid herself, calling on the HPCSA to ‘do its job or shut down’. She said it was ‘abundantly clear’ that the council could not fulfil its stated goals and that it was, ‘in fact, detrimental to the state of healthcare’. One of the HPCSA’s statutory obligations (its mission is ‘to protect the public and serve the profession’) is to ensure that hospitals maintain minimum standards to enable effective teaching and thus retain official council accreditation. Ramathuba also accused the council of taking too long to register new doctors (i.e after the community service year is completed) and not rectifying the living conditions of comserve doctors. ‘Dysfunctional systems, coupled with the sheer incompetence and indifference of some council staff results in unnecessary delays in registration,’ she added.

Doctors and dentists want to break away from HPCSA

SAMA chairperson, Dr Mzukisi Grootboom, agreed that the problems faced by junior doctors were ‘actually very serious,’ describing them as symptomatic of a government unable to service its rural communities. In a tangentially related controversy, he confirmed that SAMA was consulting lawyers about the Medical and Dental Professions Board (MDPB) (one of 12 under the HPCSA umbrella) breaking away from the HPCSA. He also revealed that SAMA and a cross-section of healthcare worker unions and organisations were

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planning a ‘campaign for positive change’. ‘South Africans will have to stand up as we historically did, to say that what’s happening is unacceptable.’ Declining to reveal campaign details, he spoke of SAMA’s frustration in appealing repeatedly to the National Health Minister and his provincial counterparts to deal with ‘the basics’ in improving healthcare delivery and doctor working conditions. He illustrated the dilemma of disparate provincial health administrations, some of them severely dysfunctional, quipping, ‘if the National Health Minister fails in this, then who are we?’ ‘When these young souls [comserves] finish their training, a lot are looking forward to leaving government service. Even their managers report not feeling wanted.’

Rogue provinces sabotage health solutions

While downplaying Ramathuba’s invective, Grootboom said that she met regularly with Health Minister, Dr Aaron Motsoaledi. ‘Unfortunately he has an overall mandate; running the actual hospitals rests with the provincial heads of department and MEC’s, so that’s where we need to focus, admit to problems and address them.’ Referring to the non-payment of junior doctors in the Eastern Cape for nearly three months in 2013 and the ugly and unprecedented (mainly junior) doctor strike that spread nationwide from KwaZulu-Natal in 2009, he said ‘little or no progress’ had followed. He had appealed to the health leaders in both provinces, the first time at a memorial service for the Durban comserve, Dr Senzokwakhe Mkhize (murdered on duty in 2012) and then after the Eastern Cape protest march on Bhisho by a broad protest coalition late last year. Despite promises and ‘shocked’ reactions, the provincial leaders remained unavailable for subsequent meetings. Grootboom added, ‘I’m afraid nothing has changed. We’re hamstrung. We don’t want to point fingers, we just want to engage and put things right, but we seem unable to make a breakthrough. It’s time all the healthcare unions stood up together. We have an obligation to protect our members and we make no apology for that, but at the same time we’re prepared to co-operate with the authorities.’ Pressed on the Erasmus research and Desroches court challenge, he said the government ‘needs to keep its side of the bargain and ensure fair conditions of service – we have

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some solutions in mind which I cannot divulge at present, but we’ve consulted broadly – we cannot keep quiet any longer or be spectators. This speaks to the core of our relevance as SAMA and the doctor’s we represent.’ Asked if or when SAMA would break away from the HPCSA, he said the MDPB did not believe it was ‘appropriate at this stage, but they’ve not thrown it out the back door completely which tells me some on their board share our policy aim.’ SAMA’s National Council resolved in 2009 to create a separate medical and dental council because they believe the doctor/ dentist voice is drowned out in a large and bureaucratic State-controlled general health council replete with competing interests. ‘We’re out-regulated, outvoted and stripped of any cogent ability to self-regulate – a fundamental tenet of professions the world over,’ Grootboom added, citing the nursing and pharmacy councils as examples of stand-alone professional associations. He said SAMA’s immediate goal was to get the

National Health Professions Act revised by parliament.

HPCSA admin the real problem – SAMA deputy

His deputy, Dr Mark Sonderup, drew a distinction between the HPCSA’s admini strative and regulatory dysfunction, citing the conviction of apartheid-era secret biological weapons specialist, Dr Wouter Basson, as a ‘time-consuming but appropriate outcome.’ ‘The public don’t see the processes behind that. Experts in committees of first, second and third enquiry are all volunteers, there of their own goodwill, retired or partly retired folk – I’m not so fussed about the council’s regulatory side. But administratively things are clearly problematic. In 2012 it took me nine months to get my registration card [after paying his annual specialist physician registration fees]. Last year I got it in June, an improvement of five months, so maybe things are improving. What I think some people miss is that many of these (Desroches-

linked) issues have little to do with the council – it’s the health departments!’ Sonderup, a former chairperson of the Registrar’s Association of South Africa and veteran of the medico-political struggle, was in the frontline of the original comserve battle. His testimony to the Parliamentary Portfolio Committee in 1997 resulted in some degree of choice in postings and an undertaking to take into account an intern’s personal circumstances. Desroches described the publicity generated by the ConCourt challenge as ‘a small victory, because people took notice. Questions are being asked and people are starting to think about the humanity of doctors now.’ Chris Bateman chrisb@hmpg.co.za 1. Section 24A, Health Professions Act 56 of 1974. Pretoria: Government Printer, 1974. http://www.hpcsa.co.za/downloads/ health_act/health_act_56_1974.pdf (accessed 26 February 2014).

S Afr Med J 2014;104(4):263-265. DOI:10.7196/SAMJ.8084

E Cape health officials nearly turn TB victims into cash cows Only intervention by the Treatment Action Campaign (TAC) prevented thousands of unsuspecting TB sufferers from being used as human guinea pigs in a lucrative and potentially dangerous experiment. Government and top health officials in the province were on the verge of rolling out an untested and unapproved ‘immuneboosting remedy’ to all local TB hospitals in what appears to be a cynical, predatory scheme that would have raked in millions for a natural health products company. This came after at least a dozen patients at primary healthcare clinics were illegally put on the unregistered and unapproved drug upon being falsely reassured that it was an approved ‘pilot’ scheme. Early this March, inspectors from the Medicines Control Council (MCC) swooped on various provincial health offices and private premises in and around

Port Elizabeth, effectively impounding a R1.4 million consignment of the bovine colostrum-based Immutides Spray. Its distributors and a local district health clinician had punted it to the bewildered clinical chiefs of three TB hospitals, who were summoned to Port Elizabeth to hear about its alleged immune-boosting properties in a suspect trial done on a small number of HIV-positive patients in Nigeria. Izindaba sources said a Dr Francois Fourie, in charge of primary healthcare clinics in the region, appeared to know ‘more about the product than the two guys from the marketing company,’ suggesting that the TB hospital chiefs use unspent money from their pharmacy budgets to purchase stocks of the unapproved ‘medication’. The chief of one hospital was told that he should buy enough to roll it out for 6 months and the other two (one of whose hospital deals exclusively with multidrug-resistant TB patients) for 2 years.

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MCC turned down spray, citing ‘safety concerns’

Immutides had been evaluated and turned down because of ‘genuine safety concerns’ by two national MCC committees (one for veterinary products and the other for complementary medicines). The so-called ‘immune-booster’ remedy has been discredited as having no therapeutic value. The scam is the latest in a long history of corrupt practices and inept management involving top politicians and senior management in the EC – with national government until now seemingly powerless to intervene effectively. For the third year in succession, not a single provincial department received a clean audit, with local Standing Committee on Public Accounts (SCOPA) Chairperson, Max Mhlati, declaring this March, ‘there are no consequences for non-compliance,’ which he says is crippling the administration. He baldly told his legislature, ‘the budget is

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there, but the people involved in corruption are here today to see where they’re going to get a cut out of this budget’. The directors of Saulez Agencies CC, which supplies the suspect spray, include Mr Mike Xego, a former Member of the Provincial Legislature and former ANC Chief of the Nelson Mandela Bay region. The criminal investigation, in terms of the Medicines Act and the Public Service Act, centres on an official directive sent out to the three provincial TB hospitals in the Nelson Mandela Bay region by Dr Lulekwa Mayekiso, a relatively junior doctor with little administrative experience, recently parachuted into the influential position of District Health Manager. She is the daughter of Dr Elizabeth Mamisa Chabula-Nxiweni, Chief Operating Officer for the Nelson Mandela Metro and its former Executive Director of Health (for greater Port Elizabeth). Mayekiso’s predecessor, Dr Tommy Oliver, resigned over a series of senior management directives ‘inappropriate to his budget’, and has since emigrated. His post was advertised at least three times over 18 months with several applicants being rejected. Once in the job, Mayekiso attached now-discredited documentation purporting to give official ‘approval’ for the TB spray to a directive to all senior managers involved in caring for patients in the TB hospitals (all located in her district). In it she ordered them to dispense the spray to all patients for the duration of treatment – and to issue scripts for the spray upon hospital discharge. The order was to have taken effect from 1 March this year.

Immutides had been evaluated and turned down because of ‘genuine safety concerns’ by two national Medicines Control Council committees (one for veterinary products and the other for complementary medicines). The so-called ‘immune-booster’ remedy has been discredited as having no therapeutic value.

TAC tipped off and acted – just in time

Just weeks before, the TAC got wind of the scheme and sent an urgent letter to the Provincial and National Directors General of Health, Dr Thobile Mbengashe and Precious Matsoso, resulting in those officials intimately involved protesting that ‘nothing

Former Eastern Cape Health Chief, Dr Siva Pillay. Picture: Chris Bateman.

actually happened’ and denying any patient was put on the drug on their watch. The rollout directive, a copy of which is in Izindaba’s possession, was addressed to the three TB hospital chiefs, the regional drug depot manager, the Nelson Mandela Bay Health District (NMBHD)’s senior clinical manager, its deputy directors for TB management and clinical support services, as well as the district pharmacist. Bewildered NMBHD TB chiefs questioned the missive, which also orders a 6-month ‘research project’ (from 1 March) to evaluate the effect of the spray when added to the treatment regimen of TB patients. Mayekiso’s missive asks for a final written report by the end of October, which she says will be ‘evaluated by the NMBHD’s top management, for future use of the Immutides Spray’. She asks her underlings to ‘please note’ that the initiation of the remedy ‘will continue during the compiling and evaluation of the research report,’ and concludes, ‘it is with great excitement that I give this directive to investigate every means to [sic] our disposal to facilitate better outcomes for our TB patients. I would like to thank all stakeholders who will be involved in this project in advance, and may God bless our effort.’

Shadowy practices at top level

According to Izindaba sources, the doctors who questioned the roll-out were told that if they wanted to work in the region, ‘they need to learn to accept directives’. Some years ago Xego approached Dr Siva

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Pillay, while he [Pillay] was the provincial Director General of Health in an initial bid to seek approval for an Immutides roll-out. When approached by Izindaba for comment, Pillay said ‘I told him he had to go through the proper channels and obtain the right approvals before it was given to any patients … that international norms and standards must be followed’. Xego is understood to have then approached the Health MEC, Sicelo Qobana (with whom Pillay had a long-standing feud over healthcare delivery and suspect departmental practices). Sicelo’s response was apparently that ‘black business people are being frustrated’. Subsequently Mrs Nomalanga Makwedini, the province’s then Acting Deputy Director General for Clinical Management Services, issued an official document, dated 20 March 2012, whose subject line reads ‘Acknowledgement of approval – Immutides Spray’. In it she ‘confirms’ that ‘Saulez Agencies CC applied to the NDoH [National Department of Health] for approval to register and supply Immutides Spray as a complementary medicine’. She then says that according to documents received from the NDoH [which were attached to the communique] ‘permission has been granted for Immutides Spray to be imported and sold as complimentary medicine in accordance with Government Gazette Notice 23128’. This was in spite of two MCC committees and her provincial Therapeutics Committee having rejected the remedy.

Fraudulent document

Shown copies of the document emanating from his NDoH office which purports to give approval for the importation and selling of the spray (as a complementary medicine), Mr Griffith Molewa, Director General of the Inspectorate of Law Enforcement in the Pharmaceutical and Related Product Regulation Management Unit, said it did no such thing. He said Saulez Agencies submitted an application in terms of legislation aimed at quantifying what types of complementary medicines there were on the South African market, and permission to release their drug shipment from the port health authorities. ‘That doesn’t give them the right to sell or distribute – it just saves them harbour storage costs and enables them to put it into quarantine. The only body that can make any such pronouncement is the MCC – and that’s only after you’ve provided data substantiated by a clinical trial for which you must register with the MCC’. He said the legislation cited in the

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documents attached to Mayekiso’s directive was rendered obsolete by a law introduced in November last year. Called an MDR 20.8, the newly required approval gives a timetable of when to register products. ‘The second (provincial) document you quote as giving acknowledgement of approval is simply wrong,’ he added. Quackdown, an internet database maintained by Section 27, lists Immutides as ‘untested and implausible,’ labelling it as an untested treatment for HIV and claiming that, ‘disturbingly’, a local distributor introduced it to four orphanages in the EC in 2012.[1] An internet search reveals the spray to be manufactured by US-based MicroBasics and imported by Mark KaneBerman, a director of MicroBasics Africa and NutriBasics, leading local suppliers of animal-feed additives based in Standerton.[2] The TAC’s letter of complaint says any documentation suggesting that it was found safe and effective by the MCC was ‘a gross misrepresentation of the facts’. An exhaustive search on the US National Institutes of Health’s PubMed database returned no results for clinical trials conducted on human beings using bovine colostrum. Neither is there any evidence of any clinical trials published in reputable scientific journals supporting the use of this product in human beings with HIV or TB. Besides not having ethical or MCC approval, using an unregistered product on TB patients in the public sector is unlawful and unethical. The TAC said it doubted whether any targeted patients (research subjects or not) would be given the opportunity for informed consent. In its letter to the two health ministers, the organisation urges them to stop the project immediately to safeguard patients, to probe why the directive was issued and whether Dr Mayekiso is suitable to head the NMBHD. Requesting copies of all documentation relating to the EC Department of Health’s purchase of Immutides, the TAC said it viewed the acquisition as ‘irrational and potentially in contravention of the Public Finance Management Act’. National Director General of Health, Precious Matsoso, told Izindaba that Mayekiso’s directive was in contravention

Precious Matsoso, former MCC Chief and current National Director General of Health. Picture: Chris Bateman.

of both the Medicines Act and the Public Service Act. ‘We are requesting records from individuals involved – they broke the law, I can tell you that upfront. It is clear some strange things have been happening.’ She said her MCC team was gathering evidence and criminal charges would follow. The NDoH document attached to Mayekiso’s directive saying Immutides ‘may be imported and sold as complimentary medicine in South Africa’, was suspect and the national (law enforcement) official involved would be questioned, she added. ‘Inspectors don’t issue authorisations – the product had already been rejected so she had no authority whatsoever to issue that letter,’ Matsoso said. On the narrowly averted drug roll-out and ‘pilot’, she said, ‘as clinical people we can’t do that on human subjects without an ethics panel or MCC approval of the trial protocol. The MCC says it’s an unregistered medicine. They also undermined the procurement process. We never called for tenders for that. How did they come about buying it? I say it was fraudulent.’

Spray cost more per patient than AIDS drugs

Izindaba sources said provincial officials ‘insisted’ the remedy was MCC-registered. One clinician officially pressured during the attempted roll-out commented, ‘the spray would have cost more per patient

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dosage than what it costs monthly for the equivalent [antiretrovirals] ARVs – they were targeting the most vulnerable patients lying in TB hospitals, the sickest of the sick. It’s just shocking.’ Ironically, Mike Xego, who was present during at least one of the presentations to the TB hospital chiefs, has since threatened to sue the NDoH for ‘stringing him along’ (‘leading’ him to believe) he could distribute his company’s product. Matsoso retorted, ‘he’s welcome to go ahead and sue us. We have a duty and a responsibility to protect the public.’ One EC clinician who spoke to Izindaba off the record, said using bovine colostrum without pasteurisation ran the risk of re-introducing bovine TB into the population via nosocomial (hospital) infections. Alternatively, pasteurising it meant all antibodies contained in the milk were rendered ineffective. ‘I’m not familiar with their manufacturing process but I do know that much,’ he said.

‘They were targeting the most vulnerable patients lying in TB hospitals, the sickest of the sick.’ – senior clinician. Veteran and trustworthy Izindaba sources in the EC Department of Health said that if the probe simply ‘scapegoated’ a few individual officials in the National and Provincial Departments of Health it would ‘simply be papering over the cracks’. ‘This thing leads directly to Bhisho head office where the authority was initially falsified and manipulated – senior heads must roll,’ one added. Chris Bateman chrisb@hmpg.co.za 1. Quackdown. Quackbase: Claim number 74. http://www. quackdown.info/quackdown/claims/74/ (accessed 12 March 2014). 2. MicroBasics. http://microbasics.com/promise/ (accessed 12 March 2014).

S Afr Med J 2014;104(4):265-267. DOI:10.7196/SAMJ.8171

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Quack remedy cast – ‘We were pawns, not told, didn’t know, won’t say, don’t care’ The pivotal players in the Immutides Spray roll-out drama say they were either victims of bad government communication, pawns of more senior officials or simply ignorant of what was going on. These were the themes to emerge when Izindaba put the allegations to them.

application. ‘Why didn’t the DGs take this to the MEC? I’m friends with [Public Service Minister] Lindiwe [Sisulu] and [Deputy President] Kgalema [Motlanthe] – and I never wanted their influence. In my layman’s view I thought I was doing the right thing. Why did I get those VC and EC numbers for procurement? Must you be a Gupta in this country? F*** this thing now, let’s leave it!’

Mr Mike Xego

Dr Lulekwa Mayekiso

Spitting expletives aimed at central and provincial government officials whom he defiantly claimed had assured him that all the necessary authorisations and documentation were in order, an enragedsounding former ANC regional chief, Mike Xego, vowed to sue national government for ‘misleading’ him after he imported ‘nearly R2 million’ of Immutides Spray. He said he cancelled plans to destroy the (effectively impounded) consignment after learning that it had expired – because ‘further research’ by his suppliers in Arizona, USA, revealed that its lifespan could actually be extended for another 12 months.

Xego’s response to the documents claiming to give Saulez Agencies permission to ‘import and sell’ was the following, ‘Who cares? I had permission to procure. Their systems are not my systems. Personally I don’t care. They are professionals, they know their own system – they should have advised me otherwise.’ ‘Right now I’m f****** stuck with stock that has a 12-month lifespan. I order stock and who pays for it? I’m a layman who applied [for the relevant clearances] like any other layman that does business. I complied, going from office to office – all responded positively. Must I be “Gupta’d” so easily? … It seems if you follow the protocols … I don’t want to talk about this s*** anymore. I own a big factory in [Port Elizabeth] PE. I was helping two white boys who were going to be stuck on their own (his fellow Saulez

Mr Mike Xego, former ANC regional chief. Picture: The Herald.

Agencies CC company directors, Guy Saulez and Gary Karison). I went to Bhisho to get permission … they asked me for a V number for national. I did that. National came back to me and said I’d done nothing wrong.’ Xego said he left the ‘boring mediocrity’ of the Eastern Cape (EC) provincial legislature in 1999 to focus on his business ventures, adding, ‘I’m not a parliamentarian – I’m a money-maker’. His response to the documents claiming to give Saulez Agencies permission to ‘import and sell’ was the following, ‘Who cares? I had permission to procure. Their systems are not my systems. Personally I don’t care. They are professionals, they know their own system – they should have advised me otherwise. I have nothing written from them about any pharmaceutical committee. They’re not my friends … I don’t care about them. I’m a radical politician who lives his own life and has his own mind. I don’t care about how they work except that they keep their heads above their water – they mustn’t sink and do things wrong. I’ve done nothing wrong. If people in the townships want this medicine I’m going to give it to them.’ He claimed three EC Health Directors General (DGs), with the exception of the current DG, Dr Thobile Mbengashe, saw documentation involving the Immutides

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Nelson Mandela Bay’s District Health Manager, Dr Lulekwa Mayekiso, grudgingly accepted responsibility for the controversial directive after it was put to her that its language was replete with imperatives, but insisted she initially viewed it as ‘a proposal’. She said her district clinical manager, Dr Francois Fourie, had approached her and asked her to write it. ‘For me it was a proposal, an internal instruction. I was very busy and don’t have an office manager so he did it for me. I didn’t write it myself. He was to report to me after meeting the TB hospital doctors and then we would evaluate if the stakeholders agreed on this issue. I then said let’s call it off because it was ill received.’ She said the first company director to contact her was Immutides company owner, Mr Guy Saulez, ‘about November’ last year (she was appointed in October). ‘He presented to me and said he had a contract with the [Nelson Mandela] Metro, supplying the clinics, but that it had been abruptly stopped. I issued the directive after several subsequent meetings with my team and them. My mistake was in not understanding the word that means “directive” and all those issues meaning I’d over-rolled [sic] everybody. I told Dr Fourie it’s not supposed to go out without me knowing. His answer was that if it’s a directive it’s not a secret. We were still supposed to get final buy-in from stakeholders and present to province for approval. It was prematurely sent out.’ She confirmed that Immutides was used on public sector patients at a number of clinics before she took up her current post. When it was put to her that it appeared as a cynical, predatory money-making venture, she responded; ‘Yo! … no … ayi … I don’t want to comment. That one was just doing the job. In my district there’s a lot of TB crisis and it’s actually … we have a lot of [multidrug-resistant] MDR [TB]

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her daughter a ‘pawn’. ‘I live my life from work to home to church. I never wanted to be a politician. I’ve always aspired to be a straightforward administrative servicedelivery person. A chance to save people of the metro where I was born is a priority of my life. She described her widowed daughter as ‘a girl of 43 who’s never been in a big place like PE. It’s a coveted post and there’s a lot of envy around. I’ve told her not to resign – she must fight on.’ She said she had called ‘Mike’ (Xego) and told him, ‘do you realise the thing you’ve let my child into?’ Asked if she was angry with Xego, she replied, ‘not really, he’s a good friend’.

patients and its growing. So really I was just concerned about the patients. For me it was not about the money. I didn’t even think about the money. For me it was about the immune booster.’ She confirmed that senior officials from the National Department of Health (NDoH)’s Law Enforcement office had visited her office to ‘follow up the directive – they wanted to check the evidence. When it started, how it came about … I didn’t feel any stress. It was a normal process … part of their duties.’ Mayekiso said she was not considering resigning, ‘If I regret anything, it’s even thinking about the concept of bringing in this project. I regret having met with them [Saulez Agencies CC]. If they didn’t come I wouldn’t have written all these things.’

Mrs Nomalanga Makwedini

Dr Francois Fourie

Dr Francois Fourie responded, ‘I’m not going to really discuss anything or give my opinion above her [Mayekiso] … We communicate through our district manager. Even if I have a different opinion I’m not going to voice it out of professionalism. To be quite honest I’m not going to change the integrity I have because somebody else changes theirs … the bottom line is if somebody wants to crucify me or blame-shift, effectively if will mean that human judgment is above God’s. No matter how badly I want to answer that question [speak outside the protocol] … to save my behind, that’s not my choice. I’m going to be ethical even if it kills me. I hope the senior people can answer the major questions and if they can’t, they can instruct me to speak to you. I’m not sitting here with fear in my heart. I must say all of this is intriguing for me.’ (Izindaba put his response to Mayekiso, who said she’d ‘think about it.’)

Mayekiso said she was not considering resigning’ ‘If I regret anything, it’s even thinking about the concept of bringing in this project. I regret having met with them [Saulez Agencies CC]. If they didn’t come I wouldn’t have written all these things.’

Dr Mamisa Chabula-Nxiweni

Chief Operating Officer for the Nelson Mandela Metro, Dr Mamisa Chabula-

Dr Elizabeth Mamisa Chabula-Nxiweni, Chief Operating Officer for the Nelson Mandela Metro. Picture: Ivor Markman, The Herald.

Nxiweni called and pleaded with Izindaba to await a ‘thorough investigation, rather than [participate in] the destruction of my daughter,’ denying she’d done anything to influence her child getting the job or any knowledge of an elaborate money-making scheme. ‘I don’t know if she can take any more. This whole saga is a political thing. As far as I’m concerned, this was approved by Siva Pillay and Mrs Makwedini with Francois Fourie who made them order the medication at the depot. I’ve been through so many allegations made by people in my own life – I don’t want my child to go through this.’ Chabula-Nxiweni, a mother of 10 university graduates, four of them doctors, said she knew Xego as a ‘comrade and fellow school colleague of my brother. I came to know him in the political field. He’s just a friend, like I call you my friend. I’m in no network of Xego’s. I’ve always practiced ethically.’ She described her children as ‘very independent – if I’d used my influence I could have had my way with my son (now an orthopaedic surgeon in Namibia), getting him a job here. I knew there was not a single orthopod in Port Elizabeth!’ She said Fourie had once prematurely terminated another of her doctor son’s contracts, yet she had not interfered, even dissuading her son from taking the matter to the labour court. ‘I’ve kept myself clean and taught my kids good ethics.’ She considered

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Acting Deputy Director of EC Clinical Services at the time (now CEO of the Nelson Mandela Academic Hospital), Mrs Nomalanga Makwedini, said Xego was referred to her by Dr Thabo Sibeko, the EC Deputy Director for Strategic Planning in Health. Xeko showed her documentation from the NDoH that seemed to support his contention that the Medicines Control Council had approved the Immutides Spray. ‘He never asked me how to go about it. It was as if he’d already done that. It looked to me that what was being proposed would be good for the patient and I had no objection [given the national “approval”]. I knew that Xeko would still have to go via the required national tender process, so there was nothing untoward. The paper he showed said he’d been to national and there was nothing wrong with the drug.’ Asked why she had not checked, Makwedini said the document was on an official NDoH letterhead and seemed authentic. She said she was unaware of any previous Immutides ‘pilot roll-out,’ as this would have happened in the actual district. ‘I know the research protocols very well. You don’t just impose things and say people will do this. Who underwrote the study? Which university? We (the EC) don’t have an ethical committee anymore. There are so many loopholes as we speak… .’ Health MEC Sicelo Qobana was unavailable for comment. Chris Bateman

chrisb@hmpg.co.za S Afr Med J 2014;104(4):268-269. DOI:10.7196/SAMJ.8173

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Obituaries Ivan James Nurick

Dr Ivan J Nurick was born on 25 August 1934 in Queenstown, after which his family moved to Indwe in the Eastern Cape. In 1952, when I arrived at Driekoppen (Belsen) residence at the University of Cape Town (UCT), the first person I ran into was Ivan and our long friendship began. We later both moved into the Medical Residence. We both married in 1959, within weeks of each other, and spent two years at Edendale Hospital outside Pietermaritzburg. Ivan returned to Cape Town where he had a stint in general practice, but went on to specialise as an anaesthetist, training at Groote Schuur Hospital. He practised as a specialist anaesthetist until he retired in June 2008, due to ill health. Always interested in the running of his alma mater, he achieved a variety of positions on committees. He was elected to the Student Representative Council (SRC) and the Medical Students Council (MSC), as well as the National Union of South African Students (NUSAS). He had the honour of being awarded the Abe Bailey Scholarship in 1957 and there is no doubt that he treasured this proud achievement, which took him to the UK along with other recipients of this award from other universities in South Africa. He knew all the initials, and full names, of our class of 1957 (and those of all the directors and CEOs of share companies on

the Johannesburg Stock Exchange, one of his great interests). He was a keen facilitator of our class reunions. He enjoyed playing detective, tracing classmates wherever they were in the world, taking great pride in tracking them down, and somewhat annoyed if he received a poor response to his letters. He was a keen sportsman, attending virtually every 1st Team UCT rugby game for more than 50 years. He wrote two books on the history and personalities of UCT rugby, and was also an ardent supporter of UCT cricket. He was a keen long-distance runner, and ran the Medical 10 a number of times. Ivan’s interests were broad and varied: he loved opera, restaurants and cats (his beloved cat, Chelsea, was named after his favourite soccer team). He read newspapers from everywhere, national and international; he loved history, especially Jewish history, and gave talks locally on the subject, particularly on the Anglo-Boer War. He was interested in politics – local, Israeli and American. His Afrikaans was erudite and of an academic quality, and he read Die Burger every day for more than 50 years. Latterly, Ivan did courses in history and anti-Semitism at UCT, and loved being back at varsity. A deeply spiritual man, he practised his religion honourably. He loved attending synagogue services, and also felt it incumbent upon him to attend funerals, prayers and consecrations, even when he knew the families only slightly. His health deteriorated in 2008, and after a long struggle with his illness, he passed away quite suddenly on 29 November 2013. We wish his wife, Shirley, and his sons Matthew, Phillip and Gideon and their families, a long life. I, personally, will miss my best friend very much. Basil Michaelides Retired physician tpepler@melbro.co.za

Hessel Utian

Hessel Utian was born on 18 February 1932 and passed away on 26 February 2012. After matriculating, at the age of 16 years, from Jeppe High School for Boys, Hessel

enrolled at Wits Medical School, graduating with an MB BCh in 1954. Having completed his junior training, he went to the UK for two years, during which time he obtained a DCH (RCP, London) and an MRCP (Edinburgh), gaining experience in paediatrics at the then Hospital for Sick Children, Great Ormond Street, London. On his return to South Africa in 1959, he was appointed as a registrar in paediatrics at Transvaal Memorial Hospital for Children (TMHC). After registration as a paediatrician with the then South African Medical and Dental Council (now the Health Professions Council of South Africa), he joined the private practice of Drs Seymour Heymann and Sam Javett in 1962, continuing as a part-time consultant in paediatrics at TMHC, with attendance at the Cardiac Clinic and one of the general paediatric units. In 1972, he was elected an FRCP (Edinburgh). His long association with the Department of Paediatrics, Wits University, was recognised in 1988, when he received a certificate from the vice-chancellor and principal of Wits University for 25 years of dedicated service. The Wits connection was maintained for another 25 years! Latterly, he was in charge of a special outpatient clinic that dealt with rheumatoid arthritis and other autoimmune diseases. He also lectured to nurses undertaking postgraduate training for their diplomas in paediatrics, and served as examiner for the FCPaed (SA) and for the final-year medical student examinations. Hessel was regarded as an astute clinician and will be fondly remembered by staff of the Department of Paediatrics. At his home, he grew roses and, when they flowered, would arrive for a ward round with a beautiful rose proudly pinned to his lapel. Our condolences go to his wife Norma (Diploma in Occupational Therapy, Wits, 1958), his four children and eight grandchildren. Solly Levin

Emeritus Professor of Paediatric Cardiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa solcynth@yebo.co.za

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Book Review A School of Struggle: Durban’s Medical School and the Education of Black Doctors By Vanessa Noble. Scottsville: University of KwaZulu-Natal Press, 2013. ISBN 978-186914-252-0.

Vanessa Noble has pulled a rabbit out of a hat by weaving what is essentially a scholarly monograph into an extraordinarily vibrant narrative on the history of black medical training in South Africa, specifically at the University of Natal Medical School, now the Nelson Mandela School of Medicine of the University of KwaZulu-Natal. The book is exceptionally well researched from primary sources, with numerous references and footnotes, and yet written in a style that makes it a page-turner. It chronicles the convoluted evolution of medical training for black South Africans that culminated in the establishment of the Durban Medical School (DMS). It recounts how this process was shaped by the then prevailing white social attitudes, and buffeted by a succession of socio-political and historical quirks, including the Christian missionaries, the emergence of black political consciousness, World War II, the ambiguously ‘liberal’ yet segregationist politics of the Smuts era, the gradual formalisation of the healthcare system

for black people, and the race-based rigidities of the apartheid era following the electoral victory of the National Party in 1948. The author traces this history from the formation of the Union of South Africa in 1910, at which time the racially segregated health services for black South Africans were reported to be ‘disorganised, underfunded and in a state of general neglect’ and, as described in an SAMJ editorial in the 1940s, ‘all patchwork, a patch here and a patch there and no planning’. Services that did exist were focused on curative interventions with no provision for preventive public health approaches to combat the infectious diseases that were rampant in many black rural and urban areas. Moreover, the system lacked black medical practitioners. Black students were barred from studying at the country’s recently established medical schools at the universities of Cape Town and the Witwatersrand for fear that ‘social and academic fraternisation might lead to racial mixing’ and because, in any event, blacks ‘lacked the mental capacity to

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master a difficult subject like medicine’. The fiercest antagonists were the white medical profession, who dreaded the competition black doctors would pose. In later years, both UCT and Wits were to admit a token number of black students until they were interdicted by apartheid legislation in the 1950s. Until World War II, aspirant black students who could afford it or were sponsored by missionaries went abroad (most often to Scotland, Ireland and the USA) to study. They returned to establish successful medical practices, sometimes with black and white patients, and became significant social and political leaders. The notion of a medical school dedicated to training black doctors was the brainchild of Dr James B McCord of the American Board of Foreign Missions. Founder in 1909 and first superintendent of Durban’s McCord Zulu Hospital, his passion led him to establish such a private medical school at the hospital in the early 1920s. It ended in failure, shot down by the Medical and Dental Council. He continued his advocacy for a black medical school until his retirement in 1940, when his colleague and successor, Dr Alan B Taylor, picked up the cudgel in the single-minded pursuit of McCord’s vision that eventually resulted in the establishment of Natal University’s DMS with Dr Taylor as the founding dean. Noble’s account of the years of twists and turns in this pursuit makes for compelling reading. This book represents a fitting and important archive to restore and preserve Dr Taylor’s legacy, which, sadly, time has conspired to erase from the university’s institutional memory. The chapter on the Alan Taylor Resi-dence, ‘a setting full of contradiction and ambiguities’, will no doubt conjure up bitter-sweet memories, as it did for me, for those who had the experience of living and studying there. Known to its residents as ‘Alan Taylor’, ‘Wentworth’ or simply ‘the Res’, it consisted of single-storey, asbestos-roofed rows of abandoned ‘Second World War-era barracks in the [‘coloured’] suburb of Wentworth’ adjacent to a gigantic and stinky oil refinery. Yet the Res was, in essence, the heart of the DMS. It was home to medical students throughout the six or seven years of study, and provided teaching facilities for the preclinical years. Here students were offered the rare opportunity to enter the prestigious medical profession, but in a degrading environment contrived to be as far removed from the white university campus as possible. They were forbidden to wear the university blazer, or to graduate at the same ceremony as white students. This ‘liberal’ university seemed oblivious to the irony of publicly professing opposition to the segregationist government policies while enforcing strict racial separation within its own walls. Yet life at the Res was not all doom and

gloom. I have some fond memories of the camaraderie, the student clubs, the ballroom dances, the laughter, and the intellectual debates. The Res became the epicentre of political radicalisation and mobilisation against apartheid epitomised in the story of Steve Biko and the Black Consciousness Movement. Chapters 6 and 7 provide a detailed overview of the students’ anti-apartheid struggle and political activism from the 1950s through to the 1980s, the police raids and the student arrests, with some student activists (myself among them) escaping to complete their studies abroad. The book also describes the appalling conditions at the King Edward VIII teaching hospital – the dilapidation, the chaos, the racism of some academic staff – but also the boundless learning opportunities. Notwithstanding all the challenges, tensions and contradictions, the DMS project was in many ways a huge success, as measured not only by the quality and number of doctors it produced, many of whom went on to distinguish themselves in research and clinical practice, but also by its contribution to the ‘struggle’ and its role as an incubator for many of today’s leaders. This book tells a remarkable and compelling story, and constitutes a unique and invaluable archive of an important history that should interest practitioners, academics and social scientists alike. Dan Ncayiyana Editor Emeritus, SAMJ, and Research Associate, Human Sciences Research Council, South Africa profdjn@gmail.com This is an excellent book. It took about 10 years for the author to collect and collate the material, in the course of which she interviewed many of the graduates of the medical school and those who provided years of service to it, and the book is interesting, factual and unbiased. It begins with the historical background of black medical education in South Africa between 1910 and 1945, followed by the establishment of the Medical School at the University of Natal. This difficult journey, the Alan Taylor Residence and the challenges of studying medicine in Durban are detailed. Clinical training at King Edward VIII Hospital in the 1950s and 1960s, the anti-apartheid struggle in the 1970s and 1980s, medical student political activism and its consequences, and the legacies of medical struggles in postapartheid South Africa are documented. Finally, there are the author’s reflections. The appalling conditions in which medical students worked and lived made many embittered, with some becoming politicians. In the early days of the DMS, professional opportunities for black students were restricted to medicine, law or teaching. Many who

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studied medicine came from the ‘cream’ of their society. It was inevitable that harsh and unjust discrimination would drive some to politics. They joined the African National Congress, held or are still holding key posts in the government, and are mentioned in the book. The teaching staff were mainly ‘liberal’ in outlook and dedicated to their task. The classes were small, engendering a close rapport between teachers and students. Research elevated the status of the medical school nationally and internationally. The high standard of graduates enabled many to pursue an academic career and hold senior positions locally, nationally and internationally. Sadly, the harshness of apartheid took its toll on the morale of black staff and students. Nearly all experienced discrimination. In my own case, in the 1960s, I received 65% of the salary of the white registrars I trained (and was told disingenuously that my standard of living was lower than that of whites). In 1962, having obtained my fellowship of the College of Medicine, I was promoted to consultant but was paid the salary of a medical officer, as there was no category of black consultants. In 1970, having trained in renal medicine under Sir Douglas Black in the Royal Infirmary, Manchester, UK, I was forbidden to work in the renal unit at Addington Hospital in Durban because I could not give instructions to white nurses. The renal unit was for white patients only, and was staffed by white doctors. However, in 1977 the Director of Hospital Services approached me to head the unit as, following emigration of all the white nephrologists, it could not function. I asked for three conditions to be fulfilled, viz. that the unit would treat patients irrespective of race, that doctors and nurses could work there irrespective of race, and that white patients would be treated by all doctors and nurses. After conferring with politicians this was agreed. An unhappy situation occurred when a white patient refused to be treated by a black doctor and was discharged from the hospital. I enjoyed reading this book and would recommend it to all doctors who graduated from the University of Natal and KwaZuluNatal and their families. It would also be of great interest to other doctors wishing to learn about the harshness of apartheid. It is the first book written on the subject, and makes an important historical contribution. It is appropriate that the first president of democratic South Africa, Mr Nelson Mandela, agreed to the medical school’s bearing his name. Challenges continue, however, and a ‘school of struggle’ it remains. Y K Seedat Emeritus Professor of Medicine, University of KwaZulu-Natal, Durban, South Africa seedaty1@gmail.com

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CLINICAL PRACTICE

Diagnosis and management of Pompe disease L Bhengu, A Davidson, P du Toit, C Els, T Gerntholtz, K Govendrageloo, B Henderson, L Mubaiwa, S Varughese Louisa Bhengu is a medical geneticist in the Department of Human Genetics, University of the Witwatersrand, Johannesburg, South Africa. Alan Davidson is associate professor and Head of the Haematology/Oncology Service, Red Cross War Memorial Children’s Hospital and University of Cape Town, South Africa. Paul du Toit is a physician in private practice in Johannesburg, South Africa. Carla Els is a paediatric pulmonologist in private practice in Johannesburg, South Africa. Trevor Gerntholtz is an adult nephrologist in private practice in Johannesburg, South Africa. Kenny Govendrageloo is a paediatric cardiologist in private practice in Johannesburg, South Africa. Bertram Henderson is a senior lecturer in the Department of Human Genetics and Head of the Clinical Unit, Department of Neurology, University of the Free State, Bloemfontein, South Africa. Lawrence Mubaiwa is a paediatric neurologist in the Department of Neurology, University of KwaZulu-Natal, Durban, South Africa. Sheeba Varughese is a paediatrician at the Gaucher and HIV Clinics, University of the Witwatersrand, Johannesburg, South Africa. The authors comprise the Lysosomal Storage Disorder Medical Advisory Board, South Africa. Corresponding author: K Govendrageloo (kennyg@doctors.netcare.co.za) Disclaimer: The Medical Advisory Board meetings were sponsored by Genzyme, a Sanofi company.

Pompe disease (PD) is an autosomal-recessively inherited neuromuscular disease that, if not diagnosed and treated early, can be fatal. It can present from early infancy into adulthood. Due to the lack of acid α-glucosidase, there is progressive intracellular accumulation of glycogen. The severity of the disease is determined by age of onset, organ involvement including the degree of severity of muscle involvement, as well as rate of progression. PD is classified into two groups: infantile and late-onset, each having two subgroups. The need for two tests performed by separate methods (screening and confirmatory) is outlined. It is imperative to try to reduce the time to diagnosis and to recognise the possibilities of false-positive results. A multidisciplinary team approach to treatment of affected patients is optimum with, as team leader, a physician who has experience in managing this rare disorder. In this article, we present a brief overview of the disease and provide guidelines for diagnosis and management of this condition in South Africa. S Afr Med J 2014;104(4):273-274. DOI:10.7196/SAMJ.7386

Pompe disease (PD) is a progressive, debilitating multisystemic neuromuscular disease. It is often fatal if not diagnosed and treated early. It is known by several names: acid maltase deficiency; glycogen storage disease type II; and glycogenosis type II. All muscle groups are affected, viz. skeletal, respiratory and, primarily in infants, cardiac muscle.[1,2] There is degeneration of muscle due to progressive intracellular accumulation of glycogen as a result of deficiency of lysosomal enzyme, acid α-glucosidase (GAA).[1] It is an autosomal recessive condition with the GAA gene located on chromosome 17q25.[2] The worldwide combined incidence is 1/40 000, though the infantile form of the disease tends to be more common among African-Americans and Chinese people.[2] PD can present from early infancy into adulthood; it encompasses a single disease continuum with variable rates of disease progression. [1,2] The severity of the disease is determined by age of onset, organ involvement including the degree of severity of muscle involvement (skeletal, respiratory and cardiac), and rate of progression.[1,2] In the

Please refer to the following article for a more detailed overview of the comprehensive management of Pompe disease: Kishnani PS, Steiner RD, Bali D, et al.; ACMG Work Group on Management of Pompe Disease. Pompe disease diagnosis and management guideline. Genet Med 2006;8(5):267-288. [http://dx.doi.org/10.1097/01.gim.0000218152.87434.f3]

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infant under a year, who is a floppy baby in cardiac failure, with cardiomegaly, the disease should be suspected.

Classification

PD is classified into two groups: • Infantile form: • Classic infantile PD is a most severe disease that is rapidly progressive and is characterised by prominent cardiomegaly with cardiomyopathy, hepatomegaly, muscular weakness and hypotonia.[3,4] Death results from cardiorespiratory failure in <1 year, if not treated. • Infantile variant form (non-classic in the <1-year group that has slower progression and less severe or absent cardiomyopathy). • Late-onset form:[5] • Childhood/juvenile or muscular variant (heterogeneous group) presenting later than infancy and typically not including cardiomyopathy. • Adult-onset form characterised by slowly progressive myopathy predominantly involving skeletal muscle and presenting as late as the 2nd - 6th decade of life.

Diagnosis in South Africa

It is imperative to make an early diagnosis to optimise disease management and outcomes. Testing is by way of two separate methods performed on the same day and involves: screening for the disease via dried blood spot (DBS) sent to Europe; confirmation, requiring whole blood samples sent to the National Health Laboratory Service

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(NHLS) in Johannesburg, South Africa, for GAA enzyme assay in lymphocytes, with absent or markedly reduced GAA enzyme activity offering a conclusive diagnosis. Fibroblasts obtained from a skin biopsy may also be tested for GAA, but a limiting factor is that the time to diagnosis is 4 - 6 weeks. A muscle biopsy may be confirmatory, but limiting factors are that it requires general anaesthesia, which can have a fatal outcome. Tissue samples must be frozen and shipped to the USA for analysis. Genetic studies may be performed in the USA or Europe, if required.

Screening

• Whole blood onto four spots on the DBS card – after DBS is dry and all details are provided on the card, it can be sent to Europe for analysis. • If infantile-onset PD is suspected, urgent testing should be requested.

Confirmation

• Arrange courier to be available through a local laboratory. • Draw whole blood (3 - 5 ml into an acid citrate dextrose (ACD) tube), preferably in the early morning. Samples should include blood from: • patient • control: unrelated donor (e.g. doctor, nurse, lab technician). • Wrap both tubes in tissue paper and place on an ice-brick in a polystyrene container (do not freeze). • Specimens should be delivered to the NHLS within three hours of the sample being drawn (i.e. before midday). • It is advisable to inform the NHLS lab technician to expect samples – this will facilitate quicker transit to the lab from the NHLS reception. • It is preferable not to test on a Friday as there is a huge risk of samples being unattended, resulting in higher false-positive results. • Results are usually available within 7 - 10 working days. A positive diagnosis of PD is made when both the screening and confirmatory tests corroborate each other.

Management

As this is a multisystem disorder, management requires a multidisciplinary team led by a physician with experience in managing this disorder. The team comprises a: • metabolic disease specialist/biochemical geneticist (to co-ordinate care) • cardiologist • pulmonologist/respiratory therapist • neurologist, neuromuscular specialist, physical therapist, occupational therapist, audiologist and speech therapist • intensivist • orthopaedist • genetic counsellor • metabolic dietician. Due to overall hypotonia and respiratory muscle weakness, patients are at high risk for pneumonia, leading to respiratory failure

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requiring ventilatory support; there may be ventilator dependence and even death.[5] There should be a low threshold to treat infections. Immunisations are required, including: seasonal influenza vaccine for patients and household members; pneumococcal vaccine; palivizumab is recommended during respiratory syncytial virus (RSV) season in infants and young children and older patients who have not received these immunisations (for which special motivation to the medical funders may be required). General anaesthesia[5] must be performed by someone familiar with anaesthesia in PD patients as ‘routine’ drugs may result in a fatality, and surgical procedures must be grouped for a single anaesthetic where possible. Since the end of 2012, enzyme replacement therapy (ERT) (as alglucosidase alfa) has been registered with the Medicines Control Council in South Africa for use in PD patients. Patients with infantileonset PD who receive ERT have significantly prolonged survival, decreased cardiomegaly, and improved cardiac and skeletal muscle function. The cardiac response appears to be good irrespective of the stage of disease at initiation of ERT, while the skeletal muscle response appears more variable than cardiac muscle. The best skeletal muscle response occurs when ERT is administered prior to skeletal muscle damage.[6,7] Treatment with alglucosidase alfa in late-onset PD is associated with improved walking distance and stabilisation of pulmonary function.[8] Alglucosidase alfa is available in 50 mg dried powder vials. There are specific guidelines to ensure proper reconstitution of the solution. The infusions are performed every 2 weeks (dosage 20 mg/kg) in an environment with correct observation of vital signs and equipment available for full resuscitation. Infusion-associated reactions (IARs) occur in ~50% of patients treated with alglucosidase alfa. IARs occur at any time during, and mostly up to two hours after, the infusion of alglucosidase alfa, and are more likely with higher infusion rates. Patients may be pre-treated with antihistamines, antipyretics and/or steroids. The prescribing information should be consulted before administration. Patients can eventually receive their infusions in a home-based environment.

1. Hers HG. Alpha-glucosidase deficiency in generalized glycogen storage disease (Pompe’s disease). Biochem J 1963;86:11-16. 2. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: Acid alpha-glucosidase (acid maltase) deficiency. In: Beaudet A, Scriver C, Sly W, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill, 2001:3389-3420. 3. Kishnani P, Hwu W, Mandel H, Nicolino M, et al.; Infantile-onset Pompe Disease Natural History Study Group. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Peds 2006;148(5):671-676. [http://dx.doi.org/10.1016/j.jpeds.2005.11.033] 4. Marsden D. Infantile onset Pompe disease: A report of physician narratives from an epidemiologic study. Genet Med 2005;7:147-150. [http://dx.doi.org/10.1097/01.gim.0000154301.76619.5C] 5. Kishnani PS, Steiner RD, Bali D, et al.; ACMG Work Group on Management of Pompe Disease. Pompe disease diagnosis and management guideline. Genet Med 2006;8(5):267-288. [http://dx.doi. org/10.1097/01.gim.0000218152.87434.f3] 6. Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid α-glucosidase: Major clinical benefits in infantile-onset Pompe disease. Neurology 2007;68(2):99-109. [http://dx.doi.org/10.1212/01. wnl.0000251268.41188.04] 7. Nicolino M, Byrne B, Wraith JE, et al. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease. Genet Med 2009;11(3):210-219. [http:// dx.doi.org/10.1097/gim.0b013e31819d0996] 8. Van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med 2010;362:1396-1406. [http://dx.doi.org/10.1056/NEJMoa0909859]

Accepted 27 August 2013.

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MEDICINE AND THE LAW

The Teddy Bear Clinic Constitutional Court case: Sexual conduct between adolescent consenting children aged under 16 years decriminalised and a moratorium on the reporting duties of doctors and others D J McQuoid-Mason David McQuoid-Mason is Professor of Law at the Centre for Socio-Legal Studies, University of KwaZulu-Natal, Durban, South Africa, and publishes and teaches in medical law. Corresponding author: D J McQuoid-Mason (mcquoidm@ukzn.ac.za)

The Constitutional Court in the Teddy Bear Clinic appeal case held that the sections of the Sexual Offences Act that impose criminal liability for sexual offences on adolescent children under 16 years of age are invalid. The invalidity was suspended for 18 months to allow Parliament to correct the Act’s defects. A moratorium was imposed on all investigations into, arrests in, prosecutions in, and criminal and ancillary proceedings regarding such section 15 and 16 offences. This includes the duty to report consensual sexual conduct between children under 16 years of age in terms of section 54 of the Act – pending Parliament’s correction. However, it is submitted that the ‘best interests of the child’ principle in the Children’s Act and the Constitution should guide all obligatory reporting situations involving sexual and other conduct of children, irrespective of whether they are adolescents under 16 years old or between 16 and 17 years old. S Afr Med J 2014;104(4):275-276. DOI:10.7196/SAMJ.7653

In The Teddy Bear Clinic appeal case,[1] the Constitutional Court held: (i) sections 15 and 16 of the Sexual Offences Act are invalid, where they impose criminal liability for sexual offences on adolescent children aged under 16 years; (ii) the invalidity is suspended for 18 months to allow Parliament to correct the Act’s defects; (iii) a moratorium is imposed on all investigations into, arrests in, prosecutions in, and criminal and ancillary proceedings regarding such section 15 and 16 offences – including the duty to report such consensual sexual conduct between children aged under 16 years in terms of section 54 of the Act[1] – pending Parliament’s corrections; and (iv) convictions or diversion orders made because of such offences committed by children aged under 16 years in terms of these sections of the Act must be expunged from the criminal record register and the National Register for Sexual Offenders.

Declaration of invalidity of sections 15 and 16 of the Sexual Offences Act

The court found that the parts of sections 15 and 16 of the Act that criminalised consensual sexual penetration or sexual violation between adolescent children under the age of 16 years violated the constitutional rights to dignity and privacy and the ‘best interests of the child’ provisions of the Constitution, and could not be saved by the limitation clause.[2] Sections 15 and 16 violate the dignity of such children because they punish ‘forms of sexual expression that are developmentally normal’, which ‘degrades and inflicts a state of disgrace on adolescents’.[1] Convicted adolescents are also stigmatised by having their names placed in the National Register for Sexual Offenders.[1] Parts of these sections infringe the right to privacy of adolescents under 16 years of age because they allow ‘police officers, prosecutors

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and judicial officers to scrutinise and assume control of their intimate relationships, thereby intruding into a deeply personal realm of their lives’.[1] Furthermore, the relationship is undermined between adolescents and ‘trusted third parties’ (such as doctors and social workers) who ‘are obliged to disclose information which may have been shared with them in the strictest confidence, on pain of prosecution’.[1] The ‘best interests of the child’ principle in the Constitution[2] is violated because the offences created in the sections ‘exacerbate harm and risk to adolescents by undermining support structures, preventing adolescents from seeking help and potentially driving their sexual behaviour underground’.[1] They ‘create a rupture of family life and invite a breakdown of parental care by severing the lines of communication between parent or guardian and child’.[1] Criminal liability could ‘at worst lead to imprisonment, and, at best, lead to diversion procedures’. In the latter case the adolescent ‘may still be arrested and forced to interact with arresting and investigating police officials’ and ‘acknowledge “responsibility for the offence” to a magistrate’ before diversion can take place.[1] The adolescent would also be forced to ‘disclose and have scrutinised details of his or her intimate affairs’.[1] The alleged safeguard of ‘prosecutorial discretion’ does not exist, because before it can be exercised such information must be provided.[1] The court concluded that it was ‘fundamentally irrational to state that adolescents do not have the capacity to make choices about their sexual activity, yet in the same breath to contend that they have the capacity to be held criminally liable for such choices’.[1] Sections 15 and 16 were not saved by the limitation clause of the Constitution[2] ‘because there was no evidence that criminalising such consensual sexual behaviour would deter adolescents from engaging in it’.[1] On the contrary, the court accepted the evidence that the

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sections cause ‘caregivers and institutions [to be] disempowered in dealing with adolescents because … in the course of attempting to provide guidance and assistance, they may well be told intimate information which they will be obliged to report to the authorities’. [1] The court also doubted whether the prohibitions in the sections could ‘ever be shown to be a constitutionally sound means of preventing the occurrence of such risks as teenage pregnancy’,[1] as the state’s lawyers contended. The court therefore confirmed the declaration of constitutional invalidity by the North Gauteng High Court,[1,3] of the parts of sections 15 and 16 affecting consensual sexual conduct by adolescent children under 16 years of age.

Invalidity suspended for 18 months to allow Parliament to correct the defects

The Constitutional Court did not accept the North Gauteng High Court’s decision to sever parts of sections 15 and 16 and to read in other parts. Firstly, this was because ‘the impugned provisions serve an important function insofar as they impose criminal liability on an adult for engaging in sexual conduct with a consenting adolescent’, which is not provided for elsewhere in the Act and must be preserved.[1] Secondly, because the sections are interlinked with other provisions in the Act, ‘severing portions from, and reading words into, those sections might therefore have unintended consequences’ and ‘holistic revision by Parliament would be more appropriate to address the concerns’ in the judgment.[1] The court also mentioned that Parliament may wish ‘to reconsider the close-in-age’ defence and whether it should be applied to sexual penetration as advocated by the applicants in the case,[1] as also suggested elsewhere.[4] In addition, Parliament ‘may wish to regulate “sexual penetration” between an adolescent and a minor aged 16 or 17 in a manner different to that proposed by the applicants’.[1] Therefore, although parts of sections 15 and 16 were declared invalid, ‘justice and equity warrant that their invalidity should be suspended for a period of 18 months in order to allow Parliament to remedy the defects in the statute’.[1]

Moratorium on criminal and ancillary proceedings regarding section 15 and 16 offences

The court ordered a moratorium on all investigations into, arrests in, prosecutions in, and criminal and ancillary proceedings regarding section 15 and 16 offences involving consensual sexual conduct between adolescent children under 16 years of age. The moratorium on the duty to report consensual sexual conduct between children under 16 years of age was not specifically mentioned,[1] but the court’s language earlier makes it clear that ‘ancillary proceedings’ include the duty to report such conduct – pending Parliament’s correction of the Act.[1] Doctors and other health professionals therefore have no duty to report consensual sexual conduct between adolescent children under 16 years of age. Although the declaration of the invalidity of the relevant parts of sections 15 and 16 was suspended, the court did not impose a moratorium on criminal liability for sexual conduct by children aged 16 or 17 years. It is submitted, however, that in such instances the ‘best interests of the child’ principles in the Children’s Act[5] and the Constitution should apply, as the latter is paramount. [2] Guidance regarding the factors that should be taken into account when determining the ‘best interests of the child’ are set out in the Children’s Act.[5] Therefore, whether children facing criminal liability for sexual conduct are under or over 16 years of age, doctors and other

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healthcare practitioners should be guided by the ‘best interests of the child’ principle when it comes to reporting such conduct. For instance, even if both the adolescents are under 16 years of age it may still constitute child abuse if one of them is in a position of power or control over the other. Such sexual conduct cannot be regarded as ‘consensual’ and must be reported.

Expunging of criminal and diversion records of adolescent children

The Constitutional Court ordered the Minister of Justice and Constitutional Development to have the criminal records or diversion orders of any adolescents under 16 years of age expunged as a result of sections 15 or 16 of the Sexual Offences Act, and their details to be removed from the National Register for Sexual Offenders.[6]

Conclusion

The following conclusions can be drawn from the Constitutional Court’s decisions: • The findings of invalidity of sections 15 and 16 of the Sexual Offences Act are limited to those that criminalise sexual conduct of adolescent children under 16 years of age.[2] • Doctors and other health professionals no longer need to report consensual sexual conduct of adolescent children under 16 years of age to the authorities in terms of the Sexual Offences Act.[2] • Criminalisation of non-consensual sexual conduct is not affected, ‘including cases of undue influence or other instances where consent has not properly been given’, or the criminalisation of sexual conduct between adults and children or between adolescents and children older than 16 years.[1] • The court had insufficient evidence to decide that sections 15 and 16 of the Sexual Offences Act ‘have the same constitutional implications for 16 and 17 year olds as they do for adolescents’, and was not prepared to read in a ‘close-in-age’ defence or confirm the Gauteng High Court’s judgment in this respect.[1] • The decision only applies to the reporting obligations of doctors and others regarding the sexual conduct of adolescent children under 16 years of age in terms of the Sexual Offences Act.[1,6] However, it is submitted that the ‘best interests of the child’ principle in the Children’s Act[5] and the Constitution[2] should guide all obligatory reporting situations involving sexual and other conduct of children – irrespective of whether they are adolescents under 16 years or between 16 and 17 years of age.[4]

1. The Teddy Bear Clinic for Abused Children Case and RAPCAN and Others v. Minister of Justice and National Director of Public Prosecutions CCT 12/13 [2013] ZACC (3 October 2013). http://www. saflii.org/za/cases/ZACC/2013/35html (accessed 14 October 2013). 2. South African National Government. The Constitution of the Republic of South Africa 1996. Pretoria: Government Printer, 1996: http://www.thehda.co.za/uploads/images/unpan005172.pdf (accessed 14 October 2013). 3. McQuoid-Mason D. Decriminalization of consensual sexual conduct between children: What should doctors do regarding the reporting of sexual offences under the Sexual Offences Act until the Constitutional Court confirms the judgment of the Teddy Bear Clinic case? South African Journal of Bioethics and Law 2013;6(1):10-12. 4. McQuoid-Mason D. Mandatory reporting of sexual abuse under the Sexual Offences Act and the best interests of the child. South African Journal of Bioethics and Law 2011;4(2):74-78. 5. South African National Government. The Children’s Act No. 38 of 2005. Pretoria: Government Printer, 2005. http://www.justice.gov.za/legislation/acts/2005-038%20childrensact.pdf (accessed 14 October 2013). 6. South African National Government. Criminal Law (Sexual Offences and Related Matters) Amendment Act 32 of 2007. Pretoria: Government Printer, 2007. http://www.justice.gov.za/ legislation/acts/2007-032.pdf (accessed 14 October 2013).

Accepted 7 November 2013.

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CLINICAL PRACTICE

The risks of gastrointestinal injury due to ingested magnetic beads S Cox, R Brown, A Millar, A Numanoglu, A Alexander, A Theron The authors are based in the Department of Paediatric Surgery, Red Cross War Memorial Children’s Hospital and University of Cape Town, South Africa. Corresponding author: S Cox (sharon.cox@uct.ac.za)

Accidental ingestion of foreign bodies is a common problem in children. Magnetic bead toys are hazardous, having potentially lethal consequences if ingested. These magnets conglomerate in different segments of bowel, causing pressure necrosis, perforation and/or fistula formation anywhere along the gastrointestinal tract. A clinical diagnostic pitfall is that the appearance on the initial abdominal radiograph may be misinterpreted by the uninitiated as a single metallic object without any intervening intestinal wall. Symptoms do not occur until complications have developed, and even then, unless magnet ingestion is suspected, treatment may initially be mistakenly expectant, as with any other foreign body. After observing a case of multiple magnet ingestion that led to the rapid onset of small-bowel inter-loop fistulas and peritonitis, we attempted to reproduce the likely sequence of events in a laboratory setting using fresh, post-mortem porcine bowel as an animal model and placing magnetic toy beads within the bowel lumen. Pressure-induced perforation appeared extremely rapidly, replicating the operative findings in two of our cases. We propose that if magnet ingestion is suspected, early endoscopic or surgical retrieval is mandatory. Appropriate, rapid surgical intervention is indicated. Laparoscopy offers a minimally invasive therapeutic option. S Afr Med J 2014;104(4):277-278. DOI:10.7196/SAMJ.7500

Accidental ingestion of foreign bodies is a common problem in children. Ordinarily, most of these pass through the gastrointestinal tract (GIT) unnoticed. Since 1995, there have been an increasing number of reports on the consequences of toy magnet ingestion. [1] One ingested magnet should not cause any problems, but when multiple individual magnets are ingested, they can cause considerable morbidity.[2] This occurs when magnets conglomerate in different segments of bowel with forces of up to 1 300 G,[1] causing pressure necrosis, perforation and/or fistula formation anywhere along the GIT.[3] Other reported magnet-induced problems include ulceration,[4] gastric outlet or bowel obstruction,[5] oesophageal perforation,[6] gastro-enteric fistulas,[7] small-bowel volvulus,[8] and appendicitis due to ileocaecal fistulation.[9] The serious consequences of multiple magnet ingestions have become apparent to the Department of Paediatric Surgery, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa, in the past year. We have recently published a case report of a 2-year-old girl who underwent surgery after presenting with a magnet-induced bowel perforation.[2] Subsequent to this report, we have operated on another two children. One patient was a 3-year-old boy, with seven retained magnets (Fig. 1). At endoscopic removal, two were found to be in the lower oesophagus and adherent to five in the gastric fundus. Perforation had not occurred, but ulceration was evident (Fig. 2). The latest patient is a 3-year-old child who presented with an acute abdomen and septic shock. At laparotomy, she was found to have free pus in the abdomen and two small perforations in her distal ileum, the result of magnet-induced pressure necrosis. She spent 2 days in intensive care postoperatively, but made a full recovery. Numerous magnet toys have been implicated in this growing problem, with an estimated 1 700 ingestions treated in emergency departments in the USA between January 2009 and December

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Fig. 1. Chest X-ray showing seven closely approximated beads in a 3-yearold child presenting with abdominal pain. The top two beads were in the oesophagus, while the remaining five were endoscopically retrieved from the fundus of the stomach.

2011. [10] The magnets ingested by our patients have been spherical, powerful rare-earth magnets ~4 mm in diameter. They are freely available at many large retail stores and sold as an executive stress toy (Fig. 3.) The packaging indicates that they are not suitable for children

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Fig. 2. Endoscopic view of ulceration in the fundus after removal of the magnetic bead.

Fig. 3. Magnetic beads.

Fig. 4. Perforation in bowel after separation of magnets (arrow), caused by pressure of the attracting magnets.

Fig. 5. Simulated model demonstrating attraction between the instrument tip and intraluminal magnet. Arrows indicate the position of the magnets.

and warns consumers to seek medical advice if ingested. Most are made of neodymium, iron and boron or other rare-earth metals and are extremely powerful magnets. The magnetic field typically produced by rareearth magnets can be in excess of 1.4 teslas. There have been product recalls on certain magnetic toys in the USA because of these issues; however, we are unaware of any such action in South Africa to date. After the first case of multiple magnet ingestion led to the rapid onset of smallbowel inter-loop fistulas and peritonitis,[2] we attempted to reproduce the likely sequence of events in a laboratory setting. We used a 60 cm segment of fresh, postmortem porcine bowel as an animal model. We placed magnetic toy beads within the bowel lumen at intervals along its length. The bowel was gently manipulated to simulate normal small-bowel movement in the peritoneum. We used the facilities in our Surgical Skills Training Centre including a laparoscopic training box, a 30-degree lens and Karl Storz high-definition stack and monitors to observe the sequence of events. We introduced standard 5 mm instruments to assess our ability to intervene therapeutically in these cases. There was immediate conglomeration of the magnets, that came within 2 cm of each other trapping intervening bowel wall. Pressure-induced perforation appeared extremely rapidly, within a few minutes (Fig. 4). This replicated the operative findings in two of our cases. The magnets were strongly attracted to the tips of the laparoscopic instruments and enabled delivery of bowel for further surgical intervention (Fig. 5). Most reported complications of multiple magnet ingestion are due to pressure necrosis-induced perforation or fistulation. The injury model described attests to the fact that the sequence of events occurs very rapidly. In clinical practice, a high degree of suspicion is required to differentiate a swallowed magnet conglomerate or similar foreign body from two separate groups of magnets in different parts of the intestine that have attracted each other and are causing pressure necrosis. A clinical diagnostic pitfall is that the appearance on the initial abdominal radiograph may be misinterpreted by the uninitiated as a single metallic object without any intervening intestinal wall. Symptoms do not occur until

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complications have developed, and even then, unless magnet ingestion is suspected, treatment may initially be mistakenly expectant, as with any other foreign body.[11] Appropriate, rapid surgical retrieval of these magnets is recommended. To make the connection between these seemingly innocuous foreign bodies and the potentially fatal consequences of their ingestion, we would like to introduce the problem to a wider medical audience than the readers of specialist paediatric surgical journals in which the problem has been increasingly presented. We propose that if magnet ingestion is suspected, early endoscopic or surgical retrieval is mandatory. Laparoscopy is potentially very useful in locating the magnets, as they will adhere to the instrument tips. The magnet-containing bowel can then be exteriorised for magnet extraction and repair. Intra-operative radiological screening would confirm that all magnetic beads have been removed.

Conclusion

Magnetic bead toys are hazardous, having potentially lethal consequences if ingested. Appropriate, rapid surgical intervention is indicated. Laparoscopy offers a minimally invasive therapeutic option. 1. Honzumi M, Shigemori C, Ito H, et al. An intestinal fistula in a 3-year-old child caused by the ingestion of magnets: Report of a case. Surg Today 1995;25(6):552-553. [http://dx.doi. org/10.1007/BF00311314] 2. Adikibi BT, Arnold M, van Niekerk G, Alexander A, Numanoglu A, Millar AJ. Magnet bead toy ingestion: Uses and disuses in children. Pediatr Surg Int 2013;29(7):741-744. [http://dx.doi. org/10.1007/s00383-013-3275-y] 3. Kabre R, Chin A, Rowell E, et al. Hazardous complications of multiple ingested magnets: Report of four cases. Eur J Pediatr Surg 2009;19(3):187-189. [http://dx.doi. org/10.1055/s-2008-1038824] 4. Cortés C, Silva C. [Accidental ingestion of magnets in children: Report of three cases]. Rev Med Chil 2006;134(10):1315-1319. [http://dx.doi.org/10.4067/S0034-98872006001000016] 5. Oestreich AE. Multiple magnet ingestion alert. Radiology 2004;233(2):615. [http://dx.doi.org/10.1148/radiol.2332041446] 6. Seo TJ, Park CH, Jeong HK, et al. Endoscopic removal of impacted magnetic foreign bodies in the gastroesophageal junction. Surg Laparosc Endosc Percutan Tech 2011;21(6):e313-e315. [http:// dx.doi.org/10.1097/SLE.0b013e318231206f] 7. Brown JC, Murray KF, Javid PJ. Hidden attraction: A menacing meal of magnets and batteries. J Emerg Med 2012;43(2):266269. [http://dx.doi.org/10.1016/j.jemermed.2011.09.003] 8. Nui A, Hirama T, Katsuramaki T, et al. An intestinal volvulus caused by multiple magnet ingestion: An unexpected risk in children. J Pediatr Surg 2005;40(9):e9-e11. [http://dx.doi. org/10.1016/j.jpedsurg.2005.05.065] 9. Robinson AJ, Bingham J, Thompson RL. Magnet induced perforated appendicitis and ileo-caecal fistula formation. Ulster Med J 2009;78(1):4-6. 10. Consumer Product Safety Commission. Safety standard for magnet sets. 16 CFR Part 1240. Fed Reg 7(171):53781-53801. 11. Van Schie K. Fake tongue ring lands girl in hospital. The Star. 30 August 2013. http://www.iol.co.za/news/south-africa/gauteng/ fake-tongue-ring-lands-girl-in-hospital-1.1570452 (accessed 18 February 2014).

Accepted 25 September 2013.

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CLINICAL PRACTICE

The safety of osteoporosis medication F S Hough, S L Brown, B Cassim, M R Davey, W de Lange, T J de Villiers, G C Ellis, S Lipschitz, M Lukhele, J M Pettifor, for the National Osteoporosis Foundation of South Africa The authors are councillors of the National Osteoporosis Foundation of South Africa (NOFSA) Corresponding author: F S Hough (bonedoc@stephenhough.co.za)

Osteoporosis is a common, costly and serious disease, which is still too often regarded as an inevitable part of the normal ageing process and therefore sub-optimally treated, especially in the elderly – in fact, only two out of every 10 patients who sustain a hip fracture receive any form of assessment or prophylactic therapy for osteoporosis. One out of five patients die within 1 year after a hip fracture, and <50% are capable of leading an independent life. Yet very effective anti-fracture therapy, capable of reducing fracture risk by 35 - 60%, is available. A number of publications have recently questioned the safety of drugs routinely used to treat patients with osteoporosis. This paper attempts to put the situation into perspective and expresses the National Osteoporosis Foundation of South Africa’s view on the safety of these drugs. Their efficacy in preventing skeletal fractures and their cost-effectiveness are not addressed in any detail. The paper emphasises the fact that all osteoporosis medications have side-effects, some of which are potentially life-threatening. S Afr Med J 2014;104(4):279-282. DOI:10.7196/SAMJ.7505

Conventionally, osteoporosis medication is classified into anti-resorptive drugs, anabolic agents or stimulators of bone formation, and agents with a dual or complex action on bone.

Anti-resorptive agents Calcium and vitamin D

Treatment of osteoporosis with calcium and vitamin D only is associated with a modest reduction in fracture risk, and calcium with or without vitamin D has also been a mandatory component in all drug trials assessing the anti-fracture efficacy of potent bone-active drugs. Calcium and vitamin D have generally been regarded as safe and largely without side-effects when used in their recommended doses – supplemented as approximately 600 mg elemental calcium per day (to ensure a total daily intake of about 1 000 mg per day) and 800 - 1 200 IU vitamin D per day. Higher doses of vitamin D may be used in pregnancy and lactation, and to treat proven osteomalacia. Constipation is not uncommon in patients on calcium supplements, especially when calcium carbonate is used, and this is an important cause of poor drug adherence. An increased risk of renal stones (10 - 15%) has been reported, but there is a paucity of controlled or prospective data. Hypercalcaemia generally only occurs when high and prolonged doses of vitamin D or one of its active metabolites (not recommended for routine osteoporosis treatment) are used. Bolland et al.[2] recently published a meta-analysis suggesting that high-dose calcium supplementation in postmenopausal women with osteoporosis is associated with an increased risk of cardiovascular disease (CVD). On further scrutiny of the paper it is, however, quite clear that the increased risk of CVD was only evident in subjects who consumed at least 800 mg calcium per day in their diet, in addition to the high-dose supplementation. Furthermore, results of the recently published Canadian Multicentre Osteoporosis Study, which involved 10-year longitudinal follow-up of over 9 000 participants, showed that calcium supplementation of up to 1 000 mg per day was associated with no harm, and in fact with reduced mortality, in women.[3]

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It is therefore fair to conclude that: • Whenever possible, an adequate dietary intake of calcium is preferable to supplementation. • Calcium should not be supplemented in those with an adequate dietary intake. • When used in recommended doses to prevent/treat osteoporosis, calcium and vitamin D are safe. • Care should be taken when considering supplementing patients with established CVD or impaired renal function.

Menopausal hormone therapy

Menopausal hormone (oestrogen with or without progestin) therapy (MHT) has been convincingly shown to increase bone mineral density (BMD) and to reduce clinical fracture risk at all sites (including the spine and hip), not only in subjects at high risk of sustaining an osteoporotic fracture, but specifically in those with a near-normal BMD and no prior fracture. This was suggested by numerous observational studies, conclusively proven by the Women’s Health Initiative (WHI),[4] and further corroborated by the large National Osteoporosis Risk Assessment (NORA)[5] and Million Women Studies.[6] Initial results from the WHI, however, suggested that MHT was associated with an increased risk of CVD, thrombo-embolic disease (TED), stroke and breast cancer.[7] These agents have therefore largely been abandoned as first-line treatment for osteoporosis by most regulatory authorities. Objections to the conclusions drawn from the WHI have again been highlighted recently[8] and include: • Incorrect or inappropriate study design (e.g. heavy emphasis was placed on a single, unvalidated tool to assess the safety of MHT, the so-called ‘global index’). • Poor data analysis (e.g. lack of distinction between nominal and adjusted risk, and emphasis on relative as opposed to absolute risk – e.g. emphasising the 2-fold increase in TED that accompanies the use of MHT, yet omitting the fact that the absolute risk increases from 1 in 1 000 postmenopausal women to 2 in 1 000 women). • Disregard for the high rates of discontinuation in the active treatment arm (42%) and crossover to active treatment in the placebo arm (11%).

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• Extrapolation of data obtained in 64-year-old subjects (the average age of women included in the WHI) to young 50-year-old individuals – stratification of especially CVD according to age/ time since menopause has subsequently been shown to be critical. • Inadequate differentiation between data obtained from the oestrogen-only and the oestrogen-plus-progestin study arms – e.g. available evidence suggests that the increased risk of breast cancer associated with the use of MHT is entirely limited to the use of oestrogen plus progestin, and does not apply to the use of oestrogen-only therapy. • Generalisation about the specific progestin used in combined hormone therapy. • Disregard for the protective role of transdermal MHT on the development of the metabolic syndrome and its associated vascular complications. A detailed discussion of this debate is beyond the scope of this paper. Suffice to reiterate the recommendations of the National Osteoporosis Foundation of South Africa (NOFSA) guidelines, published in 2010,[1] namely: • MHT should only be initiated for specific indications in subjects without contraindications to its use (e.g. current breast cancer, undiagnosed genital bleeding, current deep-vein thrombosis, untreated hypertension/CVD). • In the absence of contraindications, the use of MHT in women aged 50 - 60 years is safe and appropriate to manage osteoporosis – in fact, in individuals with menopausal symptoms it should be regarded as the drug of choice. • It is best not to initiate MHT after age 60 years for the sake of skeletal protection only; continued use of MHT after age 60 may, however, be considered if other treatment options are contraindicated. • If fracture protection is sought, doses of hormone therapy known to provide fracture protection (i.e. 0.625 mg/day conjugated equine oestrogen or equivalent) should be used. Low-dose hormone therapy has been shown to protect against loss of BMD, but fracture data are still awaited. • A reduction in BMD may occur once MHT is discontinued, and treatment with another bone-active drug should therefore be considered at that stage.

Calcitonin

Calcitonin was previously reserved for individuals who could not tolerate more effective therapy (e.g. with a creatinine clearance rate <30 ml/min).[1] Up to a third of patients experienced nausea, diarrhoea and flushing. Calcitonin has recently been associated with a 1 - 3% increase in the risk of systemic malignancies and has therefore been withdrawn from the market as a useful and safe agent to treat osteoporosis.[9]

Bisphosphonates

The bisphosphonates (BPs) are universally regarded as a first-line treatment for osteoporosis in postmenopausal and elderly women, in men, and in a number of secondary osteoporoses, including glucocorticoid-induced osteoporosis. Oral BPs may cause an erosive oesophagitis (especially if taken incorrectly) with nausea, heartburn, chest pain and vomiting. The intravenous BPs may precipitate acute renal failure (when rapidly injected) and have been associated with a severe flu-like syndrome (usually a first-dose, acute-phase reaction that responds to paracetamol or non-steroidal anti-inflammatory drugs), hypocalcaemia (especially in the presence of vitamin D deficiency),

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or diffuse bone pains. Skeletal retention of BPs is very long (terminal half-life >10 years) and, under certain circumstances, even lifelong. Concerns regarding fetal safety have therefore been expressed where women of child-bearing age have been subjected to many years of BP treatment. No conclusive data that BPs are harmful to the fetus have been forthcoming, but clinicians should be alerted regarding unnecessary and unproven treatment with BPs of younger women with isolated, modest decreases in BMD. Initial concerns about oesophageal cancer with oral BPs and atrial fibrillation with intravenous zoledronic acid have not been substantiated by a recent Food and Drug Administration audit.[10-13] Two other side-effects, namely osteonecrosis of the jaw (ONJ) and atypical fragility fractures (AFFs), however, warrant discussion. The first report of an association between ONJ and the use of BPs was published in 2004, and it has subsequently become clear that up to 80% of cases occurred in patients with an underlying malignancy (often myeloma or breast cancer), and 90% were receiving high-dose intravenous BPs.[14-16] In this regard, it is important to reiterate that such patients generally receive a dose of BPs that is ten-fold higher than doses used to treat osteoporosis. Other predisposing factors include dento-alveolar surgery and local oral disease (inflammation, cancer), systemic factors (advanced age, diabetes, renal impairment, smoking, alcohol), and a genetic predisposition. In patients with osteoporosis treated with BPs, the incidence of ONJ is extremely low (0.01 - 0.0004%) and probably not different from that of the general population. For this reason, NOFSA recommends[1] that: • Patients and dentists need to be reassured that ONJ is extremely rare in association with the doses of BPs approved for the treatment of osteoporosis. Whether BPs are administered orally or intravenously does not seem to affect the risk of ONJ. • Good oral hygiene and regular dental visits are advisable. It is, however, not necessary to recommend a dental examination before starting BP therapy for osteoporosis. If major dental surgery is anticipated, it seems prudent to suggest that this be completed before starting BP treatment. • In subjects already receiving a BP, dental implant surgery is not contraindicated. Some suggest stopping the BP, but there are no data to support this. The use of bone turnover markers has been suggested, but cannot be supported. • In subjects with established ONJ, surgical treatment should be conservative, infection should be treated with appropriate antibiotics, and pain relief is important, as is referral to an experienced maxillofacial surgeon. Given the availability of alternative bone-active agents, it is probably reasonable to discontinue the BP. Following earlier suggestions by Ott[17] of atypical fractures after long-term alendronate therapy, in 2005 Odvina et al.[18] (senior author Charles Pak) described nine cases of severely suppressed bone turnover with spontaneous non-spine fractures and delayed fracture healing. Subsequently numerous case reports, retrospective reviews and register-based national cohort studies have confirmed an increased prevalence of AFFs in patients receiving alendronate, prompting regulatory bodies in Europe, the UK and the USA to alert healthcare professionals to this association and to insist that product information for alendronate be updated to include a warning about AFFs. This syndrome is characterised by:[17-20] • A history of chronic alendronate use – limited data are available for the other BPs in support of a causal association with AFFs, but this probably reflects their lower use and the limited availability of long-term data.

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• AFFs most often involve areas rich in cortical bone (e.g. subtrochanteric or diaphyseal femur, pelvic bones), and are sustained either spontaneously or following minimal trauma. • A prodrome of pain and tenderness over the impending fracture site. • Concomitant use of glucocorticoids or oestrogen. • Quantitative bone histology shows severely suppressed bone turnover, similar to the so-called adynamic bone disease found in a subset of patients with chronic renal failure; serum biomarkers of bone turnover are usually decreased, but often not as markedly as the bone histology. • Radiographs may show typical cortical stress fractures or a simple transverse or oblique fracture of the femur with beaking of the cortex and diffuse cortical thickening of the proximal femoral shaft. • Bilateral disease is not infrequent – contralateral pathology may be evident on clinical assessment (e.g. tenderness over the femur shaft), standard radiographs or an isotope bone scan. • History of delayed or absent fracture healing.

treated worldwide with PTH. It is therefore very unlikely that teriparatide is associated with any increased risk of osteogenic sarcoma. Nonetheless, regulatory bodies worldwide have limited the use of teriparatide to treat osteoporosis to an 18 - 24-month period (18 months in South Africa), following which alternative agents (e.g. a bisphosphonate) should be employed to preserve bone mass, which otherwise decreases rapidly after teriparatide has been discontinued. It has also been recommended that teriparatide should not be used in subjects with an increased risk of developing osteosarcoma (e.g. prior skeletal radiation), in patients with malignancy, in growing children, in pregnancy and lactation, in subjects with hypercalcaemia, and in individuals with impaired renal function (glomerular filtration rate <30 ml/min). Nausea, headaches and leg cramps are not infrequent in patients treated with teriparatide. Hypercalcaemia occurs in up to 10% of patients, but hypercalciuria, hyperuricaemia and renal stone disease are rare.[21-27]

Correct management of this syndrome is difficult, given the current state of our knowledge. Clearly BP treatment needs to be discontinued in the event of an atypical fracture, and an alternative anti-fracture agent should be considered. Contralateral disease should be sought and may require intervention (e.g. prophylactic orthopaedic pinning). Appropriate measures to prevent the development of AFFs include greater awareness of the condition and possibly limiting the duration of BP treatment to 4 - 5 years. In this regard it is, however, imperative to note that BP-induced AFF is a rare phenomenon, with an estimated prevalence of around 1 in 1 000. Moreover, limiting BP treatment to <3 years has been shown to provide ineffective protection against conventional osteoporotic fractures. Much more harm may therefore emanate from the indiscriminate, premature discontinuation of BP treatment in an attempt to prevent AFF. There are no clear recommendations to circumvent this conundrum at present, other than to suggest that any osteoporosis treatment strategy should be reassessed following 4 - 5 years of BP therapy and the need for continued treatment with a BP or alternative antifracture agent appraised.

Drugs with dual or complex actions on bone

Stimulators of bone formation Teriparatide

Parathyroid hormone (PTH 1-84) or the PTH fragment (hPTH 1-34), teriparatide, have been shown to be potent anabolic agents that stimulate osteoblastic bone formation (peaks within 3 - 6 months and is maintained for 18 - 24 months) and reduce vertebral and non-vertebral fracture risk. Osteoclastic bone resorption is also stimulated, but since this only peaks some 12 - 24 months later, an ‘anabolic window’ is created that results in a very significant increase in areal and volumetric bone mass, size and strength.[21-27] Teriparatide is used in the management of osteoporosis, but only for specific indications – these include failed anti-resorptive therapy, severe fracturing disease, and glucocorticoid-induced osteoporosis with a markedly decreased BMD. These specific indications have been published in position papers by NOFSA.[24,25] The use of teriparatide is limited by its expense and certain contraindications. Long-term studies with high-dose PTH, administered lifelong to Fischer 344 rats, have demonstrated a dose-related increase in the risk of osteogenic sarcoma. All primate studies have failed to show a similar association, and osteosarcomas do not occur with increased frequency in humans with primary hyperparathyroidism, nor have they been noted in any of the trials performed in many thousands of patients treated with PTH for >3 years. To date, a single case of osteosarcoma has been reported in >300 000 patients

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Strontium ranelate

Strontium ranelate has a dual mode of action resulting in the stimulation of bone formation and inhibition of resorption. Large clinical studies such as the pivotal Spinal Osteoporosis Therapeutic Intervention (SOTI)[28] and Treatment of Peripheral Osteoporosis (TROPOS)[29] trials have demonstrated that this agent significantly increases BMD and decreases fracture risk at both the spine and hip over prolonged periods of time. Furthermore, the drug is effective in patients with only a modest decrease in BMD and also in the very old (>80 years).[28-30] Gastrointestinal side-effects, notably nausea and diarrhoea, occur frequently in the first 3 months of treatment but can usually be managed by slow titration of the dose. In pooled data from the SOTI and TROPOS studies, a small but significant (0.9% v. 0.6%) increased risk of venous thrombo-embolism (VTE) was documented, and although the cause of this is unknown, it is recommended that strontium ranelate is best avoided in patients at risk of VTE. During post-marketing surveillance of patients treated with strontium ranelate, cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome as well as toxic epidermal necrolysis and Stevens-Johnson syndrome were reported[31] – to date, <2 dozen cases from a total of more than a half million patient years of exposure have been documented. The DRESS drug hypersensitivity syndrome is not unique to strontium ranelate and is associated with a large number of commonly used drugs including the anti-epileptics and allopurinol. Since systemic involvement (hepatitis, nephritis, endocarditis) following continued use can be fatal, it is important to be aware of the association and to discontinue the drug if any significant skin disorder occurs within 2 - 3 months after initiating treatment. In April 2013, the European Medicines Agency (EMA) released their report of a routine assessment conducted by their Pharmacovigilance Risk Assessment Committee (PRAC) on pooled data from seven studies in >7 500 women treated with strontium ranelate. Compared with placebo, those treated with strontium ranelate showed an increased risk of non-fatal myocardial infarction (1.7 v. 1.1%, with a relative risk of 1.6; 95% confidence interval 1.07 - 2.38).[32] This increased risk was confined to patients with poorly controlled hypertension (blood pressure >160/90 mmHg) or known ischaemic heart disease (IHD). Based on the report of the PRAC, the EMA Committee for Medical Products of Human Use made certain recommendations regarding the indications for

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and contraindications to strontium ranelate in the treatment of osteoporosis.[32] Further evaluations are being conducted. Locally, these findings have been submitted to the Medicines Control Council (MCC), which is currently reviewing the data. NOFSA’s views on the matter can be summarised as follows: • Strontium ranelate is a useful anti-fracture agent to manage patients with osteoporosis or those at high fracture risk, if the following precautions are adhered to: • Strontium ranelate should not be used in patients with a current or past history of IHD, peripheral arterial disease (PAD) and/ or CVD, or in patients with uncontrolled (>160/90 mmHg) or untreated hypertension. • Before embarking on treatment with strontium ranelate, the presence of risk factors for CVD (e.g. dyslipidaemia, dysglycaemia/diabetes, obesity, hypertension, smoking) should be carefully assessed. If present, treatment with strontium ranelate should be undertaken only after careful consideration. • Risk factors for and/or the presence of CVD should be assessed at regular intervals during treatment, and treatment should be discontinued if the patient develops uncontrolled hypertension, IHD, CVD or PAD. These recommendations of NOFSA will of course all be subject to the final recommendations from the MCC.

Conclusions

If it is used appropriately, the benefits of treatment of osteoporosis far outweigh the risks. Every patient with osteoporosis therefore deserves a thorough assessment and in-depth consideration of therapeutic options before initiating the most appropriate, most effective and safest treatment. 1. Hough S, Ascott-Evans B, Brown S, et al. NOFSA guideline for the diagnosis and management of osteoporosis. Journal of Endocrinology, Metabolism and Diabetes of South Africa 2010;15(3):109-151. 2. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: A meta-analysis. 2010. http://www.bmj.com/content/341/bmj.c3691.full. pdf+htm?sid =3736a780-4539-4cbd-8445-c4c45b62eece (accessed 19 December 2013). 3. Langsetmo L, Berger C, Kreiger N, et al. Calcium and vitamin D intake and mortality: Results from the Canadian Multicentre Osteoporosis Study (CaMos). J Clin Endocrinol Metab 2013;98(7):3010-3018. [http://dx.doi.org/10.1210/jc.2013-1516] 4. Cauley JA, Robbins J, Chen Z, for the Women’s Health Initiative (WHI) investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: The Women’s Health Initiative randomised trial. JAMA 2003;290(13):1729-1738. [http://dx.doi.org/10.1001/jama.290.13.1729] 5. Barrett-Connor E, Wehren LE, Siris ES, et al. Recency and duration of postmenopausal hormone therapy: Effects on bone mineral density and fracture risk in the National Osteoporosis Risk Assessment (NORA) study. Menopause 2003;10(5):412-419. [http://dx.doi.org/10.1097/01. GME.0000086467.82759.DA] 6. Banks E, Beral V, Reeves G, et al. for the Million Women Collaborators. Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 2004;291(18):2212-2220. [http://dx.doi.org/10.1001/jama.291.18.2212] 7. Rossouw JE, Anderson GL, Prentice RL, et al.; Writing Group for Women’s Health Initiative Investigators. Risks and benefits of estrogen and progestin in healthy postmenopausal women. JAMA 2002;288(3):321-333. [http://dx.doi.org/10.1001/jama.288.3.321]

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8. De Villiers TJ, Stevenson JC. The WHI: Effect of hormone replacement therapy on fracture prevention. Climacteric 2012;15(3):263-266. [http://dx.doi.org/10.3109/13697137.2012.659975] 9. MMRA. Drug safety update. Calcitonin (Miacalcic): Increased risk of cancer with long-term use – all intra-nasal formulations for osteoporosis to be withdrawn. http://www.mhra.gov.uk/ Safetyinformation/DrugSafetyUpdate/CON180634 (accessed 19 December 2013). 10. Wysowski DK. Reports of esophageal cancer with oral bishosphonate use. N Engl J Med 2009;360(1):8990. [http://dx.doi.org/10.1056/NEJMc0808738] 11. Heckbert SR, Li J, Cummings SR, et al. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008;168(8):826-831. [http://dx.doi.org/10.1001/archinte.168.8.826] 12. Loke YK, Jeevanantham V, Singh S. Bisphosphonates and atrial fibrillation: Systematic review and metaanalysis. Drug Safety 2009;32(3):219-228. [http://dx.doi.org/10.2165/00002018-200932030-00004] 13. Mak A, Cheung MW, Ho RC, et al. Bisphosphonates and atrial fibrillation: Bayesian meta-analyses of randomized controlled trials and observational studies. BMC Musculoskelet Disord 2009;10(1):113120. [http://dx.doi.org/10.1186/1471-2474-10-113] 14. Woo S, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144(10):753-761. [http://dx.doi.org/10.7326/0003-4819-144-10-200605160-00009] 15. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22(10):14791491. [http://dx.doi.org/10.1359/jbmr.0707onj] 16. Ruggiero SL, Dodson TB, Assael LA, et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws – 2009 update. J Oral Maxillofacial Surgery 2009;67(5):2-12. [http://dx.doi.org/10.1016/j.joms.2009.01.009] 17. Ott SM. Fractures after long-term alendronate therapy. J Clin Endocrinol Metab 2001;86(4):18351841. [http://dx.doi.org/10.1210/jc.86.4.1835-a] 18. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Severely suppressed bone turnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90(3):12941301. [http://dx.doi.org/10.1210/jc.2004-0952] 19. Neviaser AS, Lane JM, Lenart BA, et al. Low-energy femoral shaft fractures associated with alendronate. J Orthop Trauma 2008;22(5):346-350. [http://dx.doi.org/10.1097/BOT.0b013e318172841c] 20. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008;358(12):1304-1306. [http://dx.doi.org/10.1056/NEJMc0707493] 21. Lindsay R, Nieves J, Formica C, et al. Randomised controlled study of effects of parathyroid hormone on vertebral bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997;350(9):550-555. [http://dx.doi.org/10.1016/S0140-6736%2897%2902342-8] 22. Rosen CJ, Bilezekian JP. Anabolic therapy for osteoporosis. J Clin Endocrinol Metab 2001;86(3):957964. [http://dx.doi.org/10.1210/jc.86.3.957] 23. Neer RM, Arnaud CD, Zanchetta JR, et al. Effects of parathyroid hormone(1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344(19):1434-1441. [http://dx.doi.org/10.1056/NEJM200105103441904] 24. Hough S, Ascott-Evans B, de Villiers T, et al. Position paper of the National Osteoporosis Foundation of South Africa (NOFSA) on the use of parathyroid hormone (PTH 1-34) in the treatment of osteoporosis. S Afr Med J 2004;94(3):175-177. 25. Brown SL, for the National Osteoporosis Foundation of South Africa (NOFSA). Position paper on the indications for the use of parathyroid hormone (PTH 1-34) in the treatment of osteoporosis. Journal of Endocrinology, Metabolism and Diabetes of South Africa 2009;14(1):61-62. 26. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349(13):1207-1215. [http:// dx.doi.org/10.1056/NEJMoa031975] 27. Finkelstein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003;349(13):1216-1226. [http://dx.doi.org/10.1056/ NEJMoa035725] 28. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350(5):459-468. [http://dx.doi. org/10.1056/NEJMoa022436] 29. Reginster J, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of non-vertebral fractures in postmenopausal women with osteoporosis: Treatment of peripheral osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90(5):2816-2822. [http://dx.doi.org/10.1210/jc.2004-1774] 30. Reginster J, Bruyere O, Sawicki A, et al. Long-term treatment of postmenopausal osteoporosis with strontium ranelate: Results at 8 years. Bone 2009;45(6):1059-1064. [http://dx.doi.org/10.1016/j. bone.2009.08.004] 31. Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): An update. Dermatology 2003;206(4):353-356. [http://dx.doi.org/10.1159/000069956] 32. European Medicines Agency. Recommendation to restrict the use of Protelos/Osseor (strontium ranelate). http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/04/news_ detail_001774.jsp&mid=WC0b01ac058004d5c1 (accessed 19 December 2013).

Accepted 17 October 2013.

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CLINICAL PRACTICE

Acute intermittent porphyria presenting as progressive muscular atrophy in a young black man C H Albertyn, M Sonderup, A Bryer, A Corrigall, P Meissner, J M Heckmann Christine Albertyn is a neurology registrar in the Division of Neurology, Department of Medicine, Groote Schuur Hospital and University of Cape Town (UCT), South Africa. Mark Sonderup is a senior specialist in the Department of Medicine, Division of Hepatology and Lennox Eales Porphyria Laboratories, Groote Schuur Hospital and UCT. Alan Bryer is an associate professor and head of the Division of Neurology, Department of Medicine, Groote Schuur Hospital and UCT. Anne Corrigall is chief research oďŹ&#x192;cer in the Porphyria Laboratories, Department of Medicine, UCT. Peter Meissner is professor and head of the Division of Medical Biochemistry in the Department of Clinical Laboratory Sciences, a member of the Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, and director of the Porphyria Laboratories, Department of Medicine, UCT. Jeannine Heckmann is an associate professor of Neurology in the Department of Medicine, UCT. Corresponding author: C H Albertyn (christine.albertyn@uct.ac.za)

Acute intermittent porphyria, the most common porphyria affecting the nervous system, typically presents with neurovisceral crises followed by a motor neuropathy. We describe a 23-year-old black South African man presenting with a progressive stuttering, lower motor neuron syndrome developing over months. He had not experienced pain or neuropsychiatric symptoms. One year after symptom onset he was bed-bound with a flaccid quadriparesis. There was marked amyotrophy, but without fasciculations. Sensation was intact apart from a hypo-aesthetic patch over the thigh. Electrophysiological investigations showed an active motor axonopathy. Urinary porphyrins, Î´-aminolaevulinic acid and porphobilinogen were elevated. Mutation analysis revealed the c445C>T (R149X) mutation in the porphobilinogen deaminase gene. The patient responded dramatically to haem arginate and could walk with assistance 2 weeks later. We identified the first molecularly confirmed acute intermittent porphyria in a black South African. The clinical presentation mimicked a progressive lower motor neuron syndrome. S Afr Med J 2014;104(4):283-285. DOI:10.7196/SAMJ.7785

Acute intermittent porphyria (AIP), the most common porphyria affecting the nervous system, typically presents with neurovisceral crises followed by a motor neuropathy. We describe an unusual presentation in a young man with molecularly confirmed AIP.

Case presentation

A 23-year-old university student was referred to Groote Schuur Hospital, Cape Town, South Africa, with suspected motor neuron disease. Over the preceding year he had noticed insidious progressive weakness of both upper limbs. Initially, the weakness affected grip strength bilaterally, but within 9 months progressed to also involve proximal arm function. Ten months after onset, he developed profound leg weakness over a period of days, rendering him unable to walk without support. He had no bowel or bladder sphincter involvement and no bulbar symptoms, but complained

of a weak cough. He had not experienced any neuropsychiatric symptoms or abdominal pain. Examination showed a thin and wasted man with marked amyotrophy involving all four limbs, both proximally and distally (Fig. 1). He was bed-bound, and unable to turn in bed, feed or dress himself. He had mild symmetrical facial weakness and a weak cough with a reduced vital capacity (<80% of expected). He had truncal weakness and a flaccid quadriparesis, but no fasciculations were noted: upper limb strength Medical Research Council (MRC) grade 1/5 proximal, 2/5 distal; lower limb strength 2/5 proximal, 3/5 distal. He was areflexic in the legs with either hyporeflexia (biceps and supinator reflexes) or areflexia (triceps reflexes) in the arms. Findings on sensory examination were normal apart from a patch of reduced sensibility for pinprick and touch over the left anteromedial thigh region.

Fig. 1. (A) Upper limbs showing marked wasting of both proximal and distal muscles with flattening of forearms in the anteroposterior plane. (B) Lower limbs showing marked wasting of proximal and distal muscles with bilateral foot drop. (C) Dorsal aspect of right hand showing wasting of thenar and hypothenar muscles, and ulnar clawing.

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The following tests were either normal or negative: full blood count, renal function and electrolytes, liver profile, erythrocyte sedimentation rate, fasting glucose, γ-globulin electrophoresis, serum lead levels, HIV and syphilis serology. The cerebrospinal fluid was acellular with normal chemistry. Nerve conduction studies demonstrated a motor axonopathy in all four limbs with normal sensory responses. Electromyography studies of proximal and distal limb muscles showed denervation with fibrillation potentials in keeping with an active neurogenic process. This unusual and severe motor neuropathy, but without fasciculations and a with single patch of numbness, prompted a porphyria screen. It was strongly positive with a δ-aminolaevulinic acid (ALA) level of 678 μmol/10 mmol creatinine (upper limit of reference range ≤45) and a porphobilinogen (PBG) level of 1 477 μmol/10 mmol creatinine (upper limit of reference range ≤16). Plasma porphyrin fluoroscanning demonstrated an emission peak at a wavelength of 619 nm (excitation wavelength 405 nm). This pattern, together with urinary ALA and PBG characterisation, was compatible with a diagnosis of AIP. His urinary porphyrin excretion profile showed greatly elevated porphyrin concentrations (10- to 13-fold) with a preponderance of uroporphyrin, typical of acute porphyria. The diagnosis of AIP was confirmed by identifying the R149X mutation, c445C>T in exon 9 by sequencing the PBG deaminase gene (also known as hydroxymethylbilane synthase). On additional questioning it became evident that 4 months after symptom onset, he had experienced paraesthesiae over both thighs and buttocks. This resolved partially over days with residual numbness over his left anterior thigh. Also, over the preceding 3 years he had had intermittent episodes of constipation, at times even requiring hospitalisation for laxative treatment.

Clinical course

The patient was treated with standard dosage intravenous haem arginate (Normosang), a formulation of haematin, for 6 days. He started improving within 3 days of treatment initiation and was able to turn in bed and hold his mobile phone to his ear. After 2 weeks he was able to stand and mobilise with assistance; both shoulder abduction and hip flexion had improved by at least one grade (shoulder 4/5; hip ≥3/5). The distal power remained unchanged. Over the following 6 months, our patient re-presented twice with relapses: on one occasion characterised by abdominal pain and constipation; and on the other with only worsening hand weakness and constipation. Further courses of intravenous haem arginate were administered with resolution of abdominal pain and improvement in distal arm strength. He still has weak intrinsic hand muscles (MRC 2/5), but lives independently.

Discussion

We report an unusual presentation of AIP in a young black South African man with a chronic progressive, albeit stuttering, presentation of extensive proximal and distal muscle wasting and weakness developing over the course of 1 year, masquerading as a lower motor neuron syndrome. Our case was atypical in that there were no overt episodes of severe abdominal pain or neuropsychiatric symptoms throughout the course of the illness. A history of recurrent bouts of constipation, probably reflecting the autonomic neuropathy of AIP, was only obtained retrospectively once the diagnosis had been established. AIP is a dominantly inherited condition resulting from the deficiency of PBG deaminase, which leads to markedly elevated

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urinary ALA and PBG during an acute attack. Urinary porphyrins are also frequently raised. It is the most common and typically most severe of the acutely presenting porphyrias.[1] The older literature on the neurological manifestations of AIP tends to emphasise the classic triad of abdominal pain, neuropathy and psychosis.[2,3] Autonomic nervous involvement may manifest with tachycardia, fluctuating blood pressure and abdominal pain secondary to ileus. [1] The neuropathy usually follows a few days later, with maximum deficit typically reached over 1 month.[1] Characteristically, the neuropathy of AIP is a predominantly motor neuropathy with a predilection for upper limb involvement and proximal more than distal weakness. Unusual sensory symptoms sometimes occur in a bathing trunk distribution.[1] It is held that the neuropathy associated with AIP usually resolves slowly over months and recovery depends on the extent and magnitude of axonal degeneration.[1] Reports have documented gradual improvement of muscle strength over months[4] to years, but up to 50% of patients may have residual weakness[5] and 4% remain quadriparetic. [6] However, fairly rapid improvement on haem arginate, similar to that which our patient experienced, has been observed in several cases.[7,8] The dramatic clinical recovery observed in our patient’s proximal muscles over a few days argues for a substantial contribution from neural dysfunction rather than neural degeneration. The exact mechanism whereby AIP causes neurotoxicity is uncertain, although it has been postulated that ALA (or other metabolites) which are produced in excess by the liver, are neurotoxic.[3,9] This is supported by the benefit seen following liver transplantation in patients with severe AIP.[3] In addition, ALA-induced oxidative damage has been demonstrated in animal models,[10] and ALA levels are also significantly increased in lead poisoning, which may produce a porphyria-like neuropathy.[1] As a critical component of mitochondrial cytochromes, haem participates in the electron transport chain and adenosine triphosphate (ATP) production. Fast axonal transport is highly dependent on this energy.[9] Haem deficiency may result in Na+/ K+ pump failure, altered membrane potential with consequent neuronal injury, and even axonal death.[11] Acute attacks of AIP are precipitated by triggers that either directly induce hepatic ALA synthase 1 (ALAS1) activity, or increase the demand for haem synthesis, thereby reducing the negative feedback on ALAS1.[3] These events include menstrual hormonal changes, fasting, smoking, infections, and exposure to porphyrinogenic drugs. Haematin therapy temporarily down-regulates hepatic ALAS1 activity, thereby reducing the overproduction of potentially neurotoxic metabolites by the liver.[1,3] Symptom onset in our patient correlated with his student life, which included erratic meals and alcohol binges. However, relapses following the diagnosis and counselling did not have clear precipitants, although relative undernutrition may have contributed. The absence of clearly defined clinical attacks in our patient complicates future treatment decisions, especially as porphyrin levels and clinical status do not correlate well.[12]

Conclusion

While AIP is known to exist in all racial groups, it remains a poorly diagnosed and documented condition in black Africans, with only a few PBG deaminase gene defects reported.[13] The PBG deaminase c445C>T (R149X) mutation in our patient is novel in a black African. This case illustrates the need to consider AIP as a possible cause of a progressive severe predominantly motor neuropathy, even in the apparent absence of other features associated with hepatic porphyria.

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Acknowledgements. The authors thank Brandon Davidson and Maglona Paul for performing the porphyrin biochemistry and DNA extraction. The PBG deaminase mutation work and porphyrin diagnostic studies were funded in part by the South African MRC and the National Research Foundation (NRF), where PM is the holder of an MRC grant to study the molecular genetics of AIP in South Africa, and has NRF incentive funding as a rated researcher.

1. Albers JW, Fink JK. Porphyric neuropathy. Muscle Nerve 2004;30(4):410-422. [http://dx.doi. org/10.1002/mus.20137] 2. Becker DM, Kramer S. The neurological manifestations of porphyria: A review. Medicine (Baltimore) 1977;56:411-423. [http://dx.doi.org/10.1097/00005792-197709000-00003] 3. Puy H, Gouya L, Deybach J. Porphyrias. Lancet 2010;375(9718):924-937. [http://dx.doi.org/10.1016/ S0140-6736(09)61925-5] 4. Kuo HC, Lee MJ, Chuang WL, Huang CC. Acute intermittent porphyria with peripheral neuropathy: A follow-up study after hematin treatment. J Neurol Sci 2007;260(1-2):231-235. [http://dx.doi. org/10.1016/j.jns.2007.03.018] 5. Sorensen AWS, With TK. Persistent paresis after porphyric attacks. S Afr Med J 1971;45(Special issue):101-103.

6. Wikberg A, Andersson C, Lithner F. Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphyria. J Intern Med 2000;248(1):27-32. [http://dx.doi.org/10.1046/j.13652796.2000.00697.x] 7. Diot E, Corcia P, Zannad N, Chauvet MA, Borie MJ, Maillot F. Favorable outcome of acute porphyric neuropathy after treatment with haem arginate. Rev Neurol (Paris) 2007;163(11):1100-1102. [http:// dx.doi.org/10.1016/S0035-3787(07)74184-X] 8. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore) 2005;84(1):48-60. [http://dx.doi.org/10.1097/01.md.0000152454.56435.f3] 9. Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: The pathophysiology of acute porphyric neuropathy. Clin Neurophysiol 2011;122(12):2336-2344. [http://dx.doi.org/10.1016/j. clinph.2011.07.036] 10. Demasi M, Penatti CAA, Delucia R, Bechara EJH. The prooxidant effect of 5-aminolevulinic acid in the brain tissue of rats: Implications in neuropsychiatric manifestations in porphyrias. Free Radic Biol Med 1996;20(3):291-299. [http://dx.doi.org/10.1016/0891-5849(95)02035-7] 11. Lin CS, Krishnan AV, Lee MJ, et al. Nerve function and dysfunction in acute intermittent porphyria. Brain 2008;131(9):2510-2519. [http://dx.doi.org/10.1093/brain/awn152] 12. Gorchein A, Webber R. Delta-aminolevulinic acid in plasma, cerebrospinal fluid, saliva and erythrocytes: Studies in normal, uraemic and porphyric subjects. Clin Sci 1987;72(1):103-112. 13. Robreau-Fraolini AM, Puy H, Aquaron C, et al. Porphobilinogen deaminase gene in African and AfroCarribbean ethnic groups: Mutations causing acute intermittent porphyria and specific intragenic polymorphisms. Hum Genet 2000;107(2):150-159. [http://dx.doi.org/10.1007/s004390000323]

Accepted 26 November 2013.

The neurological manifestations of the acute porphyrias The porphyrias are a group of eight metabolic disorders, each of which is associated with a specific enzymatic alteration in the haem biosynthetic pathway.[1] In general, the porphyrias share one or both of two clinical symptom complexes: cutaneous photosensitivity, which results from the interaction of light and photoactive porphyrin molecules in the skin; and the acute attack, a serious complication associated with a phase of accelerated hepatic porphyrin synthesis. The acute attack is a feature of four porphyrias: acute intermittent porphyria (AIP); variegate porphyria; hereditary coproporphyria; and aminolaevulinic acid (ALA) dehydratase porphyria. All four are so-called ‘hepatic’ porphyrias, in which the haem synthetic defect is expressed in non-erythroid cells, notably hepatocytes. The acute attack is a potentially severe illness that may result in severe debilitation and death. The clinical features are metabolic, principally hyponatraemia, and neurological, related to autonomic, motor and cerebral dysfunction.[2-4] Autonomic dysfunction is associated with a characteristic diffuse, severe and poorly localised abdominal pain, sympathetic over-activity manifesting as tachycardia, hypertension or a labile blood pressure and cardiac arrhythmias, and gastrointestinal dysfunction causing nausea, vomiting and ileus. Cerebral dysfunction may present as seizures, transient cerebral ischaemia, posterior reversible encephalopathy syndrome (PRES) or coma.[5] Seizures may be precipitated by hyponatraemia, cerebral ischaemia and the administration of epileptogenic medication, such as pethidine (meperidine) prescribed for pain relief.[6] Hyponatraemia may result from the syndrome of inappropriate antidiuretic hormone secretion (SIADH), renal tubular dysfunction and the administration of hypotonic intravenous fluids such as dextrose.[7] Rarely, brainstem dysfunction may occur in response to transient ischaemia or hyponatraemia,[8] as may cerebral infarction.[9] Acute psychotic states are occasionally observed.[10] All these alarming features, other than

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the pain, nausea and cardiovascular effects, are seen in a minority of cases, and usually accompany a particularly severe and often unrecognised, untreated acute attack. A more common manifestation of more severe attacks is a sudden-onset, predominantly motor, peripheral neuropathy. The typical presentation is of a rapid onset of muscle weakness following a prodrome of 1 - 2 days of abdominal pain and other symptoms of the acute attack. Sensory symptoms are never prominent. Muscle weakness is symmetrical and evenly distributed in the proximal and distal muscle groups of the upper limbs, although it may typically start proximally, particularly in the legs. [11] In our experience, it is not infrequently misdiagnosed as Guillain-Barré syndrome. Progressive weakness can progress to respiratory failure. Cranial nerve involvement may occur. Before the introduction of modern techniques of assisted ventilation, such attacks were fatal. Quadriparesis is reversible, but may require prolonged ventilatory support and many months of rehabilitation. Occasionally patients present with atypical neurological manifestations. Single cases of mononeuritis multiplex[12] and ‘pseudomyasthenia’ during an acute attack have been described. Patients with pre-existing neuropathy who experience recurrent attacks may demonstrate a transient decrease in muscle strength with a return to baseline following cessation of the attack.[13] Nerve conduction studies and pathological examination typically indicate a pattern of axonal necrosis rather than demyelination.[3] The pathogenesis is poorly understood. A direct, toxic effect of the porphyrin precursors, particularly ALA, on neuronal tissue has been postulated. Interestingly, the chemical structure of ALA closely resembles that of γ-aminobutyric acid (GABA), a known neurotransmitter.[13] A contrasting hypothesis is that porphyria-associated impaired haem synthesis results in intraneuronal haem deficiency, with consequent intracellular energy depletion and dysfunction.[14] This view has become less tenable since repeated experience with liver transplantation has shown that this effectively removes the potential for future acute attacks

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in patients subject to frequent and debilitating recurrent attacks,[15] even though haem biosynthesis in all non-erythroid cells, including neurons (with the exception of the engrafted hepatocytes), continue to operate in a haem-deficient environment. The symptomatic patient with an acute, severe porphyria therefore typically presents with a sudden onset of a characteristic syndrome of acute abdominal pain, accompanied by other clinical features as described above, which may then progress to a sudden onset of quadriparesis over the course of a few hours. Recovery thereafter may be prolonged. The unfortunate patient may have further acute attacks following the same pattern. In this issue of the SAMJ, an atypical neurological presentation of AIP in a young man is described.[16] Two points are of particular interest. Firstly, although the observed pattern of neurological dysfunction was quite compatible with an acute porphyria, the expected history of an abrupt onset preceded by a short prodrome of typical porphyric symptoms was completely absent. There were no preceding symptoms suggestive of an acute attack, and weakness developed cumulatively over a prolonged period. It is not surprising that a condition such as motor neuron disease featured prominently in the initial differential diagnosis. The patient was fortunate in that, certain inconsistent features having been recognised, he was referred to a neurology unit where exclusion of porphyria is a standard practice for patients with unexplained neuropathy, given the very high prevalence of porphyria in the South African population.[17] The second point of interest is the rapid improvement in neurological function in response to definitive therapy for porphyria with haem arginate. Given that the predominant underlying pathological state is one of severe axonal necrosis, rapid improvement is not expected. Yet, in this case treatment was followed by a prompt, though partial, improvement. That it was incomplete is easily explained given that neurophysiological studies did indeed confirm the presence of axonal necrosis. It does, however, support the suggestion that, in at least some cases, motor neuron function is transiently depressed under circumstances of haem depletion, with the potential for rapid improvement when this is corrected.[6] Two conclusions may be drawn from this report. For the clinician it is a reminder that acute forms of porphyria should never be forgotten when confronted with a patient with unexplained motor neuropathy, whether or not the characteristic features of the acute attack are present. For those with a research interest in neuropathophysiology, it is an invitation: an interesting, fruitful and under-explored field â&#x20AC;&#x201C; the interplay of disordered haem synthesis and neuronal function â&#x20AC;&#x201C; awaits detailed study and definitive answers.

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Mark W Sonderup Department of Medicine, Division of Hepatology and Lennox Eales Porphyria Labs, University of Cape Town, Faculty of Health Sciences and Groote Schuur Hospital, Cape Town, South Africa msonderup@samedical.co.za Richard J Hift School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa Corresponding author: M W Sonderup (msonderup@samedical.co.za)

1. Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. 2. Pischik E, Kauppinen R. Neurological manifestations of acute intermittent porphyria. Cell Mol Biol (Noisy-le-grand) 2009;55(1):72-83. 3. Simon NG, Herkes GK. The neurologic manifestations of the acute porphyrias. J Clin Neurosci 2011;18(9):1147-1153. [http://dx.doi.org/10.1016/j.jocn.2011.01.003] 4. Lin CS, Park SB, Krishnan AV. Porphyric neuropathy. Handb Clin Neurol 2013;115:613-627. [http:// dx.doi.org/10.1016/B978-0-444-52902-2.00036-9] 5. Ni J, Zhou LX, Hao HL, et al. The clinical and radiological spectrum of posterior reversible encephalopathy syndrome: A retrospective series of 24 patients. J Neuroimaging 2011;21(3):219-224. [http://dx.doi.org/10.1111/j.1552-6569.2010.00497.x] 6. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine 2005;84(1):48-60. [http://dx.doi.org/10.1097/01.md.0000152454.56435.f3] 7. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005;142(6):439-450. [http://dx.doi.org/10.7326/0003-4819142-6-200503150-00010] 8. Barraza G, Serranova T, Herrero C, et al. Brainstem dysfunction in variegate porphyria. Muscle Nerve 2012;46(3):426-433. [http://dx.doi.org/10.1002/mus.23367] 9. Mullin S, Platts A, Randhawa K, Watts P. Cerebral vasospasm and anterior circulation stroke secondary to an exacerbation of hereditary corproporphyria. Pract Neurol 2012;12(6):384-387. [http://dx.doi. org/10.1136/practneurol-2012-000288] 10. Kumar B. Acute intermittent porphyria presenting solely with psychosis: A case report and discussion. Psychosomatics 2012;53(5):494-498. [http://dx.doi.org/10.1016/j.psym.2012.03.008] 11. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: Pathogenesis of neurological manifestations. Semin Liver Dis 1998;18(1):43-52. [http://dx.doi.org/10.1055/s-2007-1007139] 12. King PH, Petersen NE, Rakhra R, Schreiber WE. Porphyria presenting with bilateral radial motor neuropathy: Evidence of a novel gene mutation. Neurology 2002;58(7):1118-1121. 13. McGillion FB, Thompson GG, Goldberg A. Tissue uptake of o-aminolaevulinic acid. Biochem Pharmacol 1975;24(2):99-301. 14. Kauppinen R. Porphyrias. Lancet 2005;365(9455):241-252. [http://dx.doi.org/10.1016/S01406736(05)70154-9] 15. Seth AK, Badminton MN, Mirza D, Russell S, Elias E. Liver transplantation for porphyria: Who, when, and how? Liver Transpl 2007;13(9):1219-1227. [http://dx.doi.org/10.1002/lt.21261] 16. Albertyn CH, Sonderup M, Bryer A, Corrigall A, Meissner P, Heckmann JM. Acute intermittent porphyria presenting as progressive muscular atrophy in a young black man. S Afr Med J 2014;104(4):283-285. [http://dx.doi.org/10.7196/SAMJ.7785] 17. Meissner PN, Dailey TA, Hift RJ, et al. A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet 1996;13(1):95-97. [http://dx.doi.org/10.1038/ng0596-95]

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Increased visibility and discoverability of South African health-related research Editors, publishers and researchers gathered in São Paulo, Brazil, in October 2013 to celebrate the 15th anniversary of the Scientific Electronic Library Online (SciELO), a significant developing-country, openaccess publishing project. This subsidised collection of mainly Latin American journals was joined by SciELO South Africa (SA) as its first African extension in 2009. SciELO SA was established by the Academy of Science of South Africa (ASSAf), and is funded by the Department of Science and Technology. [1] Its aim is to become a fully indexed open-access journal collection in the service of the SA research community through effective quality assurance, worldwide visibility, and amenability to bibliometric analysis. In effect, SciELO SA is set to become a prestigious, free-to-access, freeto-publish, searchable collection of a large number of selected, highquality SA scholarly journals, embedded in the much larger SciELO collections of other member countries. The collection will promote SA research through enhancing the visibility of, and access to, much of the best research. Currently there are 35 scholarly SA journals drawn from many disciplines on the platform, and it is envisaged that eventually as many as 150 - 180 titles will be hosted on the platform. Two Health and Medical Publishing Group journals, namely the SAMJ and the South African Journal of Surgery, are already accepted onto the platform.

What does this mean for SA scholarly journals on the SciELO SA platform?

Since April 2013, the collection has been licensed officially as a certified, locally managed segment of the wider SciELO Network Portal, which is fast becoming the most promising multinational journal indexing and publishing model in the developing world. The system aims to enhance the quality, visibility, reputation and value of national/regional research/ scholarly journals, only a relatively small proportion of which are freely accessible online or are indexed in the well-known indexed databases of Thomson Reuters (Web of Knowledge) or Elsevier (Scopus). This will result in much wider stakeholder usage and collaboration among the SA, regional and global scientific communities. Thomson Reuters: Intellectual Property and Science announced recently that it is now collaborating with the SciELO Network Portal to integrate the SciELO Citation Index into the Web of Knowledge. [2] This initiative will bring even greater visibility and improved access to research from emerging countries like SA, in turn enabling SA researchers to review and analyse relevant regional content along with that in the top-tier international literature within the Web of Knowledge. In 2003, the Department of Education (now the Department of Higher Education and Training (DHET)) promulgated the Policy and Procedures for Measurement of Research Output of Public Higher Education Institutions.[3] The purpose of the policy is to ‘encourage research productivity by rewarding high-quality research output at public higher education institutions’. It must be emphasised that the policy assumes that the research outputs to be recognised are of high (assured) quality, that they are widely accessible across the globe, and that they provide a sound basis for grant making involving public funds, research and development strategies, and high-level human capital development in SA. Peer review is identified as the primary measure of quality for all recognised output, and only journals that appear on certain accredited indexes are accepted for subsidy purposes. Initially journals were reviewed by the DHET according to a small set of mainly descriptive criteria, but it soon became clear that

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departmental officials did not have the necessary expertise in the broad range of subject areas to assess the quality of the journals concerned. For this reason, the DHET approached the ASSAf in 2009 to assist with implementation of its policy by putting new applications for accreditation through the ASSAf ’s peer review process to ascertain the journals’ quality in the context of local and international norms. The ASSAf published a report in 2006 that comprehensively reviewed research publications in scholarly journals.[4] Based on recommendations in this report, the ASSAf developed an appropriate methodology for a discipline-grouped, independent, multiple-peer review of local journals, overseen by council-appointed peer review panels. This was to be followed by the release of formal consensus reports. To date, over 130 journals have been, or are being, subjected to this process. (The above-mentioned ASSAf quality assurance process is the same one used when evaluating journals for DHET accreditation.) It is also worth mentioning that the ASSAf ’s peer review panel for the health sciences and related medical journals has just completed its review and will publish its report by mid-2014. The panel dealt with a total of 35 journals, of which 22 call themselves South African, 6 southern African and 5 African; only 1 is an international journal in the sense that it is the official journal of an international organisation but is published in SA, while the remaining journal does not refer to its target area in its title. Accordingly, most of the journals publish mainly local authors, and the content is focused heavily on local issues and topics. However, some titles have definitely become important owing to their continental reach, with their authors drawn from many African countries, and the quality and breadth of their articles reflecting a wide focus (e.g. HIV and AIDS research). The majority of the journals (33) are published online and only two are exclusively published as hard/ print copies. The peer review panel generally felt that the quality of the research articles published in this collection of SA health sciences and related journals was generally ‘good to very good’, and that the processes and policies of the journals were generally sound. It is therefore hoped that the global reach and potential impact of scientific research in SA will be greatly enhanced by these efforts to boost the quality and quantity of work that is locally published, and that this work will increasingly be made available on the SciELO SA platform and its connected international indexing services. S Veldsman Director of the Scholarly Publishing Unit, ASSAf, South Africa W Gevers Co-ordinator of the peer review panels and Advisor to the ASSAf Council on Scholarly Publishing in South Africa (CSPiSA), South Africa Corresponding author: W Gevers (wieland@telkomsa.net) 1. Wild S. SA research now free online. Mail & Guardian. 26 July 2013. http://mg.co.za/article/2013-0726-00-sa-research-now-free-online (accessed 24 February 2014). 2. Thomson Reuters. Thomson Reuters collaborates with SciELO to showcase emerging research centres within Web of Knowledge. 24 October 2013. http://thomsonreuters.com/press-releases/102013/ SciELO-Collaboration (accessed 25 February 2014). 3. National Department of Education. Policy and Procedures for Measurement of Research Output of Public Higher Education Institutions. Pretoria: DoE, 2003. http://www.dhet.gov.za/LinkClick.aspx?file ticket=XZUiHeXFbzQ%3d&tabid=416&mid=1225 (accessed 24 February 2014). 4. Academy of Science of South Africa. Report on a Strategic Approach to Research Publishing in South Africa. Pretoria: ASSAf, 2006. http://www.assaf.org.za/wp-content/uploads/2011/02/2466-ASSAFStrategic-approach-to-research-publishing-2.pdf (accessed 24 February 2014).

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RESEARCH

High prevalence of cisplatin-induced ototoxicity in Cape Town, South Africa H Whitehorn,1 BSc, BSc (Med) Hons, MSc (Med); M Sibanda,2 BSc, MSc (Audiology); M Lacerda,3 BBusSc Hons, MSc, PhD; T Spracklen,1 BSc, BSc (Med) Hons; L Ramma,2 AuD, MPH, CCC-A; S Dalvie,4 MB ChB, FC (Rad Oncol); R Ramesar,1 MSc (Microbiology, Biochemistry, Genetics), PhD (Microbial Genetics), PhD (Molecular Genetics), MBA Division of Human Genetics, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, South Africa Division of Communication Sciences and Disorders, Groote Schuur Hospital, Cape Town, South Africa 3 Department of Statistical Sciences, Faculty of Science, University of Cape Town, South Africa 4 Department of Radiation Oncology, Groote Schuur Hospital, Cape Town, South Africa 1 2

Corresponding author: R Ramesar (raj.ramesar@uct.ac.za) Background. Cisplatin is administered as the first-line treatment of soft-tissue cancers. It has a reported cure rate of up to 85%, but is associated with a high incidence of ototoxicity, characterised by irreversible bilateral hearing loss and affecting 23 - 50% of adults who receive the drug. Objectives. To determine the incidence of cisplatin-induced ototoxicity at Groote Schuur Hospital (GSH), Cape Town, South Africa. Methods. A retrospective cross-sectional study of cisplatin-receiving cancer patients attending GSH between January 2006 and August 2011. Results. A total of 377 patients were recorded as receiving cisplatin therapy during the study period. A 300% increase in new cisplatin-receiving patients receiving audiological monitoring was observed between 2006 and 2010. However, only patients with all clinical data as well as baseline and follow-up audiometric analyses were investigated. One hundred and seven such patients were identified, 55.1% of whom developed cisplatininduced ototoxicity while receiving high-dose (≥60 mg/m2) cisplatin treatment. Higher cumulative cisplatin dosages were associated with development of significant hearing loss (p=0.027). The odds of developing cisplatin-induced hearing loss were elevated for patients with head and neck tumours and lymphoma (p=0.0465 and p=0.0563, respectively) and were significantly lower for those with reproductive cancers (p=0.0371). Conclusion. Comprehensive audiological monitoring should be available for every patient during cisplatin treatment to minimise the development of disabling hearing loss. S Afr Med J 2014;104(4):288-291. DOI:10.7196/SAMJ.7389

Cisplatin is one of the most widely used and effective cytotoxic agents currently available for the treatment of soft-tissue cancers, with a reported cure rate of 85%.[1] This antineoplastic drug inhibits tumour growth through the formation of DNA interstrand and intrastrand crosslinks, which disrupts the double-stranded DNA helical structure. This in turn prevents cell division and growth due to inhibition of DNA replication and transcription, leading directly to apoptosis.[2] Use of cisplatin is limited by the relatively high incidence of associated adverse drug reactions, including neurotoxicity, ototoxicity and nephrotoxicity, due to the drug’s narrow therapeutic index. Cisplatininduced ototoxicity is characterised by high-frequency sensorineural bilateral hearing loss, which can be irreversible and progressive[3] and is often associated with tinnitus and ear pain. The hearing loss usually begins at high frequencies (>8 000 Hz) and may later progress to lower frequencies that are important for conversational speech. According to international reports, cisplatin ototoxicity affects 23 - 50% of adults and up to 60% of children.[4-6] However, some studies have reported elevated hearing thresholds in up to 100% of cisplatin-treated cancer patients.[1] Limited data are available on the incidence of drug-induced hearing impairment in Africa. The reported prevalence of cisplatin-induced hearing impairment and tinnitus is strongly dependent on the criteria and diligence of the audiological evaluation. The Chang ototoxicity grading scale is a modification of the original Brock criteria for ototoxic hearing loss.[7] Importantly, these criteria specify the severity of hearing loss and can be used reliably by audiologists, oncologists and clinical research personnel to standardise ototoxicity monitoring.

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Drug-induced ototoxicity negatively influences an individual’s verbalauditory communication, resulting in a detrimental effect on learning and socio-emotional status.[5] Hearing loss can have educational and economic disadvantages including delayed speech acquisition and literacy and impaired cognitive skills in children, and social isolation. These consequences are greater in developing countries because of the inadequacy of rehabilitation and social service facilities. The development of adverse drug reactions such as ototoxicity often leads to discontinuation of cisplatin treatment or reduction of the dose. This affects compliance with treatment and ultimately leads to decreased survival rates in cancer patients. Variation in susceptibility to the development of cisplatin-induced ototoxicity has been attributed to age at initiation of treatment, renal dysfunction, cumulative cisplatin dosages, cranial irradiation, co-administration with other ototoxic drugs, noise exposure and genetic factors.[8-10] The majority of studies investigating cisplatininduced ototoxicity have been performed on European and South American patient cohorts,[4-6,10] with only a single study examining the development of ototoxicity in Japanese head and neck cancer patients. The incidence rate of cisplatin-induced ototoxicity was reported as 77.3% in the 44 Japanese patients investigated.[11] No clinically proven treatments for the prevention or amelioration of ototoxicity exist, although recent studies have highlighted the value of co-administration of cisplatin with otoprotectors such as D-methionine.[12] However, the development of ototoxicity remains the most significant dose-limiting factor in cisplatin-based chemotherapy owing to the cumulative, and often irreversible, manner in which it develops. Ototoxicity frequently affects the outcome of treatment,

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Methods Patients

A 5-year retrospective cross-sectional study was carried out on patients receiving highdose (≥60 mg/m2 per cycle) cisplatin-based chemotherapy with audiological monitoring at GSH between January 2006 and August 2011. Ethical approval was granted by the Human Research Ethics Committee, University of Cape Town. Socio-demographic and clinical data including pre-existing hearing loss, previous noise exposure, anatomical site of cancer and cumulative cisplatin dosage (mg/m2) were collected from patient medical records. Inclusion criteria were the availability of a baseline, and at least one additional, audiological assessment.

Audiometric monitoring

Assessment of hearing thresholds was conducted using conventional pure-tone audiometry in an audiometric booth using a GSI 61 audiometer. Air and bone conduction thresholds were determined at frequencies between 0.5 and 8 kHz. Clinical ototoxicity was classified according to the American Speech-Language-Hearing Association (ASHA) guidelines[13] as a 20 dB HL or greater hearing loss decrease in pure-tone threshold at any single test frequency or a 10 dB HL or greater hearing loss decrease at any two adjacent test frequencies in air conduction. Patients presenting with significant hearing loss following cisplatin treatment were further classified according to severity using the Chang ototoxicity scale.[7]

Statistical analysis

Descriptive statistics were used to analyse the data using the statistical environment R and the IBM SPSS statistics package. KaplanMeier survival analysis was used to assess the rate of development of ototoxicity based on the time to hearing loss after initiation of cisplatin treatment. p-values of <0.05 were considered statistically significant.

Results

A total of 377 patients received cisplatin therapy during the study period. One hundred and seven cisplatin-receiving patients with comprehensive clinical and audiometric data were identified; however, clear cumulative cisplatin dosages were only available for 86

Table 1. Demographic characteristics of individuals with and without ototoxicity following cisplatin treatment

Ototoxicity free (N=48)

Ototoxicity (N=59)

p-value

Age (years), mean (min; max)

41.6 (14; 72)

44.4 (14; 75)

0.910*

Gender (male), n (%)

37 (77.1)

42 (71.2)

0.665†

Cumulative cisplatin dose (mg/m2), median (min; max)

180.70 (79.11; 431.65)

236.84 (47.62; 511.56) 0.027*‡§

Ototoxicity free = patients who did not develop significant hearing loss; ototoxicity = patients who developed significant hearing loss. * Wilcoxon rank-sum test. † Fisher’s exact test. ‡ Statistically significant at type 1 error rate of 5%. § One-sided hypothesis test.

New cisplatin-receiving patients, n

yet its prevalence in cancer patients in South Africa (SA) is largely unreported. This study aimed to determine the incidence of cisplatin-induced ototoxicity in a population of patients attending Groote Schuur Hospital (GSH), Cape Town, SA.

2006

2007

2008

2009

2010

Aug 2011

Year of entry Fig. 1. Frequency of new cisplatin-receiving patients with audiological monitoring at Groote Schuur Hospital. The frequency of these patients displays an increasing exponential trend between 2006 and 2010. Pale blue represents patients who experienced significant cisplatin-induced hearing loss and dark blue represents patients who did not experience hearing loss.

of these patients. The study cohort consisted of 79 males (73.8%) and 28 females (26.2%). Patients were classified into two groups, based on the development of significant hearing loss following cisplatin-containing chemotherapy – the ototoxicity-free (no significant hearing loss) and ototoxicity (significant hearing loss) groups. The ototoxicity-free group comprised 48 patients, of whom 77.1% were male, and the ototoxicity group 59 patients, of whom 71.2% were male (Table 1). The mean ages for the ototoxicity-free and ototoxicity groups were 41.6 and 44.4 years (range 14 - 72 years

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and 14 - 75 years), respectively. Gender was not associated with significant hearing loss (Fisher’s exact test, p=0.665), and there was no significant difference in the age distribution for patients who did and did not experience hearing loss (Wilcoxon test, p=0.910). A total incidence of cisplatin-induced ototoxicity of 55.1% was observed in this SA population, of whom 62.7% experienced bilateral hearing loss. Only 3 patients in the ototoxicity cohort had self-reported previous noise exposure, and another 2 reported experiencing tinnitus during cisplatin treatment.

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treatment (log rank test, p=0.490) or severity of hearing loss (log rank test, p=0.450).

Kruskal-Wallis p-value = 0.316

400 300 200 100

Cumulative cisplatin dosage (mg/m2)

500

Discussion

Chang ototoxicity grade Fig. 2. Distribution of cumulative cisplatin dosage based on severity of hearing loss. The distribution displays an increasing trend with increasing severity of hearing loss experienced. The Chang ototoxicity grading scale was used to assess severity, with grades 1A and 1B and 2A and 2B grouped into grades 1 and 2, respectively, owing to small sample size. Patients with grade 3 ototoxicity (n=3) are not shown.

Approximately half of the study participants (53.3%) had hearing loss before initiation of cisplatin-based chemotherapy, as classified by ASHA.[13] As expected, pre-existing hearing loss was significantly associated with age at baseline (Wilcoxon test, p<0.001), but it was not associated with subsequent cisplatin-induced hearing loss (Fisherâ&#x20AC;&#x2122;s exact test, p=0.696). The age distribution differed significantly according to anatomical tumour location (p<0.001), patients with reproductive cancers and osteosarcoma being younger at baseline audiometric analysis. The frequency of new cisplatin-receiving patients per year, who were audiologically monitored during treatment, increased by 300% between years 2006 and 2010, with the exception of 2009 (Fig. 1). It is expected that the frequency of cisplatin-receiving patients continued to increase between September and December 2011, since data were only recorded up to the end of August 2011. The median cumulative cisplatin dosages were 180.70 mg/m2 and 236.84 mg/m2 for the ototoxicity-free and ototoxicity groups, respectively. Patients who received higher cumulative dosages during chemotherapy

were more likely to develop significant hearing loss (Wilcoxon test, p=0.027) (Table 1). The median cumulative cisplatin dosages displayed an increasing trend with the severity of the hearing loss, although this association was not statistically significant (Kruskal-Wallis test, p=0.316) (Fig. 2). The rate of development of hearing loss following cisplatin initiation was assessed using Kaplan-Meier survival analysis. The rate at which patients developed hearing loss differed significantly depending on the anatomical location of the tumour (log rank test, p=0.022). Patients with head and neck cancers or lymphoma developed hearing loss faster than the rest of the patients (Fig. 3). The odds of developing cisplatin-induced hearing loss were elevated for patients with head and neck tumours and lymphoma (logistic regression, odds ratio (OR) 1.824; p=0.0465 and OR 2.250; p=0.0563, respectively), and significantly reduced for patients with reproductive cancers (OR 0.111; p=0.0371). Notably, only 1 of the 10 patients with reproductive cancer developed hearing loss. The rate of hearing loss did not differ significantly according to gender (log rank test, p=0.515), age at initiation of

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Ototoxicity has been recognised as an adverse effect of cisplatin treatment for almost three decades,[14] yet because of its high cure rate[1] it is administered in the first-line treatment of many cancer types. Furthermore, cisplatin has been shown to significantly increase the lifespan of patients,[15] and the benefit of chemotherapeutic treatment often outweighs the risk of ototoxicity. Sustaining the patientâ&#x20AC;&#x2122;s quality of life both during and after treatment is therefore of the utmost importance. This is the first study that provides a quantitative analysis of cisplatin-induced ototoxicity in an adult SA population. With an incidence of 55.1%, this report of cisplatininduced hearing loss illustrates that SA adult patients may be at higher risk than their European and South American counterparts, for whom incidence rates of 23 - 50% have been reported.[4-6] We suspect that this trend would be similar for many other hospitals around SA. Since not all patients receive audiological monitoring during high-dose cisplatin treatment and this study was only conducted at a single major Western Cape hospital, our findings may under-represent the incidence of cisplatin-induced ototoxicity. The increasing annual frequency of 300% for new cisplatin-receiving patients who were audiologically monitored during treatment between 2006 and 2010 can be attributed to improved awareness of the ototoxic effects of cisplatin on the part of SA oncologists. In 2009, it was reported that only half of SA oncologists referred patients receiving chemotherapy for audiological monitoring during treatment, even though 90% of them were aware that the drugs cause physical damage to the auditory system.[16] In this cohort, a minimal number (n=3) of patients experienced debilitating hearing loss (i.e. grades 3 and 4) when cisplatin was substituted for the less ototoxic carboplatin when hearing loss in the high frequencies was detected. This is testament to the benefits of the regular audiometric monitoring that these patients received during treatment. Cisplatin-induced ototoxicity has been shown to be dependent on age at initiation of treatment, paediatric (<5 years) and elderly patients (>40 years) displaying increased susceptibility.[6,17] In our study, patient ages ranged between 14 and 75 years; however, there was no significant difference in the age distribution for patients who did and did not experience ototoxicity. Patient gender was not identified as a risk factor for cisplatininduced ototoxicity until recently, when

Reproductive Head/neck Lymphoma Osteosarcoma Other

0.6

0.8

Log rank test p-value = 0.002

economic burden on SA. Our data highlight the importance of regular audiological monitoring of patients receiving high-dose cisplatin treatment. Adequate knowledge of the complication of ototoxicity on the part of clinicians may facilitate the prevention or amelioration of further ototoxic damage through administration of otoprotective agents, or a change of chemotherapeutic drugs. Further research should aim to understand other risk factors, particularly genetic predictors of cisplatin-induced ototoxicity in the uniquely diverse SA population.

0.2

0.4

References

0.0

Probability of no cisplatin-induced hearing loss

1.0

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100

200

300

400

500

600

700

Time since baseline audiogram (days)

Fig. 3. Kaplan-Meier estimates of cisplatin-induced hearing loss-free survival based on anatomical site of cancer. Head/neck cancer and lymphoma patients developed hearing loss at a faster rate than the other cancer groups investigated.

Yancey et al.[9] reported that male paediatric patients were four times more likely to experience ototoxicity than females. We found no association between gender and the development of significant hearing loss. Cumulative dosages of cisplatin have been identified as the most important predictor of cisplatin-induced ototoxicity, particularly cumulative doses above 400 mg/m2.[6,9,10] In a recent study investigating a cohort of Japanese head and neck cancer patients, the threshold cumulative dosage of cisplatin was 200 mg/m2, above which average hearing thresholds were significantly reduced in these patients.[11] Our data indicate that SA patients who received higher cumulative cisplatin dosages during chemotherapy were more likely to develop significant hearing loss, with median cumulative dosages of 180.70 mg/m2 and 236.84 mg/m2 for the ototoxicity-free and ototoxicity groups, respectively. Our findings therefore suggest that cumulative cisplatin dosage may be the most important predictor of ototoxcity in this population. The risk of developing cisplatin-induced hearing loss was significantly reduced in patients with reproductive cancers. These patients receive each cycle of cisplatin treatment intravenously over a period of

3 - 5 days, which may account for the low incidence of ototoxicity in this group. The odds of developing cisplatin-induced hearing loss were elevated in head and neck cancer and lymphoma patients, and hearing loss occurred at a faster rate than in the rest of the patients investigated. Treatment for head and neck carcinomas and lymphomas usually involves surgery, chemotherapy and cranial irradiation, either singly or in combination. Although cranial irradiation was not investigated in this cohort, it has been identified as a risk factor for the development of ototoxicity.[18,19] We hypothesise that the high incidence of hearing loss in these groups may be attributed to the use of cranial irradiation during treatment. Other previously identified risk factors for cisplatin-induced ototoxicity, including previous exposure to ototoxic agents such as the aminoglycoside antibiotics and tuberculosis treatment, were not recorded. Previous noise exposure and renal dysfunction[18,19] were not investigated in this study owing to lack of clinical data. The consequences of hearing loss can be debilitating and may limit the contribution of sufferers to society, adding to the

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1. McKeage MJ. Comparative adverse effect profiles of platinum drugs. Drug Saf 1995;13(4):228-244. [http://dx.doi. org/10.2165/00002018-199513040-00003] 2. Siddik ZH. Cisplatin: Mode of cytotoxic action and molecular basis of resistance. Oncogene 2003;22(47):7265-7279. [http:// dx.doi.org/10.1038/sj.onc.1206933] 3. Buhrer C, Weinel P, Sauter S, Reiter A, Riehm H, Laszig R. Acute onset deafness in a 4-year old girl after a single infusion of cisplatinum. Pediatr Hematol Oncol 1990;7(2):145-148. [http:// dx.doi.org/10.3109/08880019009033384] 4. Coradini PP, Cigana L, Selistre SG, Rosito LS, Brunetto AL. Ototoxicity from cisplatin therapy in childhood cancer. J Pediatr Hematol Oncol 2007;29(6):355-360. [http://dx.doi.org/10.1097/ MPH.0b013e318059c220] 5. Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: Underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 2005;23(34):8588-8596. [http://dx.doi.org/10.1200/JCO.2004.00.5355] 6. Li Y, Womer RB, Silber JH. Predicting cisplatin ototoxicity in children: The influence of age and the cumulative dose. Eur J Cancer 2004;40(16):2445-2451. [http://dx.doi.org/10.1016/j.ejca.2003.08.009] 7. Chang KW, Chinosornvatana N. Practical grading system for evaluating cisplatin ototoxicity in children. J Clin Oncol 2010;28(10):1788-1795. [http://dx.doi.org/10.1200/JCO.2009.24.4228] 8. Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V. Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res 2007;226(1-2):157-167. [http://dx.doi.org/10.1016/j. heares.2006.09.015] 9. Yancey A, Harris MS, Egbelakin A, Gilbert J, Pisoni DB, Renbarger J. Risk factors for cisplatin-associated ototoxicity in paediatric oncology patients. Pediatr Blood Cancer 2012;59(1):144-148. [http://dx.doi.org/10.1002/pbc.24138] 10. Bokemeyer C, Berger CC, Haertmann JT, et al. Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer. Br J Cancer 1998;77(8):1355-1362. [http:// dx.doi.org/10.1038/bjc.1998.226] 11. Eiamprapai P, Yamamoto N, Hiraumi H, et al. Effect of cisplatin on distortion product otoacoustic emissions in Japanese patients. Laryngoscope 2012;122(6):1392-1396. [http://dx.doi. org/10.1002/lary.23336] 12. Campbell KC, Meech RP, Klemens JJ, et al. Prevention of noise- and drug-induced hearing loss with D-methionine. Hear Res 2007;226(1-2):92-103. [http://dx.doi.org/10.1016/j. heares.2006.11.012] 13. American Speech-Language-Hearing Association. Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. ASHA Practice Policy 1994;36:11-19. [http://dx.doi.org/10.1044/policy.GL1994-00003] 14. Piel U, Meyer D, Perlia CP, Wolfe VI. Effects of cisdiamminedichloroplatinum (NSC-1 19875) on hearing function in man. Cancer Chemother Rep 1974;58(6):871-875. 15. Stewart BW, Kleihues P. World Health Organization: International Agency for Research on Cancer. World Cancer Report. Lyon: IARC Press, 2003. 16. Andrade V, Khoza-Shangase K, Hajat F. Perceptions of oncologists at two state hospitals in Gauteng regarding the ototoxic effects of cancer chemotherapy: A pilot study. African Journal of Pharmacy and Pharmacology 2009;3(6):307-318. 17. Helson L, Okonkwo E, Anton L, Cvitkovic E. cis-Platinum ototoxicity. Clin Toxicol 1978;13(4):469-478. [http://dx.doi. org/10.3109/15563657808988252] 18. Low WK, Toh ST, Wee J, Fook-Chong SM, Wang DY. Sensorineural hearing loss after radiotherapy and chemoradiotherapy: A single, blinded, randomized study. J Clin Oncol 2006;24(12):1904-1909. [http://dx.doi.org/10.1200/JCO.2005.05.0096] 19. Rednam S, Scheurer ME, Adesina A, Lau CC, Okcu MF. Glutathione S-transferase P1 single nucleotide polymorphism predicts permanent ototoxicity in children with medulloblastoma. Pediatr Blood Cancer 2013;60(4):593-598. [http://dx.doi.org/10.1002/pbc.24366]

Accepted 8 October 2013.

RESEARCH

Angiotensin converting enzyme inhibitors v. angiotensin receptor blockers in the management of hypertension: A funder’s perspective J L Makkink,1,2 MB ChB; O B W Greeff,2 MB ChB, FCFP (SA), MPharmMed, FFPM (RCP) 1 2

S outh African Police Service Medical Scheme (POLMED), Pretoria, South Africa Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa

Corresponding author: J L Makkink (jacom@polmed.co.za) Background. Hypertension poses a huge financial risk to any funder/medical aid, including the risk-mitigating strategies provided by the managed care organisations that are required to manage patients with hypertension. The South African Hypertension Guideline states that the choice of therapy – an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) – should be based on cost and tolerability. Objective. To assess the costs of ACEIs v. ARBs in the management of hypertensive patients and the prevention of cardiovascular complications for a private medical aid scheme in South Africa. Method. A Phase IV observational, retrospective cohort study of over 480 000 beneficiaries between 2010 and 2011 was undertaken. Hypertensive patients were identified by their chronic medication authorisation and were categorised into three groups: ACEI, ARB and combined groups. A cost-benefit analysis was performed on the claims data, comparing the input costs in rand against the downstream costs using analysis of variance. Results. Data from 28 165 patients were included in the study. Based on the health economic analysis that was performed, there was no statistically significant difference in the input costs between the ACEI and the ARB groups. However, a statistically significant reduction in the downstream costs was observed in the ACEI group v. the ARB and combined groups (p<0.0001). Conclusion. It is more cost beneficial to treat chronic hypertensive patients with an ACEI than ARBs in preventing cardiovascular-related complications. It is recommended that managed care companies continue recommending ACEIs rather than ARBs in the treatment of hypertensive patients. S Afr Med J 2014;104(4):292-294. DOI:10.7196/SAMJ.7593

Hypertension poses a huge financial risk to any funder/ medical aid, including the risk-mitigating strategies provided by the managed care organisations that are required to manage patients with hypertension. According to the annual report of the South African Council for Medical Schemes for 2010 - 2011, which was published on 6 September 2011,[1] hypertension is the most prevalent chronic disease among medical aid members, 11.7% of whom have this condition. Considering that the medical aid industry has 8 315 718 beneficiaries,[2] 972 940 members will therefore require treatment for hypertension. In terms of the medical aid membership on which this research article is based, the membership is 483 379 and the hypertension prevalence is 28 875 beneficiaries.[3] The most up-to-date South African Hypertension Guideline[4] includes a consensus statement on the use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for the management of hypertension, stating that the choice of therapy for either an ACEI or an ARB should be based on cost and tolerability.

Objective

To assess the costs of ACEIs v. ARBs in the management of hypertensive patients and the prevention of cardiovascular complications for a private medical aid scheme in South Africa (SA).

Method

A Phase IV observational, retrospective (2010 and 2011), cohort study was undertaken involving over 480 000 beneficiaries of a restrictive, private medical aid in SA. Hypertensive patients were identified by their chronic medication authorisation. All claims

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data of hypertensive patients who were registered members of the participating medical scheme and received either an ACEI or an ARB in their hypertensive treatment regimen were included. Claims data for 2010 and 2011 were assessed. Hypertensive patients who claimed <90 days for their chronic medication were excluded from the study. All the ACEIs and ARBs that are available in SA, were identified via their unique National Pharmaceutical Product Index (NAPPI) codes as registered with the Medicines Control Council of SA. Hypertensive patients of interest were categorised into three groups: • ACEI group • ARB group • combined group (patients that received an ACEI or an ARB in their treatment regimens during the 2-year period under review). Costs associated with the payment of the chronic medication were used as the input costs in the ‘cost-to-benefit’ health economic analysis. The cardiovascular disorders/complications, for which hypertensive patients were treated during the 2-year period under review, were identified via The International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes. Costs associated with the treatment of the cardiovascular disorders/ complications during the 2-year period under review were used as the downstream costs in the ‘cost-to-benefit’ health economic analysis. The downstream costs were used as a proxy to compare the clinical efficacy of the two classes of drugs in preventing cardiovascular complications. A cost-benefit analysis was performed on the claims data, comparing the input costs in rand (ACEIs v. ARBs as chronic medication) against the downstream costs (treatment of the cardiovascular disorders/

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complications). Because there were many independent variables associated with single members that required analysis, an analysis of variance (ANOVA) model was used.

Table 1. Total and per patient input and downstream costs per group ACEI

ARB

Combined

Total, N

19 901

7 029

1 235

Male

11 742

3 654

655

Female

8 159

3 375

580

2010

16 256 963.95

7 944 473.21

2 705 300.80

2011

17 094 598.74

8 109 171.80

2 852 782.20

Total

33 351 562.69

16 053 645.01

5 558 083.00

Patients, n

Results

Data of 28 165 patients were included. Total input costs and downstream costs are reflected in Table 1 for the ACEI, ARB and combined groups. An ANOVA model was used to determine the statistical significance in the variances observed between the input costs v. the downstream costs in the three groups under review (Table 2). When comparing the least squares means (LSMs) of the input costs of the ACEI group v. the ARB group, there was not a statistically significant difference between these two groups (p=0.24). However, when comparing the LSMs of the input costs of the combined group v. the ACEI and ARB groups, a statistically significant difference was observed (p=0.01 and p=0.05, respectively) (Table 3). When comparing the LSMs of the downstream costs in the three groups under review with one another, a statistically significant difference was seen in all three instances (p<0.0001) (Fig. 1).

Input costs (ZAR)

Cost per patient, average 2010

816.89

1 130.24

2 190.53

2011

858.98

1 153.67

2 309.95

2010

119 635 140.87

53 534 678.73

26 123 522.28

2011

130 263 702.72

63 763 614.29

31 269 660.78

Total

249 898 843.59

117 298 293.02

57 393 183.06

Downstream costs (ZAR)

Cost per patient, average 2010

6 011.51

7 616.26

21 152.65

2011

6 545.59

9 071.51

25 319.56

ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ZAR = South African rand.

Table 2. ANOVA of downstream and input costs per group Cost (ZAR), LSM (±SE)

p-value

Downstream

6 278.55 (±133.19)

<0.0001

Input

837.94 (±133.19)

<0.0001

Costs per group

Discussion

ACEI

Based on our health economic analysis, there was not a statistically significant difference in the input costs between the ACEI and the ARB groups. However, a statistically significant reduction in the downstream costs was observed in the ACEI group v. the ARB and combined groups (p<0.0001). Patients in the combined group, that were treated with an ACEI and an ARB during the period under review, were least cost beneficial. A limitation of the study was that the groups were not stratified for baseline cardiovascular risk.

ARB Downstream

8 343.88 (±224.10)

<0.0001

Input

1 141.96 (±224.10)

<0.0001

Combined Downstream

23 236.11 (±534.64)

<0.0001

Input

2 250.24 (±534.64)

<0.0001

ANOVA = analysis of variance; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; LSM = least squares mean; ZAR = South African rand; SE = standard error.

Table 3. Comparison of LSMs by data/type on downstream and input costs between groups ACEI, p-value

ARB, p-value

Combined, p-value

Downstream

Input

Downstream

Input

Downstream

Input

Downstream

<0.0001

Input

<0.0001

0.2435

<0.0001

<0.0104

Downstream

<0.0001

Input

<0.0001

0.2435

<0.0001

0.0559

Downstream

<0.0001

Input

<0.0001

0.0104

<0.0001

0.0559

<0.0001

ACEI

ARB

Combined

LSMs = least squares means; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker.

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Fig. 1. ANOVA of cost least squares means (LSMs) v. data source (p<0.0001). (ZAR = South African rand; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker.)

Conclusion

Acknowledgement. We thank Dr M van der Linde for his statistical support.

This health economic analysis reveals that it is more cost beneficial to treat chronic hypertensive patients with an ACEI than with ARBs to prevent cardiovascular-related complications. It is recommended that in the drug utilisation review process, managed care companies continue with their effort in recommending ACEIs rather than ARBs in the treatment of their hypertension patients.

References

1. Council for Medical Schemes. Annual Report 2010 - 2011. Pretoria: CMS;85. http://www.medicalschemes. com/files/Annual%20Reports/CMS-AR-2011-WEB.pdf (accessed 19 February 2014). 2. Council for Medical Schemes. Annual Report 2010 - 2011. Pretoria: CMS;81. http://www.medicalschemes. com/files/Annual%20Reports/CMS-AR-2011-WEB.pdf (accessed 19 February 2014). 3. POLMED. Key Trends Report. January 2012;22. 4. Seedat YK, Rayner BL. South African Hypertension Guideline 2011. S Afr Med J 2012;102(1):57-84.

Accepted 18 November 2013.

Mammographic screening for breast cancer in a resource-restricted environment J P Apffelstaedt,1 Dr Med, MMed (Surg), FCS (SA), MBA; L Dalmayer,2 MB ChB; K Baatjes,1 MB ChB, MMed (Surgery), FCS (SA) Department of Surgery, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa Department of Radiation Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa

1 2

Corresponding author: J P Apffelstaedt (jpa@sun.ac.za) Background. Mammographic screening is carried out at public sector hospitals as part of clinical practice. Objective. We report the experience of such screening at Tygerberg Academic Hospital (TBAH), a tertiary referral hospital in the Western Cape Province, South Africa. Methods. All mammograms performed between 2003 and 2012 at TBAH were analysed regarding patient demographics, clinical data, indication and outcome according to the American College of Radiology Breast Imaging Reporting and Data System (BIRADS). Screening mammography was offered to patients >40 years of age and mammograms were read by experienced breast surgeons. Patients with BIRADS 3 and 4 lesions were recalled for short-term follow-up, further imaging or tissue acquisition. Patients with BIRADS 5 lesions were recalled for tissue acquisition. Further imaging, method of tissue acquisition, histology results and use of neo-adjuvant therapy were also recorded. Results. Of 16 105 mammograms, 3 774 (23.4%) were carried out for screening purposes. The median age of patients undergoing screening was 54 years. Of 407 women with mammograms that were reported as BIRADS 3 - 5 (10.8% of screening mammograms), 187 (46% of recalled women) went on to have further imaging only. Tissue was acquired in 175 patients (43% of recalled women), comprising a biopsy rate of 4.6% of the total series. The malignancy rate in cases in which tissue acquisition was done was 25%. Forty-three breast cancers were diagnosed (11.4/1 000 examinations). Of the cancers, nine (31%) were ductal carcinomas in situ. Of 20 invasive cancers, nine (45%) were <10 mm in size. Of the invasive cancers, 40% were node-positive. Conclusions. The cancer diagnosis rate indicates a high breast cancer load in an urbanised population. S Afr Med J 2014;104(4):294-296. DOI:10.7196/SAMJ.7246

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Breast cancer is a growing healthcare burden, especially in the developing world.[1,2] Breast cancer is the most common female cancer in South Africa (SA) and accounts for 20% of all cancers diagnosed in women in SA.[3] Breast cancer constitutes the largest cancerrelated disease burden in women in the Western Cape (WC) Province, SA.[4] Because limited resources make mammographic breast screening difficult to implement, population screening for breast cancer is not part of WC health policy at present, and will not be within the foreseeable future.[5] Despite this, numerous screening mammograms are undertaken at public sector facilities as part of clinical practice. We report the results of such screening mammograms at an academic teaching hospital in the WC over a period of 9 years.

Methods

All mammograms performed between 2003 and 2012 at Tygerberg Academic Hospital (TBAH), serving a mostly indigent population in Cape Town, were prospectively entered into MS Access. Data entered included basic patient demographic data such as age and gender, and clinical data such as use and duration of hormone replacement therapy, evidence of previous breast surgery on examination, indication and outcome. Screening mammography was offered to patients referred to the breast clinic who were ≥40 years of age and to younger patients with significant risk factors. Patients who had a palpable mass or personal history of breast cancer were excluded. If a diagnosis of malignancy was made, the tumour stage and detailed histopathological data were recorded, as well as treatment for the malignancy. Screening was classified as ‘prevalence’ if no prior mammography performed within the past 18 months was available for comparison, or ‘incidence’ if such imaging was available. Initially, all mammograms were performed by certified mammographers, using a Senographe Mammography System (GE Healthcare, UK); later, a Giotto 6000 mammography system

(Internazionale Medico Scientifica, Italy) was used. The film used was Mamoray HDR film (Agfa Corporation, USA). Films were developed on an Agfa Classic EOS developer. From 2009, computed radiography was employed and from March 2012, a full-field digital system (Siemens, Germany) was introduced. The views taken were standard craniocaudal and mediolateral oblique; additional views such as ‘Cleopatra’ views, spot compression and magnification views and ‘valley’ views were taken, as indicated. The outcomes of the mammography were classified according to the American College of Radiology Breast Imaging Reporting and Data System (BIRADS).[6] Patients with BIRADS 3 and 4 lesions were recalled for short-term follow-up, further imaging or tissue acquisition. Patients with BIRADS 5 lesions were recalled for tissue acquisition. Further imaging, method of tissue acquisition, histology results and use of neo-adjuvant therapy were also recorded. Patients who failed to present for further work-up, despite contact by mail, were deemed ‘defaulters’. Diagnosed cancers were staged according to the TNM clinical and pathological staging system.[7]

Results

A total of 16 105 mammograms were performed between January 2003 and May 2012, 3 774 (23.4%) for screening purposes. Of these, 48% were classified as ‘prevalence’ and 52% as ‘incidence’ screening. The median age of women undergoing screening mammography was 54 years; 32% of the women were 40 - 49 years of age. Of the screening mammograms, 3 367 (89.2%) were reported as BIRADS 1 and 2, 359 (9.5%) as BIRADS 3 and 4, and 48 (1.3%) as BIRADS 5. Of 407 recalled patients, who represented 10.8% of all women who had screening mammograms, 187 (46%) went on to have further imaging that was reported as benign. Tissue was acquired in 175 patients (43%), constituting a biopsy rate of 4.6% of the total series. Thirty-four

Table 1. Comparison of the current series with global benchmark programmes Criterion

USA,[12] %

NHS (UK),[13] %

Breast Screen (Aus),[13,14] % Current series, %

Recall rate*

9.8

7.7 (prevalence) 2.8 (incidence)

4 - 12

10.8

Biopsy rate*

1.72

4.6

Malignancy rate of biopsies*

33.8

45.5

4.7

11.4

Cancers per age group (years)* All 40 - 49

7.8 (>45 years)

2.4

50 - 69

12.1 (prevalence) 5.7 (incidence)

21.6

20.6

20.2

In situ cancers (of total) Invasive cancers, size (mm) Of total

78.4

79.4

79.8

<10*

37.2

11 - 20*

31.6†

50.8 (<15 mm)

47 (prevalence) 20 63 (incidence ) (<15 mm)

>20*

21.2†

Node-negative*

79.8

Node-positive*

20.2

USA = United States of America; NHS = National Health Service; UK = United Kingdom; Aus = Australia. *Data combine incidence and prevalence rounds. † In 8.5% of invasive cancers, the size was unknown.

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recalled patients did not present for further work-up, in 4 patients workup was incomplete, 2 patients were found to have lymphoma, and 5 patients died before a definitive diagnosis could be established. The biopsy rate in cases in which tissues acquisition was done for the whole series was 4.6%; the malignancy rate of tissue acquisition was 25%. Forty-three breast cancers were diagnosed, giving a cancer diagnosis rate of 11.4/1 000 examinations. Of the cancers, nine (31%) were ductal carcinomas in situ. Of 20 invasive cancers, 45% (in nine patients) were <10 mm in size and 40% were node-positive. Fourteen patients were excluded from further analysis: 7 failed to return for cancer treatment, 1 had metastatic disease, 2 received neo-adjuvant systemic therapy, and in 4 the work-up was incomplete at the close of the database.

Discussion

A significant number of mammographic examinations in the public sector are for screening purposes and reflect adherence to good clinical practice. If surveillance mammography after a cancer diagnosis is included, about three-quarters of all mammographies in similar centres to TBAH will be done on asymptomatic women. This calls into question the frequently made distinction between symptomatic and screening mammography.[8] It is our contention that, as soon as a mammography unit is set up, the majority of examinations will be of asymptomatic women. This has important implications for resource allocation in that the required skills and technology must then be in place to address non-palpable lesions. The screening effort we report here is best described as ‘opportunistic’ screening.[9] In contrast to organised screening, in opportunistic screening there are no generally agreed performance standards and women are not invited, but present of their own volition for what is sometimes unrelated pathology.[9] Reasons for requesting screening may include a family history of breast cancer, which often turns out to be non-significant, mastalgia, referral for a mass in the breast that cannot be verified at physical examination, or simple general concern about breast cancer risk. As such, it is possible to speculate that the breast cancer diagnosis rate would be higher in such a population than in an organised screening programme. A hallmark of opportunistic screening programmes is their wide variation in quality parameters.[9,10] Despite this, and with the caveat that small numbers do not permit definitive conclusions, the results described here are remarkably similar to those of major international organised screening programmes (Table 1), with the exception of the rate of node-negative invasive cancers. This latter warrants further exploration in a larger programme, especially as the invasive cancers were remarkably similar in size to those in the other programmes quoted. However, the age composition in our series was much younger, implying diagnosis of more aggressive cancers. Owing to small numbers, no attempt was made to differentiate between ‘prevalence’ and ‘incidence’ screening; this is commonly not done in reports of opportunistic screening efforts. Recently, much discussion has centred around ‘harms’ generated by mammographic screening, inter alia psychological distress caused by unnecessary recalls, physical harms caused by unnecessary biopsies and health system harms of resources diverted to screening. These potential ‘harms’ have led to the controversially restrictive recommendations of the US Preventive Services Task Force for mammographic screening. [11] In this series, harms would have fallen within the parameters set by

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benchmark programmes and are indicative of the rigorous attention to quality at all steps of the diagnostic process. A much larger proportion (32%) of screened women in this series than in the benchmark organised screening programmes were in the 40 49-year age group; in this age group, the cancer diagnosis rate is expected to be much lower than in the 50 - 69-year age group. Only 4.3% of the screened population in the UK National Health Service (NHS) screening programme and 14.3% in Breast Screen Australia were in this younger age group; in the US programme, where an ‘opportunistic’ approach was also followed, the proportion was 34.1%. Despite this, the cancer diagnosis rate in our TBAH series is as high as in known high-incidence populations. A reason for this may be the selection of patients from a largely symptomatic service; however, it fits with data from another centre in the same geographical area engaging mostly in screening examinations.[15] The high diagnosis rate calls into question the often quoted figure of a 1/28 lifetime risk of breast cancer in our population.[3] The TBAH screening figures are more in line with those of populations where the lifetime risk is ~1/8 - 1/10 women. A further noteworthy fact is that this TBAH series was based exclusively on mammography interpretation by surgeons with a special interest in breast health. Despite this, the results compare well with international benchmarks and signal that the desired early diagnosis of breast cancer was achieved. The well-documented shortage of radiologists, specifically breast radiologists,[15] must not prevent the urgent establishment of breast centres to cater for the rapidly rising disease burden of breast cancer in our country while there are trained and experienced surgeons, with a special interest in breast health, available to interpret breast imaging. References 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893-2917. [http://dx.doi.org/10.1002/ijc.25516] 2. Bray F, McCarron P, Parkin DM. The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res 2004;6(6):229-239. [http://dx.doi.org/10.1186/bcr932] 3. National Institute for Occupational Health. Incidence of Histologically Diagnosed Cancer in South Africa, 2004. Johannesburg: National Health Laboratory Service; 2012. http://www.nioh. ac.za/?page=cancer_statistics&id=163 (accessed 6 July 2013). 4. Bradshaw D, Nannan N, Laubscher R, et al. South African National Burden of Disease Study 2000: Estimates of Provincial Mortality. Tygerberg: South African Medical Research Council, 2006. http:// www.mrc.ac.za//bod/estimate.pdf (accessed 6 July 2013). 5. Bernhardt G, Moodley J, Naledi T, Arends E. Breast Cancer Situational Analysis. Cape Town: Western Cape Department of Health, 2009. 6. American College of Radiology. ACR Breast Imaging Reporting and Data System. 4th ed. Reston, VA: ACR, 2003. 7. American Joint Committee on Cancer. Breast Cancer Staging. 7th ed. Chicago: AJCC, 2009. http:// www.cancerstaging.org/staging/posters/breast12x15.pdf (accessed 6 July 2013). 8. Mouton JP, Apffelstaedt J, Baatjes K. Surgical mammography reporting in a limited resource environment. World J Surg 2010;34(11):2530-2536. [http://dx.doi.org/10.1007/s00268-010-0530-4] 9. Bulliard JL, Ducros C, Jemelin C, Arzel B, Fioretta G, Levi F. Effectiveness of organised versus opportunistic mammography screening. Ann Oncol 2009;20(7):1199-1202. [http://dx.doi. org/10.1093/annonc/mdn770] 10. Smith-Bindman R, Chu PW, Miglioretti DL, et al. Comparison of screening mammography in the United States and the United Kingdom. JAMA 2003;290(16):2129-2137. [http://dx.doi.org/10.1001/ jama.290.16.2129] 11. US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009;151(10):716-726. [http://dx.doi.org/10.7326/00034819-151-10-200911170-00008] 12. Rosenberg RD, Yankaskas BC, Abraham LA, et al. Performance benchmarks for screening mammography. Radiology 2006;241(1):55-66. [http://dx.doi.org/10.1148/radiol.2411051504] 13. The NHS Information Centre, Screening and Immunisations. Breast Screening Programme, England 2010-11. London: NHS IC, 2012. http://www.cancerscreening.nhs.uk/breastscreen/breast-statisticsbulletin-2010-11.pdf (accessed 6 July 2013). 14. Australian Institute of Health and Welfare. Breast Screen Australia Monitoring Report 2009-2010. Cancer series no. 72. Canberra: Australian Institute of Health and Welfare, 2012. http://www.aihw.gov. au/publication-detail/?id=10737423104 (accessed 6 July 2013). 15. Apffelstaedt JP, Steenkamp V, Baatjes KJ. Surgeon-read screening mammography: An analysis of 11,948 examinations. Ann Surg Oncol 2010;17(Suppl 3):249-254. [http://dx.doi.org/10.1245/s10434-010-1241-7] 16. Rabinowitz DA, Pretorius ES. Postgraduate radiology training in sub-Saharan Africa: A review of current educational resources. Acad Radiol 2005;12(2):224-231. [http://dx.doi.org/10.1016/j. acra.2004.11.014]

Accepted 29 November 2013.

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Results of a pilot programme of mammographic breast cancer screening in the Western Cape J P Apffelstaedt,1 Dr Med, MMed (Surg), FCS (SA), MBA; R Hattingh,2 MB ChB, MMed (Rad Diag); K Baatjes,1 MB ChB, MMed (Surgery), FCS (SA); N Wessels,1 MB ChB 1 2

epartment of Surgery, Faculty of Medicine and Health Sciences, Tygerberg Hospital and Stellenbosch University, Tygerberg, South Africa D Department of Radiology, Tygerberg Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa

Corresponding author: J P Apffelstaedt (jpa@sun.ac.za) Background. Mammographic screening programmes are now established in developing countries. We present an analysis of the first screening programme in sub-Saharan Africa. Methods. Women aged ≥40 years were identified at three primary healthcare centres in the Western Cape Province, South Africa, and after giving informed consent underwent mammography at a mobile unit. After a single reading, patients with American College of Radiology Breast Imaging Reporting and Data System (BIRADS) 3 - 5 lesions were referred to a tertiary centre for further management. Results. Between 1 February 2011 and 31 August 2012, 2 712 screening mammograms were performed. A total of 261 screening mammograms were reported as BIRADS 3 - 5 (recall rate 9.6%). Upon review of the 250 available screening mammograms, 58 (23%) were rated benign or no abnormalities (BIRADS 1 and 2) and no further action was taken. In 32 women, tissue was acquired (biopsy rate for the series 1.2%); 10 cancers were diagnosed (biopsy malignancy rate 31%). For the entire series of 2 712 screening mammograms, the cancer diagnosis rate was 3.7/1 000 examinations. Of 10 cancers diagnosed at screening, 5 were TNM clinical stage 0, 2 stage I and 3 stage II. Conclusions. The low cancer detection rate achieved, and the technical and multiple administrative problems experienced do not justify installation of a screening programme using the model utilised in this series. S Afr Med J 2014;104(4):297-298. DOI:10.7196/SAMJ.7242

Mammographic breast cancer screening has reduced the mortality from breast cancer in the screened population by up to 65%.[1] Most First-World countries have therefore introduced mammographic screening programmes. Plans are afoot to establish mammographic screening in ‘resource-enhanced’ settings in the developing world, including in northern African countries such as Tunisia[2] and Egypt.[3,4] We present an analysis of the first mammographic screening pilot programme in sub-Saharan Africa.

Methods

Patients of screening age (≥40 years) were identified at three primary healthcare (PHC) centres in the Cape metropolitan area. The women were then informed about the benefits and risks of screening and underwent mammography. Mammography was performed by certified mammographers in a mobile breastscreening unit run by a corporate social responsibility organisation (Pink Drive, Cause Marketing Fundraisers Pty Ltd, Johannesburg, South Africa). The unit was equipped with a Giotto mammography machine (Internazionale Medico Scientifica, Italy); the images were processed in a Konica computed radiography processor (Konica Corporation, Japan) and printed onto discs. Discs were then batchread at a private radiology practice by one of two radiologists and classified according to the American College of Radiology Breast Imaging Reporting and Data System (BIRADS).[5] Those women whose mammograms were reported as BIRADS 3 - 5 were referred to a tertiary centre for further work-up where the mammograms were entered into a picture archiving and communication system and reviewed by a team of experienced breast surgeons and radiologists, and a management plan was established. For patients

297

with confirmed malignancy, the following data were recorded: age of the patient; stage of the cancer according to the TNM staging system;[6] type of cancer; and further management. Cancers were regarded as symptomatic if the patient had sought the attention of the PHC centre for a mass in the breast, and true screening if the patient had visited the PHC centre for unrelated reasons or for breast cancer screening specifically.

Results

Between 1 February 2011 and 31 August 2012, 2 732 mammograms were performed. Following technical failure of the mammography machine, no mammography was performed in April and May 2011. Of the total, eight patients were aged <40 years and excluded from the analysis. With the remaining 2 724 mammograms, 12 were done in women presenting for a mass in the breast, leaving a total of 2 712 screening mammograms for analysis. Of the mammograms referred for further work-up to the tertiary centre, 51 done on patients at the beginning of the series were regarded as of such poor quality that they were not suitable for interpretation, and the patients had repeat mammography performed. Eleven mammograms were not made available for review and 14 patients could not be contacted to return for work-up; these women were not seen at the tertiary centre for further evaluation. Upon review of the 250 available screening mammograms, 58 (23%) were rated ‘benign’ or ‘no abnormalities’ (BIRADS 1 and 2) and no further action was taken. For the entire series of screening mammograms (N=2 712) the cancer diagnosis rate was 3.7/1 000 examinations. Of 10 cancers diagnosed at screening, 5 were TNM clinical stage 0, 2 stage I and 3 stage II. The number of mammograms and the biopsy outcome is reflected in Table 1.

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Table 1. Mammograms and biopsy outcome Mammograms Total, N

2 712

Age group (years), n (%) 40 - 49

1 062 (39)

50 - 69

1 509 (55)

≥70

141 (5.2)

Recall, n (% of all mammograms)

261 (9.6)

Biopsies, n (% of all mammograms)

32 (1.2)

Cancers diagnosed, n (% of biopsies)

10 (31)

Discussion

Two North African mammographic screening programmes from Tunisia illustrate the difficulties of mammographic screening in a developing country: a low participation rate; and performance indicators falling short of the established screening programmes in Europe.[2,7] The methods employed, however, seem to have been sound; as illustrated, for example, by the employment of double reading and collection of data for key performance indicators. We are not aware of any report on the Egyptian screening effort in the accessible scientific literature. The mammographic screening programme described in this paper is best classified as ‘opportunistic’ or ‘community’ screening as it does not fulfil a number of the essential criteria for ‘organised’ screening as described by the World Health Organization.[8] Multiple areas of concern arise out of the large number of mammograms deemed unsuitable for screening purposes: the technology used by the screening effort was not appropriate for mass screening; and the transfer of images between different systems may have compromised image quality. (An improvement in the image quality was noted after radiographers from the tertiary centre visited the mobile unit and corrected radiographic technique, but quality still did not reach standards expected of modern digital systems.) As the authors saw only mammograms referred to the tertiary centre for work-up, questions remain concerning the quality of the 90.4% of mammograms reported as BIRADS 1 and 2 and consequently not seen at the tertiary centre. Several factors cast doubt on the quality of mammography reading: the lack of image quality was not recognised and corrected by the primary readers of the screening mammograms; a large number referred patients’ mammograms were re-reported as BIRADS 2 (benign finding) when read by the experienced team at the referral hospital; and the cancer diagnosis rate was far lower than achieved in a tertiary centre in a similar

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population and reported by a private clinic in the same geographical area. While inter-observer variation is a well-documented reality of mammographic screening,[9] the large variation in this series, especially with respect to clinical management implications, is concerning. A reason may be the lack of a second reading, which is an essential part of mammographic screening programmes. A hallmark of a successful screening programme is the diagnosis of early cancers, as evidenced by a high proportion of in-situ cancers, a high proportion of node-negative cancers and a high proportion of infiltrating cancers <1 cm in diameter. Based on the experience of the two other series reported from the same area,[10,11] we would have expected about 20 - 25 breast cancers to be diagnosed in the 2 712 asymptomatic women screened in this series. With the low number of cancers diagnosed in this screening programme, any comments on this central aspect of mammographic screening are pure speculation. A final critical concern is that 11 mammograms (4.4% of the screening mammograms read as BIRADS 3 - 5) were not received by the tertiary centre. This indicates serious deficiencies in the administration of the programme and constitutes a major potential medico-legal liability. Breast cancer screening, as performed in this series, cannot be supported in a resource-limited environment such as our own and elsewhere in sub-Saharan Africa.

References 1. Van Schoor G, Moss SM, Otten JD, et al. Increasingly strong reduction in breast cancer mortality due to screening. Br J Cancer 2011;104(6):910-914. [http://dx.doi.org/10.1038/bjc.2011.44] 2. Bouchlaka A, Ben AM, Ben AR, et al. [Results and evaluation of 3 years of a large scale mammography program in the Ariana area of Tunisia]. Tunis Med 2009;87(7):438-442. 3. Batsis C. Two-stage breast cancer screening in the developing world. World J Surg 2011;35(3):698-699. [http://dx.doi.org/10.1007/s00268-010-0808-6] 4. Abdalla A. Breast cancer in Egypt: The challenges include education and detection. The Washington Times: Communities. 11 October 2011. http://communities.washingtontimes.com/neighborhood/ egypt-pyramids-and-revolution/2011/oct/11/breast-cancer-egypt-challenges-education-treatment/ (accessed 18 February 2014). 5. American College of Radiology. ACR Breast Imaging Reporting and Data System. 4th ed. Reston, VA: ACR, 2003. 6. American Cancer Society, American Joint Committee on Cancer. Breast Cancer Staging. 7th ed. https://cancerstaging.org/references-tools/quickreferences/Cancer%20Staging%20Poster%20 Picture%20Library/BreastPoster1.jpg (accessed 18 February 2014). 7. Frikha M, Yaiche O, Elloumi F, et al. [Results of a pilot study for breast cancer screening by mammography in Sfax region, Tunisia]. J Gynecol Obstet Biol Reprod (Paris) 2013;42(3):252-261. [http://dx.doi.org/10.1016/j.jgyn.2013.01.007] 8. Strong K, Wald N, Miller A, Alwan A. Current concepts in screening for noncommunicable disease: World Health Organization Consultation Group Report on methodology of noncommunicable disease screening. J Med Screen 2005;12(1):12-19. [http://dx.doi.org/10.1258/0969141053279086] 9. Antonio AL, Crespi CM. Predictors of interobserver agreement in breast imaging using the Breast Imaging Reporting and Data System. Breast Cancer Res Treat 2010;120(3):539-546. [http://dx.doi. org/10.1007/s10549-010-0770-x] 10. Apffelstaedt JP, Steenkamp V, Baatjes KJ. Surgeon-read screening mammography: An analysis of 11,948 examinations. Ann Surg Oncol 2010;17(Suppl 3):249-254. [http://dx.doi.org/10.1245/s10434010-1241-7] 11. Apffelstaedt JP, Dalmayer L, Baatjes K. Mammographic screening for breast cancer in a resourcerestricted environment. S Afr Med J 2014;104(4):294-296. [http://dx.doi.org/10.7196/SAMJ.7246

Accepted 9 December 2013.

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Community v. non-community assault among adults in Khayelitsha, Western Cape, South Africa: A case count and comparison of injury severity S Forgus,1 MB ChB; W Delva,2-4 MD, PhD; C Hauptfleisch,1 S Govender,1 MB ChB, MFamMed; J Blitz,1 MB ChB, MFamMed ivision of Family Medicine and Primary Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa D DST/NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, South Africa 3 International Centre for Reproductive Health, Ghent University, Ghent, Belgium 4 Center for Statistics, Hasselt University, Diepenbeek, Belgium 1 2

Corresponding author: S Forgus (sforgus@gmail.com) Background. Community assault (CA) or vigilantism is widespread in the township of Khayelitsha, Cape Town, South Africa (SA). Anecdotal evidence suggests that victims of CA are worse off than other assault cases. However, scientific data on the rate and severity of CA cases are lacking for SA. Objectives. To contribute to CA prevention and management strategies by estimating the rate of CA among adults in Khayelitsha and comparing the injury severity and survival probability between cases of CA and other assault (non-CA) cases. Methods. We studied four healthcare centres in Khayelitsha during July - December 2012. A consecutive case series was conducted to capture all CA cases during this period. A retrospective folder review was performed on all cases of CA and on a control group of non-CA cases to compare injury severity and estimate survival probability. Results. A total of 148 adult cases of CA occurred (case rate 1.1/1 000 person-years) over the study period. The Injury Severity Scores (ISSs) in the CA group were significantly higher than in the non-CA group (p<0.001), with a median (interquartile range) ISS of 3 (2 - 6) in CA cases v. 1 (1 - 2) in non-CA cases. Comparison between the CA v. non-CA groups showed that a Glasgow Coma Scale <15 (20.1% v. 5.4%, respectively), referral to the tertiary hospital (33.8% v. 22.6%, respectively), and crush syndrome (25.7% v. 0.0%, respectively) were all more common in CA cases. Survival probabilities were similar in both groups (CA v. non-CA 99.2% v. 99.3%, respectively). Conclusion. The rate of CA among adults in Khayelitsha is high, and the severity of injuries sustained by CA victims is substantially higher than in other assault cases. S Afr Med J 2014;104(4):299-301. DOI:10.7196/SAMJ.7615

Rapid and uncontrolled urbanisation in the black population of South Africa (SA) in the mid-1990s was associated with deteriorating conditions in urban and peri-urban slums and increasing levels of violence.[1] Although crime rates have been decreasing steadily since then, SA still has among the highest burdens of interpersonal violence injury in the world.[2] Since many of the poorer, black, rural or urban informal settlements in SA are poorly designed without proper roads, streetlights or maintained pathways, state police are often loathe to or afraid to patrol such areas.[3] The legacy of apartheid has also left a deep mistrust of the police, as public-order policing under this regime was often associated with the use of force. [4] As a result, communities have sought out alternative means of establishing law and order and implementing justice by taking the law into their own hands and meting out punishment using violence. This phenomenon, referred to globally as vigilantism, is not unique to developing countries.[5] In SA, the terms community assault (CA), community justice, people’s courts and kangaroo courts are used.[6] These appear to have their origins in traditional African principles of restorative justice (lekgotla).[7] In this paper, the term CA will be used, as this is the name most often used in emergency units in SA. Media reports seem to imply that this form of community-initiated policing is rife in the townships of SA.[8] CA has often been observed

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to involve the use of sjamboks – robust whips traditionally made from hippopotamus or rhinoceros hide.[9] The blunt forces produced by sjamboks inflict extensive soft-tissue trauma and crush syndrome. [10] Anecdotal evidence suggests that victims of CA are more severely injured than their non-CA counterparts. Owing to the lack of any formal evaluation of the frequency and severity of CAs, the burden of this phenomenon on the SA healthcare system is unknown. To this end, we conducted a consecutive case series of CA and non-CA cases at four state healthcare facilities in Khayelitsha, a partially informal township in Cape Town, Western Cape, to estimate the rate of cases and their severity.

Methods

Study sites and study population

Study sites comprised all state healthcare facilities in Khayelitsha with emergency care (three provincial government clinics and one district hospital). The study population consisted of adult victims of CA and a comparator group. The victims of CA were either self-identified or identified as such by their escorts (family members, police officers or ambulance personnel). The comparator group were victims of non-CAs, defined as any other victim of assault where the patients neither identified themselves nor were identified by any other person as being victims of CA.

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Emergency unit registries were used to identify cases and data were collected retrospectively by folder review for both study groups. Based on informed guesses of the incidence of CA and non-CA, it was decided that data for the CA group would be collected over a period of 6 months from 1 July to 31 December 2012, while data for the non-CA group would be collected over a period of 8 days from 1 to 8 July 2012.

years[14] and the period over which the cases were observed. To compare the severity of injuries, the frequencies and percentages of the binary severity indicators were tabulated and visualised, and relative risk (RR) with surrounding 95% confidence intervals (CIs) and associated p-values were computed. Further, the median and interquartile range (IQR) of the ISS and the average survival probability were calculated for both groups. Formal comparison of the distribution of the ISS was done using a Mann-Whitney U test, while the average survival probabilities were compared using a Student’s t-test. All statistical analyses were performed using R.[15]

Variables

Results

Data collection

A number of binary indicators were used to assess injury severity, including: a Glasgow Coma Scale (GCS) <15, presence of crush syndrome, whether or not patients required intubation, and the necessity for referral to a higher level of care. Crush syndrome was defined as rhabdomyolysis (evidence of skeletal muscle injury) with a documented elevated creatine kinase level >3 times the upper limit of normal (>1 000 U/l).[11] Referral occurred either from the clinics to the district hospital for admission or imaging (X-rays after hours) or from district to tertiary level for advanced imaging, specialist opinion, surgery or intensive care if intubated and ventilated. Each case was also given an Injury Severity Score (ISS). The ISS, though not commonly used in SA, is widely used internationally and has become an integral part of all trauma registry-based severity assessment tools. The ISS is based on an anatomical scoring system (the Abbreviated Injury Score (AIS) 2005), which codes the body into nine different body regions and assigns each injury 1/6 severity scores (AIS scores).[12] The ISS (ranging from 1 to 75) is then calculated by taking the sum of the squares of the highest AIS scores in each of the three most severely affected body regions. Lastly, the probability of survival was calculated using the Trauma Audit and Research Network Outcome Prediction Model based on the ISS, age, gender and GCS of the patient and whether or not the patient was intubated.[13]

Data management and statistical analysis

Data were entered into EpiInfo 7 by a research assistant and systematically checked by the principal investigator. To estimate the rate of CA and non-CA, the number of cases was divided by the product of the estimated adult population in Khayelitsha aged ≥18

In the first 8 days of July 2012, 115 cases of non-CA were recorded, and over the entire second half of 2012, data from a total of 148 CA cases were extracted. The age of CA cases ranged from 18 to 61 years (median 24; IQR 21 - 30). In the non-CA group, ages ranged from 18 to 57 years (median 25.5; IQR 22 - 33.5). A minority of all assault cases were female: 27/115 (23.5%) in the non-CA

group and 2/148 (1.4%) in the CA group (p<0.001, Fisher’s exact test).

Rate of assault cases

Based on an estimate population of 275 300 adults in Khayelitsha of ≥18 years, the rate of adult cases of CA that received healthcare in Khayelitsha was 1.1/1 000 person-years. For non-CA, the estimated rate was 19/1 000 person-years.

Injury severity indicators

All binary injury severity indicators were more prevalent among CA cases compared with their non-CA counterparts (Table 1). The majority of cases in both groups had a GCS of 15. However, in the CA group, 20.1% (29/144) had a GCS <15, while this was true for only 5.4% (6/111) of the non-CA group (RR 3.73; 95% CI 1.60 - 8.66; p<0.001). In the CA group, 25.7% (38/148) had crush syndrome while in the non-CA group, nobody had crush syndrome. One-third of cases (50/148) in the CA group were referred for further investigations and management, while 22.6% of cases (26/115) in the non-CA

Table 1. Comparison of binary injury severity indicators in CA and non-CA cases Assault, % CA (N=148)

Non-CA (N=115)

95% CI

p-value

GCS <15

20.1

5.4

3.73

1.60 - 8.66

<0.001

Crush syndrome

25.7

0.0

Referral

33.7

22.6

1.49

1.00 - 2.24

0.055

Intubation

4.7

3.5

1.36

0.41 - 4.53

0.76

CA = community assault; GCS = Glasgow Coma Scale; RR = relative risk; CI = confidence interval; NA = not applicable.

ISS

This study received ethical approval from the Stellenbosch University Health Research Ethics Committee (ref. N11/07/212).

0 Community assault

Non-community assault

Fig. 1. Injury Severity Scores (ISSs) in community and non-community assault cases.

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group were referred (RR 1.49; 95% CI 1.00 - 2.24; p=0.055). In the CA group, 4.7% (7/148) of cases were intubated v. 3.5% (4/115) in the non-CA group (RR 1.36; 95% CI 0.41 - 4.53; p=0.76).

ISS and survival probability

The ISS ranged from 1 to 19 in the CA group and from 1 to 10 in the non-CA group with a median (IQR) ISS of 3 (2 - 5) v. 1 (1 - 2), respectively (Fig. 1). This difference in the ISS distribution between the groups was highly significant (p<0.001, Mann-Whitney U test). The average survival probabilities were very similar in both groups (99.2% in the CA group v. 99.3% in non-CA group; p=0.66, Student’s t-test).

Discussion

A significantly higher proportion of CA patients had a GCS <15, developed crush syndrome and were referred (borderline significant), while there was no significant difference between the CA and non-CA groups in the proportion of patients that were intubated. Significantly higher ISSs were observed in the CA group than in the non-CA group, but survival probabilities were similar between the two groups. This study had a few limitations. Most importantly, the severity of at least some of the referred cases was underestimated. The AIS coding rules and guidelines require that injuries be substantiated by some form of diagnostic or radiographic procedure, surgery or autopsy in order to be assigned an AIS code.[12] This resulted in conservative coding of the injuries of patients referred to another facility for these procedures, as the researchers did not have access to clinical data after referral. As a result, a lower ISS was calculated for these cases, which in turn also influenced the survival probability estimates. Furthermore, nine cases in the CA group had sustained head injuries severe enough to render them unconscious or result in a GCS sufficiently low enough that they were unable to identify themselves or provide a date of birth. Consequently, these cases were excluded from the study, based on the inability to classify these patients as being over the age of 18 years. Victims of CA often hide for hours after the assault and lack the community support necessary to seek medical attention.[9] As a result, this study did not include those cases of CA who died prior to seeking medical attention and those who did not seek medical attention at all. Despite these limitations, we believe that our study is an important contribution to the research on violence-induced injuries in SA. To our knowledge, our study is the first ever to provide objective estimates of the incidence and severity of CA cases. While the Cape Town Trauma Registry Pilot study and the National Injury Mortality Surveillance System offer insight into the magnitude and characteristics of violence with regard to homicide, violence against women and children, traffic-related and other unintentional injuries,[16] they do not allow for the sub-categorisation of CAs as a form of interpersonal violence in SA. Vigilantism is a complex phenomenon for which there is no quickfix solution. Emergency medical care only addresses the symptoms of this social disease, and not the root causes. This does not mean, however, that healthcare providers do not have a crucial, pro-active role to play in the development and implementation of strategies to improve prevention and management of CA. We argue that CA is first and foremost a primary and district level healthcare issue, for two reasons. Firstly, just as for other victims of trauma in informal settlements, victims of CA present to their local clinic or district hospital. Secondly, the community-orientated approach of primary care embraces community-based strategies for problem solving. Intersectoral collaborations between family physicians, community elders, community forums, the police and policymakers are required to

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develop and implement various solutions. Strategies include promoting community cohesion and equity, and improving community-police relations.[4] The former strategy can reduce the threshold for everyday violent behaviour.[2] Healthy community-police relations are essential to reach a balance where the law is protected, while simultaneously allowing the community to organise and protect themselves. This will mean disbanding those vigilante groups who violate human rights while allowing the police to supervise activities that operate within the law.[4] This allows a niche for lekgotla to coexist with the current criminal justice system.[1] Further research is required to assess the problem of CAs at other facilities and over longer periods of time. This will provide local data to inform resource distribution within the district healthcare system and to focus prevention efforts on CA hotspots. Social science research may help to improve our understanding of the psychology and sociology behind CAs and to develop evidence-led prevention strategies, the feasibility and effectiveness of which would also require study.

Conclusion

Through systematic, multi-site recording of CA cases, we obtained objective measures of the rate and injury severity of CA cases in a large peri-urban area near Cape Town. Our findings beg for multisectoral action to curb the medical and social consequences of violent crime in SA. Acknowledgements. We thank the clerical staff at Khayelitsha District Hospital (KDH), Site B and Nolungile and Michael Mapongwana clinics in Khayelitsha. In particular, we thank Cwengisa Magayana for her assistance in obtaining access to the folders and electronic folder system at KDH. We are indebted to the Rural Medical Education Partnership Initiative, Stellenbosch University, for their support from the US President’s Emergency Plan for AIDS Relief through the Health Resources and Services Administration under the terms of T84HA21652. References 1. Gilbert L. Urban violence and health – South Africa 1995. Soc Sci Med 1996;43(5):873-886. [http:// dx.doi.org/10.1016/0277-9536(96)00131-1] 2. Norman R, Matzopoulos R, Groenewald P, Bradshaw D. The high burden of injuries in South Africa. Bull World Health Organ 2007;85(9):695-702. [http://dx.doi.org/10.2471/BLT.06.037184] 3. Singh D. Resorting to community justice when state policing fails: South Africa. Acta Criminologica 2005;18(3):43-50. 4. Ward C, Artz L, Berg J, et al. Violence, violence prevention, and safety: A research agenda for South Africa. S Afr Med J 2012;102(4):215-218. 5. Huggins M. Vigilantism and the State in Modern Latin America: Essays on Extralegal Violence. New York: Praeger, 1991. 6. Masiloane DT. Proactive policing for the rich and reactive policing for the poor: Hypocrisy in policing in a stratified society. S Afr J Crim Just 2007;20(3):328-340. 7. Monaghan R. Community-based justice in Northern Ireland and South Africa. International Criminal Justice Review 2008;18(1):83-105. [http://dx.doi.org/10.1177/1057567708316639] 8. Brinley Bruton F. ‘Out of control’: Vigilante justice grips impoverished South African slum. NBC News, 30 June 2013. http://worldnews.nbcnews.com/_news/2013/06/30/19073793-out-of-control-vigilantejustice-grips-impoverished-south-african-slum?lite (accessed 2 September 2013). 9. Proctor M, Carter N, Barker P. Community assault – the cost of rough justice. S Afr Med J 2009;99(3):160-161. 10. Erek E, Sever M, Serdengeçti K, et al. An overview of morbidity and mortality in patients with acute renal failure due to crush syndrome: The Marmara earthquake experience. Nephrol Dial Transplant 2002;17(1):33-40. [http://dx.doi.org/10.1093/ndt/17.1.33] 11. Rosedale K, Wood D. Traumatic rhabdomyolysis (crush syndrome) in the rural setting. S Afr Med J 2012;102(1):37-39. 12. Gennarelli TA, Wodzin E. AIS 2005: A contemporary injury scale. Injury 2006;37(12):1083-1091. [http://dx.doi.org/10.1016/j.injury.2006.07.009] 13. De Jongh M, Verhofstad M, Leenen L. Accuracy of different survival prediction models in a trauma population. Br J Surg 2010;97(12):1805-1813. [http://dx.doi.org/10.1002/bjs.7216] 14. Statistics South Africa. Census 2011. Pretoria: Stats SA, 2012. https://www.statssa.gov.za/census2011/ default.asp (accessed 2 September 2013). 15. R Development Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing, 2011. http://www.R-project.org/ (accessed 2 September 2013). 16. Schuurman N, Cinnamon J, Matzopoulos R, Fawcett V, Nicol A, Hameed M. Collecting injury surveillance data in low- and middle-income countries: The Cape Town Trauma Registry pilot. Global Public Health 2011;6(8):874-889. [http://dx.doi.org/10.1080/17441692.2010.516268]

Accepted 12 November 2013.

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Self-induction of abortion among women accessing secondtrimester abortion services in the public sector, Western Cape Province, South Africa: An exploratory study D Constant,1 MPH, MSc (Anat); D Grossman,2 MD; N Lince,3 MPH, MIA; J Harries,1 PhD, MPH Women’s Health Research Unit, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa Ibis Reproductive Health, Oakland, CA, and Bixby Center for Global Reproductive Health and San Francisco General Hospital, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA 3 Ibis Reproductive Health, Johannesburg, South Africa (current affiliation: Health Economics and Epidemiology Research Office, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa) 1 2

Corresponding author: D Constant (deborah.constant@uct.ac.za) Background. Despite South Africa’s liberal abortion law permitting abortion on request in the first trimester and under restricted conditions for second-trimester pregnancies, the practice of unsafe self-induced abortion persists. However, the prevalence of this practice, the methods used and the reasons behind it are relatively under-researched. As part of a larger study seeking to improve abortion services in the Western Cape Province, we explored reports of prior attempts to self-induce abortion among women undergoing legal second-trimester abortion. Objectives. To describe the prevalence and methods of and factors related to unsuccessful attempts at self-induction of abortion by women presenting without complications and seeking second-trimester abortion at public health facilities in the Western Cape. Methods. In a cross-sectional study from April to August 2010, 194 consenting women undergoing second-trimester abortion were interviewed by trained fieldworkers using structured questionnaires at four public sector facilities near Cape Town. Results. Thirty-four women (17.5%; 95% confidence interval 12.7 - 23.4) reported an unsuccessful attempt to self-induce abortion during the current pregnancy before going to a facility for second-trimester abortion. No factors were significantly associated with self-induction, but a relatively high proportion of this small sample were unemployed and spoke an indigenous African language at home. A readily available herbal product called Stametta was most commonly used; other methods included taking tablets bought from unlicensed providers and using other herbal remedies. No use of physical methods was reported. Conclusions. The prevalence of unsafe self-induction of abortion is relatively high in the Western Cape. Efforts to inform women in the community about the availability of free services in the public sector and to educate them about the dangers of self-induction and unsafe providers should be strengthened to help address this public health issue. S Afr Med J 2014;104(4):302-305. DOI:10.7196/SAMJ.7408

From 1994 to 2005, the proportion of maternal mortality attributable to unsafe abortion in South Africa (SA) decreased by an estimated 91%.[1] This reduction was attributed to the legalisation of abortion in 1996 with the passing of the Choice on Termination of Pregnancy Act, which provided for abortion on demand through 12 weeks of gestation and for several conditions, including socioeconomic hardship, through 20 weeks of gestation. Self-induced abortion involves the use of medications other than evidence-based medical abortion regimens, as well as other substances or physical trauma, to try to end an unwanted pregnancy. Selfinduction is synonymous with unsafe abortion, defined by the World Health Organization (WHO) as ‘a procedure for termination of an unintended pregnancy done either by people lacking the necessary skills or in an environment that does not conform to minimum medical standards or both’.[2] Conditions defining unsafe abortion practices include some or all of the following: absence of pre-abortion counselling, induction by an unskilled provider, procedures undertaken in unhygienic conditions, ingestion of traditional medication or hazardous substances, use of physical devices, or incorrect prescription of medication with inadequate instructions for use and no follow-up.[2] In developed countries with liberal abortion laws, unsafe abortion is generally infrequent, while in developing countries, where access

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is often restricted, as many as 77% of all induced abortions may be unsafe.[2] The Guttmacher Institute and the WHO estimate that 58% of abortions were unsafe in 2008 in the southern African region, which includes countries beyond SA,[3] and this figure is supported by other country-specific studies. In the 2nd South African national Youth Risk Behaviour Survey,[4] 6% of female high-school learners reported having had an abortion, and 9.8% of male learners reported that their female partners had done so. Of these, only 51.5% reported that the abortion had been performed at a hospital or clinic; 20.5% of respondents had consulted a traditional healer, 10.2% went to ‘another place’, and for 5.4% the provider setting was unknown. Neither age nor race was associated with differences in where the abortion took place, but there were associations between seeking help from a traditional healer and both earlier school grade and geographical region. The highest prevalence of using a traditional healer was in KwaZulu-Natal. Data from the USA have shown that self-induction was associated with a delay in seeking or obtaining a clinic-based abortion.[5] Previous research has reported that adult SA women sought abortion care outside designated facilities because of perceived poor quality of services, oversubscribed services, ineffective referral systems within health services, and lack of knowledge of the time-limited nature of the service.[6] More recent research in SA has identified additional barriers to safe abortion, such as uneven provision between rural

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and urban areas, unsubstantiated rumours around potential harms related to abortion, and intimidation by and negative attitudes from pre-abortion counsellors.[7.8] Grossman et al.[9] found that delays in accessing services were common among women seeking second-trimester abortion services in the Western Cape, SA. We hypothesised that these delays may have been associated with prior attempts to self-induce, and undertook this exploratory study to assess this question. We describe the prevalence and practices of unsuccessful attempts at self-induction and related factors among women presenting without complications and seeking secondtrimester abortion at public health facilities in the Western Cape.

Methods

This study forms part of a larger, repeated cross-sectional study of women undergoing second-trimester abortion. The baseline survey was completed in 2008,[9] and the data reported here are derived from a second round of data collection in 2010. Study sites included four public hospitals in the Western Cape that provided second-trimester abortion services, which were selected according to the volume of women seeking abortion services. Some facilities provided surgical abortion (dilation and evacuation), while others provided medical induction using misoprostol. Women were referred to these facilities based on proximity to their home. Three of the four sites served urban communities in the Cape Town metropolitan area, while the fourth served a small town roughly 120 km away in a primarily agricultural area. Ethical approval was obtained from the University of Cape Town Human Research Ethics Committee, the Stellenbosch University Committee for Human Research, and the Allendale Investigational Review Board. All participants provided written informed consent, and confidentiality and anonymity were ensured. The study was conducted between April and August 2010. All women attending the hospitals for second-trimester abortion on days when study interviewers were present were invited to participate. Eligibility criteria included age 18 years or older, gestational age between 12.1 weeks and 20.9 weeks, and ability to communicate in English or Xhosa. Bilingual interviewers administered questionnaires in a private location at the hospitals after the women had recovered from the abortion. Data were obtained on demographic and socioeconomic indicators, reproductive history and care-seeking behaviour. In addition, participants were asked whether they had tried any other methods to end the pregnancy before the abortion procedure, and if so, what method they had attempted. Qualitative, open-ended responses were recorded and later coded into categories. Data were analysed using Stata (version 12, College Station, TX, USA). A priori factors identified for potential association with selfinduction included age, education, socioeconomic status, home language, parity, previous abortions, gestational age according to ultrasound scan, and care-seeking experiences. Proportions were compared using χ2 tests or Fisher’s exact tests when appropriate. When means were compared, Students t-tests were used. Two-sided significance tests were used throughout, and valid percentages are reported for all results. The number of subjects recruited was sufficient to detect a prevalence of self-induction of 20% (±10%), with 90% power and a two-sided alpha of 0.05.

Results

At the four facilities involved in the study, a total of 698 women had second-trimester abortions performed during the sampling period. For logistical reasons, we were only able to obtain consent from and interview 28.1% of them (N=196). Two interviews were excluded because the forms were largely incomplete, so the final sample consisted of questionnaires from 194 women.

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A total of 34/194 (17.5%; 95% confidence interval 12.7 - 23.4) women interviewed reported that they had attempted to end their current pregnancy before coming to the facility. Table 1 compares characteristics of the women who had and had not attempted prior selfinduction. Means, medians and standard deviations, or percentages by self-induction (yes/no), are shown for factors that were hypothesised a priori potentially to be associated with self-induction. These factors included age, educational level achieved, home language, type of housing and employment status (as a proxy for socioeconomic status), parity, prior abortion, gestational age at first ultrasound examination (usually at a different facility), and gestational age as calculated on the day of admission for the abortion procedure. In this small exploratory sample, the results suggest that self-induction was most common among unemployed women and those speaking an indigenous African language at home; however, no significant associations with any of these factors emerged. There also appeared to be a trend towards presenting at a later gestational age at the time of first ultrasound among women who had attempted self-induction compared with those who had not, but this association was also not significant. Table 2 summarises the methods women used for self-induction. In 2 of the 34 cases the method used for self-induction was not recorded. The most common practice (17/32, 53.1%) was ingestion of an herbal product called Stametta. According to the manufacturer’s details listed on the package, Stametta can be used for a wide range of ailments such as painful menstruation and fatigue, and to improve general well-being. The product label cautions that it should not be used by pregnant women and children under the age of 14 years. The composition includes a blend of aloe, ascorbic acid, aniseed oil, magnesium sulphate and preservative. Stametta is readily available in drug stores and shops. Other methods women used included responding to an advertisement by an illegal backstreet provider and taking tablets (unnamed) (5/32, 15.6%), using other herbal remedies (6/32, 18.7%), using other medications such as emergency contraceptives or antibiotics (2/32, 6.2%), or ‘smoking a lot’, probably cigarettes (1/32, 3.1%). Two women elaborated on their experience and their reasons for attempting self-induction. One woman who consulted an illegal backstreet provider said that she was given three tablets to take at home and that the provider called twice, but then disappeared. The other respondent explained that she had been turned away from a healthcare facility because she was there too late in the day to be seen. She then called a number from an advertisement and paid R1 600 (approximately US$220) for tablets which she took, but did not abort.

Discussion

Despite liberal abortion laws and previous reductions in maternal mortality attributable to unsafe abortion, SA continues to face problems with unsafe abortion and a relatively high rate of self-induction. SA’s Confidential Enquiry on Maternal Death (CEMDSA) or ‘Saving Mothers’ reports for 2002 - 2004[10] and 2005 - 2007[11] showed that unsafe abortion contributed to 3.5% and 3.4% of all maternal mortality, respectively. However, in the 2005 - 2007 report, this proportion rose to 4.9% after the figures for misclassified HIV/AIDS-related deaths were adjusted.[11] Unfortunately, in the latest report, for 2008 - 2010,[12] the CEMDSA committee reclassified abortion-related deaths as ‘unsafe miscarriage’, so the reports are not directly comparable; however, the prevalence was 3.8% for this period. The prevalence of self-induced abortion (17.5%) reported in this study is high compared with developed countries where abortion is legal. In two recent US studies, self-induction was reported by 4.6% of everpregnant women[5] and by 2.6% of women attending abortion clinics.[13] Although not significant, the results from our exploratory study show that self-induction was more common among African language-

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Table 1. Key characteristics of patients seeking second-trimester abortion and reporting previous attempts to self-induce Characteristic

Attempted self-induction (N=34)

Did not attempt self-induction (N=160)

p-value*

Age (years), mean (median) ±SD

25.7 (23.5) ±5.50

26.5 (26) ±5.65

0.358

1 (2.9)

8 (5.0)

9 - 12

School education (grade), n (%)

0.600 33 (97.1)

151 (95)

Home language: Xhosa/Zulu/Tswana, n (%)

29 (85.3)

122 (76.3)

0.249

SES: Informal housing, n (%)

24 (70.6)

103 (64.4)

0.489

SES: No paid work, n (%)

25 (73.5)

96 (60.0)

0.139

Parity, mean (median) ±SD

N=33 1.1 (1) ±0.96

N=153 1.3 (1) ±1.03

0.409

Pregnancies (incl. this pregnancy), mean (median) ±SD

2.2 (2) ±0.99

2.4 (2) ±1.15

0.570

Had a prior TOP, n (%)

1 (2.9)

6 (3.8)

0.645

Mean (median) ±SD

14.9 (14.7) ±2.78

14.5 (14) ±2.14

<16

21 (61.8)

120 (75)

16.1 - 19.9

13 (38.2)

40 (25)

16.0 (15.6) ±2.09

15.8 (15.6) ±1.94

Gestational age at first US (weeks), n (%)

0.116

Gestational age at admission (weeks), mean (median) ±SD

0.322

0.569

SD = standard deviation; SES = socioeconomic status; TOP = termination of pregnancy; US = ultrasound. *Two-sided t-tests for continuous variables, chi-square tests for proportions.

Table 2. Methods used for attempted self-induction of abortion Method used

N=32 n (%)

Back-street abortion provider

6 (18.7)

Saw advertisement – tablet taken

5 (15.6)

Saw advertisement – only called, didn’t go

1 (3.1)

Self-medication method

26 (81.2)

Stametta

17 (53.1)

Other remedies – aloe, lemon, herbs, laxatives

6 (18.7)

ther medications – antibiotics, emergency O contraception

2 (6.2)

Other methods – smoked

1 (3.1)

speaking and unemployed women, and that it was not associated with educational level or housing type (which was used as a proxy for socioeconomic status). This suggests that particular cultural beliefs, a reliance on self-medication for other problems, or even heightened stigma around abortion may be factors that provoke women to search for solutions to unwanted pregnancies outside the formal healthcare sector. Further in-depth interviewing and more quantitative data from larger samples are necessary to explore this. The most common methods for self-induction in this population involved the use of remedies and herbal products rather than medications procured from backstreet providers. This is not dissimilar to methods used for self-induction in other countries. US women reported using misoprostol, self-medication with vitamin C, aspirin or oral contraceptives, other foods and beverages, herbs, and in a small number of cases, physical manipulation.[13] Jewkes et al.[6] noted that in SA self-medication is a common first-line treatment response to health problems, but emphasised that even when the methods used are not necessarily harmful, these practices potentially have harmful consequences. While the failed attempts at self-induction in this

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sample of women did not appear to have been harmful to their health, they may have pushed women later into pregnancy and contributed to their seeking a second-trimester abortion, which is associated with an increased risk of complications.[14] Use of physical trauma for self-induction after the legalisation of abortion services in SA had dramatically reduced by 2005[6] and was absent in our sample. While misoprostol is potentially less hazardous than physical means, without knowledge of dose requirements and possible complications, using misoprostol supplied through backstreet sources remains a potentially hazardous path for women seeking assistance. In SA, where abortion is legally permitted within broad criteria, access to safe abortion services remains suboptimal. A scarcity of nurse providers has become apparent in recent years, and those working in abortion facilities describe services as overcrowded and overburdened. The dearth of trained and willing abortion care providers has compromised access to safe abortion services.[8] In the Western Cape, less than 75% of the 40 designated facilities are functional, and at some services are offered only every second week or on a monthly basis. First-trimester services are provided at 29 facilities, and second-trimester services at just 8 of these facilities (unpublished data, 2010). Where access is problematic, women are likely to resort to unsafe and clandestine abortion services. The current plethora of advertisements by illegal providers in public urban spaces, coupled with limited availability of services and service providers, is an alarming trend that could contribute to maternal mortality resulting from unsafe procedures.

Study limitations and recommendations

The data presented in this report are limited to women seeking secondtrimester abortion at public facilities. Our interpretations of prevalence and methods of self-induction are therefore not generalisable to women outside the formal healthcare system, those with incomplete abortions resulting from self-induction, or those presenting for abortion in the first trimester of an unwanted pregnancy. As this study included only women in their second trimester, and the whole sample may therefore be considered somewhat delayed, associations between self-induction and delays in accessing services

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are less likely to be uncovered than in a broader-based sample in which women in both the first and second trimesters are included. To address the issue of unsafe practices, further efforts should be channelled towards informing women in the community about the availability of free services in the public sector and educating them about the dangers of self-induction and unsafe providers. In this exploratory study we did not ask women why they chose self-induction before accessing legal services. Further details would have provided useful information to inform efforts to prevent unsafe practices. Service provision also needs to be strengthened by making services more acceptable and woman-friendly, including reducing the delays experienced by women seeking abortion care at public facilities.[9]

Conclusion

Seventeen per cent of women accessing second-trimester abortion services in the Western Cape public sector had resorted to selfinduction before entering legal public sector services. This reflects a high percentage of unsafe practices despite SA’s liberal abortion law and the relatively widespread availability of abortion services in urban settings. No significant associations with self-induction were found in this exploratory study. Funding. Funding for this research was provided by the Safe Abortion Action Fund.

References 1. Jewkes R, Rees H. Dramatic decline in abortion mortality due to the Choice on Termination of Pregnancy Act. S Afr Med J 2005;95(4):250. 2. World Health Organization. Information Sheet: Safe and Unsafe Induced Abortion. Global and Regional Levels in 2008, and Trends during 1995 - 2008. Geneva: WHO, 2012. 3. Sedgh G, Singh S, Shah IH, Ahman E, Henshaw SK, Bankole A. Induced abortion: Incidence and trends worldwide from 1995 to 2008. Lancet 2012;379(9816):625-632. [http://dx.doi.org/10.1016/S01406736(11)61786-8] 4. Reddy SP, James S, Sewpaul R, et al. Umthente Uhlaba Usamila – The South African Youth Risk Behaviour Survey 2008. 2010. http://www.mrc.ac.za/healthpromotion/yrbs_2008_final_report.pdf (accessed 13 December 2013). 5. Grossman D, Holt K, Peña M, et al. Self-induction of abortion among women in the United States. Reprod Health Matters 2010;18(36):136-146. [http://dx.doi.org/10.1016/S0968-8080(10)36534-7] 6. Jewkes RK, Gumede T, Westaway MS, Dickson K, Brown H, Rees H. Why are women still aborting outside designated facilities in metropolitan South Africa? BJOG 2005;112(9):1236-1242. [http://dx.doi.org/10.1111/ j.1471-0528.2005.00697.x] 7. Orner PJ, de Bruyn M, Barbosa RM, Boonstra H, Gatsi-Mallet J, Cooper DD. Access to safe abortion: Building choices for women living with HIV and AIDS. J Int AIDS Soc 2011;14:54. [http://dx.doi.org/10.1186/17582652-14-54] 8. Harries J, Stinson K, Orner P. Health care providers’ attitudes towards termination of pregnancy: A qualitative study in South Africa. BMC Public Health 2009;9:296. [http://dx.doi.org/10.1186/1471-2458-9-296] 9. Grossman D, Constant D, Lince N, Alblas M, Blanchard K, Harries J. Surgical and medical second trimester abortion in South Africa: A cross-sectional study. BMC Health Serv Res 2011;11:224. [http://dx.doi. org/10.1186/1472-6963-11-224] 10. Department of Health. Saving Mothers: Third Report on Confidential Enquiries into Maternal Deaths in South Africa 2002 - 2004. Pretoria: Department of Health, 2006. 11. Department of Health. Saving Mothers: Fourth Report on Confidential Enquiries into Maternal Deaths in South Africa 2005- 2007. Pretoria: Department of Health, 2009. 12. Department of Health. Saving Mothers: Fifth Report on Confidential Enquiries into Maternal Deaths in South Africa 2008 - 2010. Pretoria: Department of Health, 2012. 13. Jones RK. How commonly do US abortion patients report attempts to self-induce? Am J Obstet Gynecol 2011;204(1):23.e1-4. [http://dx.doi.org/10.1016/j.ajog.2010.08.019] 14. Bartlett LA, Berg CJ, Shulman HB, et al. Risk factors for legal induced abortion-related mortality in the United States. Obstet Gynecol 2004;103(4):729-737. [http://dx.doi.org/10.1097/01.AOG.0000116260.81570.60]

Accepted 17 October 2013.

Clinicians ignore best practice guidelines: Prospective audit of cardiac injury marker ordering in patients with chest pain U Bellbhudder,1 N Dip Med Tech, BTech (BioMed Tech), Dip Chem Path; J C Stanfliet,1,2 MB ChB, MMed, FCPath 1 2

ational Health Laboratory Service, Department of Chemical Pathology, King Edward VIII Hospital, Durban, South Africa N Department of Chemical Pathology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

Corresponding author: J C Stanfliet (john.stanfliet@nhls.ac.za) Background. Chest pain is a frequent presenting symptom and is a diagnostic challenge. Recent recommendations state that high-sensitivity cardiac troponin assays are the only biochemical test required in the diagnosis of acute coronary syndrome (ACS) and that other biomarkers such as myoglobin or creatine kinase (CK)-MB isoform are not indicated. Objective. To establish whether clinician ordering in the setting of suspected ACS was in keeping with recent recommendations. Methods. A prospective audit was undertaken of all requests for cardiac troponin I (cTnI) and CK-MB received at a large tertiary hospital in Durban, South Africa, during a 20-day period in December 2012. Results. A total of 193 cardiac marker requests were received: 12 (6.2%) requests were for cTnI alone; 8 (4.1%) were for CK-MB alone; and the remaining 173 (89.7%) were for both cTnI and CK-MB. Therefore, a total of 181 (93.8%) incorrect requests were received during this period. A total of 103 (53.4%) patients had values below the cut-off point of 40 ng/l for cTnI, i.e. ACS was ruled out. Of these, 15 had CK-MB values above the reference interval. A total of 12 (6.2%) patients had cTnI values >500 ng/l, i.e. ACS was ruled in; 33.3% of this group had normal CK-MB values. Conclusion. Ordering patterns in the setting of ACS did not reflect current recommendations and were wasteful and potentially dangerous. S Afr Med J 2014;104(4):305-306. DOI:10.7196/SAMJ.7381

Chest pain is common and frequently presents a diagnostic challenge.[1] Acute coronary syndrome (ACS) is a cause of significant morbidity and mortality if unrecognised, yet effective treatment is available.[2]

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Recent rationalisation of biomarker investigation has occurred, with serial measurements of troponins using highly sensitive assays being advised while other biomarkers such as creatine kinase (CK) or myoglobin are no longer indicated, given the limited evidence of

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their additional benefit.[3] However, evidence shows that uptake of guidelines by clinicians is suboptimal.[4] Anecdotal experience in the laboratory was that clinicians were continuing to order cardiac troponin I (cTnI) together with the CK-MB isoform in cases of suspected ACS. We undertook a prospective audit of requests in the setting of chest pain to ascertain the validity of this suspicion.

Methods

The National Health Laboratory Service (NHLS) chemistry laboratory based at King Edward VIII Hospital (KEH) provides routine and urgent investigations of a biochemical nature. KEH is a large public hospital that provides tertiary-level care in Durban, KwaZulu-Natal Province, South Africa (SA). A prospective audit of all requests for CK-MB and/or cTnI received at the NHLS chemistry laboratory for a 20-day period during December 2012 was undertaken; this period was chosen for convenience, as it was a quiet time because most outpatient clinics were closed. All requests for this period were examined. Both cTnI and CK-MB were measured on a Beckman-Coulter UniCel DxI 600. Troponin I was determined using the Access Accu-TnI assay, a highly sensitive troponin assay,[5] while CK-MB was measured using a mass assay. Data analyses were performed using MS Excel.

Results

A total of 193 cardiac marker requests were received during the study period; 12 (6.2%) requests were for cTnI alone, eight (4.1%) were for CK-MB alone and the remaining 173 (89.7%) were for both cTnI and CK-MB. Therefore, a total of 181 (93.8%) incorrect requests were received during this period. For cTnI, 103 (53.4%) patients had values below the cut-off point of 40 ng/l, i.e. ACS was ruled out depending on the time frame from onset of pain to sample collection. Of these, 15 had CK-MB values above the reference interval. A total of 12 (6.2%) patients had cTnI values >500 ng/l, i.e. ACS was ruled in. Four (33.3%) of this group had normal CK-MB values. If CK-MB had been the sole investigation in this group, ACS would not have been detected and appropriate therapy would not have been instituted.

Discussion

Simple arithmetic, using the state price list, reveals this argument to be fallacious – if the wasteful CK-MB requests had been avoided, the potential savings would have been sufficient for the required serial cTnI measurements. The burden of cardiac disease is predicted to increase in developing countries and rational approaches are required. Why this pattern of ordering exists remains unknown. The failure of clinicians to take up guidelines has been extensively documented and results from many factors, including the sheer numbers thereof. [10,11] Anecdotal evidence suggests that requests are driven by historical practice and, on direct questioning, most clinicians are unable to justify this. Despite ad hoc education sessions conducted by JCS and memos distributed to clinicians, there was a persistence in this practice; however, these methods are ineffective in changing ordering behaviour permanently.[12] Poorly designed test request forms may drive inappropriate ordering and the request form may need to be redesigned to remove the tick-box options provided for CK and CK-MB.[13] An alternative strategy called gatekeeping, used by several institutions, limits the tests or test repertoire that clinicians are permitted to order.

Study limitations

The clinical outcomes of the patients involved were unknown. This study was not designed to address the question of the clinical utility of the highly sensitive troponin assays, which is well established, but rather to determine the current investigative behaviour at a single centre. This raises the question of whether this study suffers from selection bias. In truth, it does, but discussion with colleagues at other centres reveals similar anecdotal evidence; whether this is generalisable to other clinical settings would be an area of potential future exploration. In addition, this study should be revisited once an intervention has been developed and implemented to assess its effectiveness.

Conclusion

This audit of laboratory test requests at an academic centre in Durban, SA, revealed that local ordering behaviour was at odds with current recommendations. Author contributions. UB obtained and analysed the data. JCS reviewed the data and wrote the manuscript References

The diagnosis of ACS is now largely biochemical. Patients can be discharged safely if certain criteria are met,[6] as the negative predictive value of this highly sensitive troponin assay is 97% and the negative likelihood ratio is 0.25.[7] There is little role for CK-MB, myoglobin or other proteins as markers. There are appropriate times to measure CK-MB, but in general these should follow discussion with the laboratory. Proponents of the CK-MB assay argue that CK-MB is released earlier from damaged cardiac myocytes than troponin is and that the assay is useful in cases of ‘false-positive’ troponin elevation such as renal failure or cardiac myopathies. Cardiac troponin is released as early as 3 hours after injury,[8] and serial measurements of troponin are advocated to identify chronic causes of troponin elevation.[9] The use of CK-MB as seen in this study may cause confusion for the inexperienced clinician as there were several instances of discordant troponin and CK-MB measurements. Troponin measurements from patients that fall between the rulein and rule-out cut-off points should be repeated in 3 hours to demonstrate a rise and/or fall in levels, to differentiate between ACS and chronic or false-positive causes of elevated troponin blood results. This is often viewed as financially unrealistic as it as an expensive test compared with the CK-MB assay. Serial measurements are therefore said not to be feasible in our resource-constrained environment.

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1. Morrow DA, de Lemos JA, Sabatine MS, Antman EM. The search for a biomarker of cardiac ischemia. Clin Chem 2003;49(4):537-539. [http://dx.doi.org/10.1373/49.4.537] 2. Mistry NF, Vesely MR. Acute coronary syndromes: From the emergency department to the cardiac care unit. Cardiol Clin 2012;30(4):617-627. [http://dx.doi.org/10.1016/j.ccl.2012.07.010] 3. Lippi G, Franchini M, Cervellin G. Diagnosis and management of ischemic heart disease. Semin Thromb Hemost 2013;39(2):202-213. [http://dx.doi.org/10.1055/s-0032-1333543] 4. El-Deeb MH, Al Riyami AM, Al Riyami AA, et al. 2012 Oman Heart Association simplified guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. Crit Pathw Cardiol 2012;11(3):139-146. [http://dx.doi.org/10.1097/HPC.0b013e31825ac653] 5. Venge P, James S, Jansson L, Lindahl B. Clinical performance of two highly sensitive cardiac troponin I assays. Clin Chem 2009;55(1):109-116. [http://dx.doi.org/10.1373/clinchem.2008.106500] 6. Bingisser R, Cairns C, Christ M, et al. Cardiac troponin: A critical review of the case for point-of-care testing in the ED. Am J Emerg Med 2012;30(8):1639-1649. [http://dx.doi.org/10.1016/j.ajem.2012.03.004] 7. Venge P, Ohberg C, Flodin M, Lindahl B. Early and late outcome prediction of death in the emergency room setting by point-of-care and laboratory assays of cardiac troponin I. Am Heart J 2010;160(5):835841. [http://dx.doi.org/10.1016/j.ahj.2010.07.036] 8. Hof D, Klingenberg R, von Eckardstein A. Sensible use of high-sensitivity troponin assays. Methods Mol Biol 2013;963:385-406. [http://dx.doi.org/10.1007/978-1-62703-230-8_24] 9. Eggers KM, Lind L, Venge P, Lindahl B. Will the universal definition of myocardial infarction criteria result in an overdiagnosis of myocardial infarction? Am J Cardiol 2009;103(5):588-591. [http://dx.doi. org/10.1016/j.amjcard.2008.11.007] 10. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999;282(15):1458-1465. [http://dx.doi.org/10.1001/ jama.282.15.1458] 11. Misra S, Barth JH. Guidelines are written, but are they followed? Ann Clin Biochem 2013;50(5):400-402. [http://dx.doi.org/10.1177/0004563213498712] 12. Fryer AA, Hanna FW. Managing demand for pathology tests: Financial imperative or duty of care? Ann Clin Biochem 2009;46(6):435-437. [http://dx.doi.org/10.1258/acb.2009.009186] 13. Fraser CG, Woodford FP. Strategies to modify the test-requesting patterns of clinicians. Ann Clin Biochem 1987;24(3):223-231.

Accepted 17 October 2013.

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Hepatitis B and HIV co-infection in pregnant women: Indication for routine antenatal hepatitis B virus screening in a high HIV prevalence setting N V Thumbiran,1 MB ChB, Dip HIV/AIDS Clin Man; D Moodley,2 BSc, MMedSc, PhD; R Parboosing,1 MB ChB, FCPath (Virology), MMed, MS (Epi); P Moodley,1 MB ChB, FCPath (Virology) 1 2

Department of Virology, National Health Laboratory Service, University of KwaZulu-Natal, Durban, South Africa Women’s Health and HIV Research Unit, Department of Obstetrics and Gynaecology, University of KwaZulu-Natal, Durban, South Africa

Corresponding author: N V Thumbiran (nthumbiran@gmail.com) Background. Sub-Saharan Africa is endemic for hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections. HBV/HIV co-infection in women of reproductive age is of clinical and public health importance because these women constitute a significant reservoir for horizontal and perinatal HBV transmission. Childhood HBV vaccination from 6 weeks of age protects most children against chronic HBV infection. However, infants born to HBV/HIV co-infected women are more likely to be infected perinatally, with an increased risk of chronic hepatitis, than infants born to HBV mono-infected women. Objectives. The aim of our study was to establish the prevalence of HBV infection and HBV/HIV co-infection in pregnant women in KwaZulu-Natal, South Africa, to inform antenatal HBV screening and childhood immunisation policies in South Africa. Methods. Stored plasma specimens obtained from 570 pregnant women were tested for hepatitis B surface antigen (HBsAg) and HBV infectivity, as characterised by the presence of hepatitis B e antigen (HBeAg) and/or HBV DNA load. Results. The antenatal HIV prevalence and HBsAg prevalence in this study were 41.6% and 5.3% (95% confidence interval (CI) 3.4 - 7.1), respectively. Overall, 3.1% (95% CI 1.7 - 4.6) of pregnant women were HBV/HIV co-infected, with HBeAg positivity and the HBV DNA load being significantly higher in co-infected women. Conclusion. We report a 5.3% HBV prevalence and a 3.1% HBV/HIV co-infection prevalence in pregnant women from this HIV-endemic region. Routine antenatal HBV screening will allow early identification of neonates who require HBV active-passive immunoprophylaxis at birth. This strategy, together with antenatal antiretrovirals, will reduce the risk of perinatal HBV transmission, especially in high-risk HBV/ HIV co-infected pregnant women. S Afr Med J 2014;104(4):307-309. DOI:10.7196/SAMJ.7299

An estimated 240 million chronic hepatitis B virus (HBV) infections have been reported worldwide despite the availability of an effective vaccine.[1] South Africa (SA) introduced the HBV vaccine into the national Expanded Programme on Immunisation (EPI) in 1995.[2] The vaccine is given to infants at 6, 10 and 14 weeks of age.[2] Adults are not routinely immunised against HBV, so women born before 1995 would have no vaccine immunity against HBV. Between 1995 and 1999, 31% of mothers of 8 - 72-month-old children in an SA study had evidence of current or past exposure to HBV.[2] Co-infection with HBV and the human immunodeficiency virus (HIV) in sexually active women of reproductive age is of significant public health importance because such women are at risk of ongoing HBV transmission, both horizontally and perinatally.[3] A fixeddose combination (FDC) antiretroviral (ARV) regimen consisting of tenofovir (TDF), emtricitabine (FTC) and efavirenz (EFV) is currently recommended for all HIV-positive pregnant women regardless of their CD4+ cell count.[4] Since TDF and FTC are also effective in the treatment of HBV infection, these prevention of mother-to-child transmission (PMTCT) guidelines are the first in SA to offer simultaneous prevention of HIV and HBV perinatal transmission.[5] In women who do not meet the eligibility criteria for ongoing treatment, i.e. a CD4+ count of ≤350 cells/µl, the FDC regimen is intended to be prophylactic and discontinued 1 week after

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cessation of breastfeeding.[4] The guidelines therefore recommend HBV screening prior to discontinuing the ARV regimen to avoid maternal HBV reactivation.[4] The potential disadvantage of this delayed screening is failure to identify the HBV-exposed neonate and protect it at birth against developing chronic HBV infection. Childhood immunisation programmes, which include HBV vaccination from 6 weeks of age, protect the majority of children and young adults against chronic hepatitis and liver-related mortality. Infants born to HBV/HIV co-infected women are, however, more likely to be infected perinatally and are at greater risk of developing chronic hepatitis than infants born to HBV mono-infected women.[3] Routine antenatal HBV screening is not offered in SA, yet local studies reported HBV prevalence rates ranging between 3.2% and 7.4% in HIV-infected pregnant women.[3,6] The aim of our study was to establish the prevalence of HBV infection and HBV/HIV co-infection in pregnant women in KwaZulu-Natal (KZN), to inform antenatal HBV screening and childhood immunisation policies in SA.

Methods

Stored (-70°C) plasma specimens were tested for HBV markers in a retrospective analysis of pregnant women who participated in an HIV sero-incidence study in KZN between March and December 2009.[7] Consent for ‘storage of plasma intended for use in further research’ was obtained from participants at enrolment into the original study. The process of participant recruitment, eligibility

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criteria and HIV testing procedures have been described previously.[7] Plasma aliquots from 570 stored specimens were selected based on an estimated HBV prevalence of 5.5%.[8] The participants’ ages, HIV status and CD4+ counts were extracted from the original study database.

Laboratory analysis

Frozen plasma specimens were thawed and tested for hepatitis B surface antigen (HBsAg) using an enzyme-linked immunosorbent assay (ELISA) from Siemens Healthcare Diagnostics (Tarrytown, NY, USA). If HBsAg-positive, specimens were further tested for hepatitis B e antigen (HBeAg), also using an ELISA from Siemens Healthcare Diagnostics, and for quantitative HBV DNA using the COBAS AmpliPrep/COBAS TaqMan HBV Test, version 2.0, from Roche Molecular Systems Inc. (Branchburg, NJ, USA). HBV infection was characterised by a positive HBsAg result and hepatitis B viral infectivity by the presence of HBeAg and/or HBV DNA quantification. Specimens with low HBsAg and HBeAg index values were not retested for confirmation owing to insufficient specimen volumes. HBsAg specimens with index values of ≥1 and ≤50 were further neutralised to confirm the presence of HBsAg, and specimens that produced technically invalid results were excluded from the analysis. HBeAg index values of ≥10 were interpreted as positive. The linear range for HBV DNA quantification was 20 - 1.7×108 IU/ml. Specimens with an insufficient volume were diluted and the final results were calculated by multiplication using the dilution factor.

Statistical analysis

Prevalence rates for HBV infection and HBV/HIV co-infection were reported as point estimates with 95% confidence intervals (CIs). Differences in proportions were determined by the chi-square test (and Fisher’s exact test, where Cochrane’s criterion was not fulfilled). Two-tailed non-parametric procedures were used to compare HBV DNA load between groups. A p-value of <0.05 was regarded as significant. SAS 9.3 (SAS Institute Inc., Cary, NC, USA) was used for statistical analysis.

Ethical considerations

Ethical approval was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee (BE028/12).

Results

Five hundred and seventeen of 570 (90.7%) pregnant women (median age 23 years,

range 16 - 47 years) had their HIV status documented; 215 (41.6%) were HIV-positive. Thirty tested positive for HBsAg, resulting in a point prevalence estimate of 5.3% (95% CI 3.4 - 7.1). Of these women, 6 were HBeAg-positive (20.0%; 95% CI 5.7 - 34.3). Twenty-five HBsAg-positive specimens (83.3%) had detectable HBV DNA, ranging from 20 to >1.7×108 IU/ml with a median log10 viral load of 3.0 (interquartile range (IQR) 2.3). Although not statistically significant, more HIV-infected women than HIV-uninfected women tested HBsAg-positive (p=0.2048) (Table 1). Overall, 16 of 509 (3.1%; 95% CI 1.7 - 4.6) pregnant women with HIV and HBsAg results were HBV/HIV co-infected. HBeAg positivity was significantly more common in HIV-infected than in HIVuninfected women (p=0.0185) (Table 1). All 16 HBV/HIV co-infected women had a detectable HBV DNA load ranging from 45 to >1.7×108 IU/ml with a median log10 viral load of 3.3 (IQR 3.9), which was significantly higher than in HIV-uninfected women (Table 1). A CD4+ cell count was available for 76/215 (35.4%) HIV-positive pregnant women, with a median of 328 cells/µl (range 45 - 822 ; IQR 183). Of these women, 41 (53.9%) had a CD4+ count of ≤350 cells/µl and would have been eligible for lifelong ARV treatment. Four of the 41 women (9.7%) with a CD4+ count of ≤350 cells/µl were HBV-co-infected, while none of the women with a CD4+ count of >350 cells/µl was co-infected (p=0.119 using Fisher’s exact test, two-tailed).

Discussion

We report an estimated HBV prevalence of 5.3% in pregnant women attending primary health clinics in KZN. It is highly likely that most of the pregnant women in our study had missed the childhood EPI vaccination. [2] One in 5 (20%) of these HBVinfected women had active viral replication, as indicated by the presence of HBeAg. We further report a 7.4% HBsAg prevalence

in HIV-infected pregnant women in KZN, which is higher than the 4.3%, 5.9% and 6.2% reported from studies in HIVinfected pregnant women in North West, the Western Cape and Limpopo provinces, respectively.[3,6] This regional variation in HBV prevalence may be due to various cultural and environmental factors that modify HBV transmission in diverse ethnic groups.[9] The non-significant difference in HBV prevalence between HIV-infected and uninfected pregnant women demonstrated in our study is similar to that reported in other SA studies and may be explained by early childhood cryptic transmission of HBV rather than shared routes of HIV and HBV transmission in adulthood.[6] The 3.1% HBV/HIV co-infection rate in our study population is clinically significant in a setting with a high HIV burden. HBV/ HIV co-infected pregnant women require complex management, since the impact on the mother and the infant must be considered. The FDC ARV regimen (TDF/ FTC/EFV) currently recommended for all HIV-positive pregnant women benefits the mother with HBV co-infection and also offers protection against HBV infection to the exposed neonate by reducing the maternal HBV DNA load, which is an independent risk factor for perinatal transmission.[5,10,11] This strategy provides a great advantage over the past zidovudine and single-dose nevirapine (NVP) PMTCT regimen in which a single postpartum dose of TDF and FTC was given.[12] While this was intended to protect the mother from developing NVP resistance, it offered no benefit to the mother or her exposed neonate if she was also HBV-infected. The use of antenatal ARVs against hepatitis B has been shown to be relatively safe and may compensate for immunoprophylaxis failure, especially in resource-limited settings where early access to immunisation is not [5,10,13] always available. The new national PMTCT guidelines recommend maternal HBV screening of all HIV-infected women

Table 1. Distribution of hepatitis B virus laboratory markers in HIV-infected and -uninfected pregnant women Laboratory markers

HIV-infected

HIV-uninfected

p-value

HBsAg+, n (%)

16/215 (7.4)

14/294 (4.8)

0.2048†

HBeAg+, n (%)

6/16 (37.5)

0/14 (0.0)

0.0185‡

HBV DNA load, median (IQR)

3.3 log10 (3.9)

1.5 log10 (2.1)

0.0058§

HBsAg = hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; + = positive; IQR = interquartile range. * Excludes 8 HBsAg invalid results. † Chi-squared test. ‡ Fisher’s exact test. § Two-tailed non-parametric test.

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receiving FDC prior to discontinuing the prophylactic ARV regimen at cessation of breastfeeding.[4] This strategy protects HBV/HIV co-infected women from developing hepatitis flares. However, postnatal HBV screening, as opposed to antenatal screening, would unfortunately be too late to identify HBV-exposed neonates who would have required HBV immunisation at birth.[4,14] Furthermore, it is highly likely that the 5.3% of neonates in our study who were HBV-exposed were not vaccinated at birth as recommended, since HBV screening in pregnancy is not routinely available and the HBV infection in these women would have gone undetected. The higher HBV infectivity demonstrated in HBV/ HIV co-infected pregnant women in our study is consistent with other recent studies, and suggests that mother-to-child transmission (MTCT) of HBV may be more common in this country than has previously been thought.[3,6,15] Perinatal HBV transmission often results in an asymptomatic neonatal infection, and 70 - 90% of these neonates remain chronically infected if HBV immunoprophylaxis is not given at birth.[16] They will subsequently contribute to the reservoir of asymptomatic HBV carriers as adults.[16] Inclusion of the HBV vaccine into the South African EPI has reduced the childhood HBV prevalence, but vaccination initiated at 6 weeks of age is inadequate to protect against perinatal HBV transmission.[3,6] Immunoprophylaxis failure has been reported despite the suppression of HBV DNA load with antenatal ARVs, suggesting that other maternal and obstetric factors may influence transmission.[11] Inability to prevent perinatal transmission from high-risk HBV/HIV co-infected mothers will result in a residual pool of HBV-infected children who will be a source of ongoing transmission to others, and this may impede current vaccination efforts. Our failure to investigate occult HBV infections may have meant that we underestimated HBV prevalence. The rate of occult HBV infection in HIV-infected individuals is estimated to be 33%.[17] Testing for occult HBV infection could not be performed in our retrospective analysis owing to inadequate specimen volume for hepatitis B core antibody testing and confirmatory molecular testing. However, the unknown clinical significance of occult HBV infection, particularly its role in HBV transmission, together with the high cost of HBV molecular screening for an accurate diagnosis, means that it is unlikely to be included in a public health policy.[18] Routine antenatal HBV screening in pregnant women in SA will allow for the timeous initiation of infant immunoprophylaxis and identification of HBV-exposed neonates who require postimmunisation serological testing to confirm HBV status. Active and passive immunisation given to the neonate within 12 - 24 hours of birth (before the development of HBV surface antigenaemia) was shown to prevent more than 95% of perinatal transmissions.[5,14] However, in a developing country where many women may not access antenatal care, initiating the HBV vaccination schedule in all infants at birth rather than at 6 weeks could aid in preventing perinatal HBV transmission.

Conclusion

We report an estimated 5.3% prevalence of HBV infection and a 3.1% prevalence of HBV/HIV co-infection in pregnant women in this HIV-endemic region. It is highly likely that most women of reproductive age who are also HIV-infected have not received

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childhood HBV immunisation. While the current HIV PMTCT guidelines provide potent antenatal ARVs with the potential to suppress HBV DNA load and decrease vertical HBV transmission in high-risk HBV/HIV co-infected women, approximately 4.8% of neonates born to HIV-uninfected women are at risk of perinatal HBV infection. Routine antenatal serological screening for HBV will identify all HBV-exposed neonates and allow active-passive HBV immunoprophylaxis to be initiated at birth, thereby reducing the risk of vaccine failure. There are no formal guidelines for PMTCT of HBV, but antenatal antiviral therapy in combination with immunoprophylaxis initiated at birth will decrease the risk of MTCT of HBV, as shown in many studies. This strategy may, in turn, reduce infant morbidity and mortality related to HBV infection as well as decrease the reservoir for ongoing horizontal HBV transmission. Our study confirms other SA reports and highlights the need for SA childhood immunisation policies to be revisited. Prospective studies assessing the impact of the current PMTCT guidelines on MTCT of HBV are needed in the future.

Acknowledgement. Funding was received from the National Health Laboratory Service Research Trust. References 1. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012;30(12):2212-2219. [http://dx.doi.org/10.1016/j.vaccine.2011.12.116] 2. Tsebe KV, Burnett RJ, Hlungwani NP, Sibara MM, Venter PA, Mphahlele MJ. The first five years of universal hepatitis B vaccination in South Africa: Evidence for elimination of HBsAg carriage in under 5-year-olds. Vaccine 2001;19(28-29):3919-3926. [http://dx.doi.org/10.1016/S0264-410X(01)00120-7] 3. Andersson MI, Maponga TG, Ijaz S, Theron G, Preiser W, Tedder RS. High HBV viral loads in HIV-infected pregnant women at a tertiary hospital, South Africa. J Acquir Immune Defic Syndr 2012;60(4):e111-e112. [http://dx.doi.org/10.1097/QAI.0b013e31825aeee7] 4. Department of Health, South Africa. The South African Antiretroviral Treatment Guidelines 2013. Date of implementation 1 April 2013. http://www.doh.gov.za/docs/policy/2013/ART_Treatment_ Guidelines_Final_25March2013.pdf (accessed 21 April 2013). 5. Spearman CWN, Sonderup MW, Botha JF, et al. South African guideline for the management of chronic hepatitis B: 2013. S Afr Med J 2013;103(5):337-349. [http://dx.doi.org/10.7196/SAMJ.6452] 6. Burnett RJ, Ngobeni JM, Francois G, et al. Increased exposure to hepatitis B virus infection in HIV-positive South African antenatal women. Int J STD AIDS 2007;18(3):152-156. [http://dx.doi. org/10.1258/095646207780132523] 7. Chetty V, Moodey D, Chuturgoon A. Evaluation of a 4th generation rapid HIV test for earlier and reliable detection of HIV infection in pregnancy. J Clin Virol 2012;54(2):180-184. [http://dx.doi. org/10.1016/j.jcv.2012.02.021] 8. Firnhaber C, Reyneke A, Schulze D, et al. The prevalence of hepatitis B co-infection in a South African (SA) urban government HIV clinic. S Afr Med J 2008;98(7):541-544. 9. Dusheiko GM, Conradie JD, Brink BA, Marimuthu T, Sher T. Differences in the regional prevalence of chronic hepatitis B in southern Africa â&#x20AC;&#x201C; implications for vaccination. S Afr Med J 1989;75(10):473-478. 10. Kumar M, Singh T, Sinha S. Chronic hepatitis B virus infection and pregnancy. J Clin Exp Hepatol 2012;2(4):366-381. [http://dx.doi.org/10.1016/j.jceh.2012.09.001] 11. Cheung KW, Seto MTY, Wong SF. Towards complete eradication of hepatitis B infection from perinatal transmission: Review of the mechanisms of in utero infection and the use of antiviral treatment during pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology 2013;169(1):17-23. [http://dx.doi.org/10.1016/j.ejogrb.2013.02.001] 12. Department of Health, South Africa. Clinical Guidelines: PMTCT (Prevention of Mother to Child Transmission). 2010. http://www.fidssa.co.za/images/PMTCT_Guidelines.pdf (accessed 21 February 2013). 13. Dusheiko G. Interruption of mother-to-infant transmission of hepatitis B: Time to include selective antiviral prophylaxis? Lancet 2012;379(9830):2019-2021. [http://dx.doi.org/10.1016/S0140-6736(11)61182-3] 14. Thorne C, Newell ML. HIV, hepatitis and pregnancy. Womenâ&#x20AC;&#x2122;s Health Medicine 2005;2(2):40-43. [http://dx.doi.org/10.1383/wohm.2.2.40.63064] 15. Mayaphi S, Rossouw TM, Masemola DP, Olorunju SAS, Mphahlele MJ, Martin DJ. HBV/ HIV co-infection: The dynamics of HBV in South African patients with AIDS. S Afr Med J 2012;102(3):157-162. 16. Levy M, Koren G. Hepatitis B vaccine in pregnancy: Maternal and fetal safety. Am J Perinatol 1991;8(3):227-232. [http://dx.doi.org/10.1055/s-2007-999384] 17. Ayuk J, Mphahlele JM, Bessong P. Hepatitis B virus in HIV-infected patients in north-eastern South Africa: Prevalence, exposure, protection and response to HAART. S Afr Med J 2013;103(5):330-333. [http://dx.doi.org/10.7196/SAMJ.6304] 18. Hoffmann CJ, Thio CL. Clinical implications of HIV and hepatitis B co-infection in Asia and Africa. Lancet Infect Dis 2007;7(6):402-409. [http://dx.doi.org/10.1016/S1473-3099(07)70135-4]

Accepted 7 December 2013.

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REVIEW

Transition from child- to adult-orientated care for children with long-term health conditions: A process, not an event A Westwood,1 MD, FCP (SA); N Langerak,2 BSc (PT) (Utrecht), MSc (Nijmegen), PhD; G Fieggen,2 MSc (Lond), MD, FCS (SA) 1 School of Child and Adolescent Health, Faculty of Health Sciences, University of Cape Town, and General Paediatrics, Metro West, Department of Health, Provincial Government of the Western Cape, Cape Town, South Africa 2 Division of Neurosurgery, Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: A Westwood (anthony.westwood@westerncape.gov.za)

This month’s CME component contains the second of a two-part series of continuing medical education articles on various aspects of spina bifida, with the focus on some of the longer-term management issues such as hydrocephalus and limb deformity, as well as quality of life. S Afr Med J 2014;104(4):310-313. DOI:10.7196/SAMJ.8201

Spina bifida is an example of a ‘long-term health condition’, a term preferred to ‘chronic disease’ (the standard term for adult continuing health problems) in the paediatric lexicon for a number of reasons. Given the child’s continuous development, time spent living with a health condition can lead to secondary health problems or disabilities in spheres such as growth and psychosocial development. The term ‘health condition’ is preferred as many of the problems that afflict children and require medical support are not diseases. Spina bifida is a prime illustration of this important distinction – the need for long-term use of health services as described in the accompanying articles, but not being primarily a disease. Importantly, in this context, children with disabilities are not dichotomised from those with diseases; they have similar needs in terms of health services and face similar challenges to their development and in their negotiation of life’s transitions. With improved survival of children with long-term health conditions, there is a need for medical care into adulthood and attention needs to be paid to the process by which the transition from child- to adult-centred care is made. This is of relevance to the primary care practitioner who can play a crucial role in ensuring the success of this process.

Long-term health conditions

A long-term health condition has been defined by Stein et al.[1] as a disorder that:

• has a biological, psychological cognitive basis • has lasted or is virtually certain to last at least a year • produces one or more of the following sequelae: • limitation of function • dependency on medications, special diet, medical technology, assistive device, or personal assistance • needs medical care or related services, psychological services and educational services over and above the usual for the child’s age. This so-called non-categorical approach promotes a generic process towards the care of children with long-term health conditions, emphasising commonalities such as psychological stresses, the need for planning of emergency care, and negotiating adolescence. Therefore, care of children with long-term health conditions needs to be tailored to the individual condition and to the many implications of the presence of the condition over time in domains such as education, psychosocial development, linear growth, family functioning, and negotiation of life stages. The more complex the condition, the more complicated the care becomes, and concomitantly the more the risks of secondary disability and maladjustment rise. With the recent advances in medical and surgical care, many children with previously fatal health problems are surviving to and through adolescence into adulthood – with complex disorders. This demographic change brings with it new challenges. In particular, the so-called ‘tasks’ of adolescence – namely ‘spousing’ (finding a life partner), ‘carousing’ (making lifestyle decisions), ‘housing’

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(developing independence and autonomy) and ‘job market browsing’ (finding a career) – are rendered more challenging and risky in the presence of a complex long-term health condition. For many children with milder conditions such as atopic diseases, care through childhood and adolescence into adulthood may occur within the primary healthcare context, with little turbulence as the life stages pass. However, most children and adolescents with more complex long-term health conditions require specialised healthcare, often rendered by a multidisciplinary team. Unfortunately the primary care practitioner is often not included in this team.

transition principles have been described and a variety of models have been proposed and implemented, outcome data are still lacking, especially those that would support one model over another’.[3] Over the last 20 years, many models have been described, theories expounded and opinions given, but there is little research to guide healthcare providers. This is not surprising, given the complex and varying situations in which transition has to occur. Health services differ, health conditions do not have the same implications and vary in severity, and significant numbers of patients and families followed up over lengthy periods are required to provide valid conclusions in any interventional research.

Transition of care

What is known about the process of transition and what impedes or promotes it

Adolescents growing older with a complex long-term health condition (and their families) almost inevitably face a change of healthcare provider/s. Specialised healthcare has to a large extent dichotomised children and adults, with adolescents often left out in the cold. This situation presents many challenges to those dealing with complex long-term health conditions. In particular, negotiating the ‘transition’ from paediatric care through adolescent-orientated care to adult care requires attention. This transition has been the subject of much discussion and many descriptions, but there has been limited research into outcomes of the transition processes. This article attempts to provide insights into this literature. Twenty years ago the Society of Adolescent Medicine defined transition as ‘the purposeful planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adult-centred healthcare systems’.[2] It was acknowledged then that much was unknown about the process. The need for the transition process to be studied and evaluated was emphasised. Ten years later the same society lamented: ‘Although

In an article analysing transition in cystic fibrosis, Schidlow and Feil[4] usefully spelt out generic factors related to the patient, the family and the healthcare providers that enhance or hinder a successful transition (Table 1). In the South African context, ‘economic concerns’ might not be expected to have the prominence given in this American perspective. Rosen[5] pointed out the cultural differences between child- and adultorientated services that may impede successful transition: in effect, the paediatric environment is nurturing while the adult one expects independent behaviour from the patient. In the long-term health condition arena, the former could inhibit the patient’s maturation, while the latter expects too much maturity. A child with a long-term health condition needs to be encouraged to take on the health problem and its implications, while the parents need to be encouraged to step back; the adult healthcare provider must not expect a fully fledged adult even if the patient is of adult age. The patient’s family usually still has a significant role to play in the life of the adult with a long-term health condition.

Table 1. Factors that influence the success of transition from child- to adult-orientated healthcare[4] The patient

Dependent behaviour Immaturity Severe illness or disability Psychopathology Lack of support systems Lack of trust in caregivers Poor adherence to treatment regimens

The paediatric caregivers

Economic concerns about programme Emotional bonds with patient and family Comfort with status quo Perception of own skills as caregivers of adults Perception of potential survival of patients Distrust of adult caregivers Ambivalence towards transition and transfer of care

The family

Excessive need for control Emotional dependency Psychopathology Parenting styles leading to overprotection Heightened perception of disease severity Lack of trust in caregivers Mistaken perception of potential survival

The adult caregivers

Economic concerns Lack of understanding of congenital disease Lack of familiarity with disease entities Heightened perception of care demands Lack of institutional commitment

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For children with significant neurodisability and cognitive difficulties, this transition is made even more complex. In an unpublished study undertaken in Cape Town in the 1990s, we found that the greatest difficulty in transition was in the neurology clinic, while the simplest transition took place in the neurosurgical service. The former has a high incidence of secondary epilepsy together with motor and cognitive difficulty, which the adult neurology service felt was not their core business and yet was (and still is) not covered well anywhere else in the health system; the neurosurgical division had staff who covered both the adult and child services (Westwood A, Henley L – unpublished report 1998). These case studies illustrate how individual health conditions and health services can impede or encourage successful transition to adult services. The biggest impediment to transition is the shortage of suitable adult services due to a lack of expertise in childhood-onset health conditions among adult service providers. This has become less of an impediment in many countries as numbers of young people growing up with conditions such as congenital heart disease and cystic fibrosis have grown. How well prepared is an adult endocrinologist or physician in South Africa to deal with the young person who has had type 1 diabetes mellitus for years? South Africa faces a particular challenge with regard to its expanding and ageing paediatric HIVinfected population. The issues have been well described in a technical brief by USAID and PEPFAR in 2012.[6] Importantly, age-based criteria for the transfer to the adult service are to be avoided. Given the wide range of levels of maturity and readiness that are likely to be found among young people, such rigid criteria are unlikely to promote successful transition. In a study of patient and parent attitudes towards transition before and after the process in the cystic fibrosis population, age-related criteria were not supported.[7] They also do not make sense developmentally. This approach has been strongly supported by the Society for Adolescent Medicine[3] and the American Academy of Pediatrics.[8]

What transition models exist and which are likely to work?

Given the complexity of transition and the lack of a large research base, there are many potentially valid models of transition. An important theme would seem to be exposure of the young person and family to the adult care providers. This can be achieved through visits to the paediatric and adult services in the years before formal transfer. Where patient numbers are adequate, adolescent transition clinics (shared by the paediatric and adult teams) have been successful. Among other advantages, these clinics provide peer support that facilitates safe passage to the adult service. The recent literature has explored the concept of a transition co-ordinator, first proposed in the position paper from the Society for Adolescent Medicine.[2] This health team member is envisaged as spearheading preparations for patients and families, while also serving

as a conduit between old and new team members. This co-ordinator will usually be a nurse, but could be a primary care practitioner. Recently, Schwartz et al.[9] attempted to operationalise the model of transition readiness that takes account of the phases of care as well as the individual factors of ‘socio-ecology’ in the child, parent and providers. In this model multiple assessments are done before the actual transfer takes place. The model espoused for HIV transition care in Africa is that of family-centred care ‘delivered by a multidisciplinary team that provides support for adolescents with HIV infection, with the adolescent infected perinatally or by sexual transmission, as well as the parent or guardian caregivers ... ’.[10] This approach reflects the special needs of HIV care in the African context where HIV tends to be a family disease, and is a unique model in the transition literature. This is the closest model one finds to a primary care-based model for transition and it challenges the assumption that co-ordination of care, including transition, needs to be led by specialised services. However, in South Africa there is currently very limited primary healthcare engagement with children with more complex long-term health conditions, especially during adolescence. This does not preclude exploration of the role of primary healthcare in transition for young people with long-term health conditions, and perhaps HIV, now the commonest complex long-term health condition in this country, will lead the way.

Specific issues in spina bifida

The value of a multidisciplinary clinic is well established, although such clinics appear to be more common in public teaching hospitals than in private practice. It also seems easier to organise such clinics in a paediatric setting than an adult service where care tends to fragment into individual specialties. Various surgical disciplines such as urology and neurosurgery need to follow up these patients through adulthood, as the life-threatening consequences of the neuropathic bladder or shunt obstruction are well known. Loss of ambulation in late childhood is a well-recognised problem[11,12] that may be due to accepting the improved energy efficiency of a wheelchair, psychological factors or weight gain, but subtle neurological deterioration due to shunt dysfunction or a tethered spinal cord must be excluded.[13] Consideration must also be given to sexuality and planning for pregnancy and delivery.

Transition in cerebral palsy

It is worth emphasising that people with other conditions associated with neurodisability, such as cerebral palsy, also face significant challenges in transition of care. This was clearly apparent to the authors in a long-term follow-up study of young adults who had undergone the neurosurgical procedure of selective dorsal rhizotomy in Cape Town. Twenty years after surgery, all the patients continued to experience sustained improvement in spasticity but none was

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receiving physiotherapy or any regular medical follow-up, despite persistence of the underlying condition.[14] A recent review of functional levels in adolescents and children with cerebral palsy pointed to the need for specific co-ordinated care, including preventive care, access to emergency services and involvement of subspecialists, which should start early in the teenage years.[15] Information systems that provide specific care protocols are of value, as well as a registry that can be used for tracking physical, behavioural and functional health status. Ensuring adequate medical care should be coupled with encouraging independence, particularly with regard to financial management and access to community resources. Modern tools, such as an online support systems, may help mentor people during their transition and thereafter connect them with a cerebral palsy community, making them less isolated and strengthening their companionship and independence.

Conclusion

Transition must be prepared for and planned during childhood from the time of diagnosis of the long-term health condition. The family and child require support to promote the young person’s ability to take ownership of his or her health situation and therapies by the time of adolescence. The paediatric and primary healthcare teams bear responsibility for this. Bilateral systems that bridge and break down the divide between child- and adult-orientated care must be set up. Many mechanisms exist that can be adapted to specific health conditions and health service configurations. Adult-orientated service needs to ensure that there is adequate understanding of the formerly paediatric-only conditions and of young adults and their families so that the ‘medical home’ of paediatrics and primary care can also be found in adult services.

Summary

• Long-term health conditions in childhood include both congenital conditions and acquired diseases. • Children with long-term health conditions face issues and potential secondary problems that are different from those of adults with chronic diseases.

• Transition to adult-orientated care for such children and adolescents is a major challenge. • Transition needs to be prepared for and planned. • A variety of possible transition models exists, depending on circumstances.

References 1. Stein REK, Bauman LJ, Westbrook LE, Coupey SM, Ireys HT. Framework for identifying children who have chronic conditions: The case for a new definition. J Pediatr 1993;122:342-347. [http:// dx.doi.org/10.1016/S0022-3476(05)83414-6] 2. Blum RWM, Garell D, Hodgman CH, et al. Transition from child-centered to adult health-care systems for adolescents with chronic conditions. J Adolesc Health 1993;14:570-576. [http://dx.doi. org/10.1016/1054-139X(93)90143-D] 3. Rosen DS, Blum RW, Britto M, Sawyer SM, Siegel DM. Transition to adult health care for adolescents and young adults with chronic conditions: Position paper of the Society for Adolescent Medicine. J Adolesc Health 2003;33:309-311. 4. Schidlow DV, Feil SB. Life beyond pediatrics. Med Clin North Am 1990;74:1113-1120. 5. Rosen D. Between two worlds: Bridging the cultures of child health and adult medicine. J Adolesc Health 1995;17:10-16. [http://dx.doi.org/10.1016/1054-139X(95)00077-6] 6. Sharer M, Fullem A. Transitioning of Care and Other Services for Adolescents Living With HIV in Sub-Saharan Africa: Technical Brief. USAID and PEPFAR. Arlington, VA: AIDSTAR-One, 2012. 7. Westwood ATR, Henley LD, Willcox P. The transition from paediatric to adult care for persons with cystic fibrosis: Patient and parent perspectives. J Paediatr Child Health 1999;35:442-445. [http:// dx.doi.org/10.1046/j.1440-1754.1999.355394.x] 8. American Academy of Pediatrics, American Academy of Family Physicians, American College of Physicians-American Society of Internal Medicine. Consensus statement on health care transitions for young adults with special health care needs. Pediatrics 2002;110:1304-1306. 9. Schwartz LA, Tuchmann LK, Hobbie WL, Ginsberg JP. A social-ecological model of readiness from transition to adult-oriented care for adolescents and young adults with chronic health conditions. Child Care Health Dev 2011;37:883-895. 10. Coovadia H, Mantell JE. Adolescents and HIV in sub-Saharan Africa: A timely issue and missed opportunity. Clin Infect Dis 2011;51:852-854. [http://dx.doi.org/10.1086/656362] 11. Bowman RM, McLone DG, Grant JA, Tomita T, Ito JA. Spina bifida outcome: A 25-year prospective. Pediatr Neurosurg 2001;34:114-120. 12. Vinchon M, Dhellemmes P. The transition from child to adult in neurosurgery. Adv Tech Stand Neurosurg 2007;32:3-24. 13. Binks J, Barden JS, Burke TA, Young NL. What do we really know about the transition to adultcentered health care? A focus on cerebral palsy and spina bifida. Arch Physical Med Rehab 2007;88:1064-1073. 14. Langerak NG, Hillier SL, Verkoeijen PP, Peter JC, Fieggen AG, Vaughan CL. Level of activity and participation in adults with spastic diplegia 17-26 years after selective dorsal rhizotomy. J Rehabil Med 2011;43:330-337. [http://dx.doi.org/10.2340/16501977-0669] 15. Frisch DF, Msall ME. Health, functioning, and participation of adolescents and adults with cerebral palsy: A review of outcomes research 2013;18:84-94.

Further reading • Sawyer SM, Drew S, Yeo M, Britto M. Adolescents with a chronic condition: Challenges living, challenges treating. Lancet 2009;369:1481-1489. • Watson R, Parr JR, Joyce C, May C, Le Couteur AS. Models of transitional care for young people with complex health needs: A scoping review. Child Care Health Dev 2011;37:780-791.

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ARTICLE SUMMARY

The orthopaedic management of myelomeningocele A Horn,1 MB ChB; S Dix-Peek,2 MB BCh, FCS SA (Orth), MMed; S Mears,2 MB ChB, FCS SA (Orth); E B Hoffman,2 MB ChB, FCS SA (Orth) 1 2

Department of Orthopaedics, Faculty of Health Sciences, University of Cape Town, South Africa Paediatric Orthopaedics, Red Cross War Memorial Children’s Hospital and University of Cape Town, South Africa

Corresponding author: S Dix-Peek (sdixpeek@gmail.com)

Despite improvement in antenatal care and screening, myelomeningocele remains the most common congenital birth defect, with a reported incidence of 1 - 2.5/1 000 patients in the Western Cape, South Africa. The multidisciplinary team involved in the Spinal Defects Clinic at Red Cross War Memorial Children’s Hospital, Cape Town, South Africa consists of neurosurgeons, urologists, orthopaedic surgeons, stomatherapists and orthotists. Orthopaedic surgeons have a protean involvement in the management of myelomeningocele.

Goals of treatment and walking potential

The holistic approach to a patient with spina bifida involves that the treating orthopaedic surgeon realises that mobility is only one of many treatment priorities. These patients’ needs, in order of importance, are a stable self-image, an adult sexual role, independent communication, daily living activities, a career and, lastly, mobility. Orthopaedic interventions should therefore be simple and tailored to the patient’s walking ability, based on neurological level. As these patients age, they tend to gain weight, thereby increasing the work of ambulation to the point where wheelchair mobility becomes preferable to walking.

Spinal deformity

Spinal deformity occurs almost exclusively in the paraplegic groups of patients. Scoliosis is a result of the weak or paralysed paraspinal musculature and usually develops by the age of 10 years. The resulting pelvic obliquity leads to loss of sitting balance and necessitates the use of the patient’s arms for support, thereby reducing function. Asymmetrical buttock pressure distribution and the absence of sensation may result in ischial pressure sores. Surgical scoliosis correction is reserved for curves exceeding 50° and involves instrumented fusion from T2 to the pelvis. This corrects sitting balance, but decreases lumbosacral mobility. It may also cause

difficulty in wheelchair transfer and an increased propensity to develop trophic ulcers.

Hip

Muscle imbalance (absent abductors and/or extensors) in the myelomeningocele patient leads to subluxation or dislocation of the hip, which is pushed laterally and superiorly. This then leads to secondary bony deformation of the femoral neck and acetabulum.

Knee

The knee rarely requires surgery in ambulatory patients. Hyperextension deformities respond well to serial plasters, particularly in patients <1 year of age. If persistent, quadriceps and capsular release procedures can be performed.

Tibial torsion

Persistent internal torsion in patients >5 years with a mid-lumbar myelomeningocele is treated with a supramalleolar de-rotation osteotomy and T-plate fixation. External tibial torsion is seen in older children. It can aggravate existing knee and ankle valgus and is treated similarly.

Foot

The aim of treatment of foot deformities is to obtain a plantigrade, mobile and braceable foot, and to avoid trophic ulceration that leads to significant morbidity and may culminate in amputation. An important study by Maynard et al. found that 94% of feet of patients with myelomeningocele require surgery. Postoperatively, the incidence of trophic ulceration in flexible plantigrade feet was 0%, in flexible non-plantigrade feet 25%, in rigid plantigrade feet 36%, and in rigid non-plantigrade feet 100%. It is therefore imperative to obtain a plantigrade foot and to avoid operations that create stiffness.

S Afr Med J 2014;104(4):314. DOI:10.7196/SAMJ.8160

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ARTICLE SUMMARY

Hydrocephalus in spina bifida T Morgado, MB ChB, MRCS (Eng); A Figaji, MB ChB, PhD, FCNeurosurg (SA) Division of Paediatric Neurosurgery, University of Cape Town and Red Cross War Memorial Childrenâ&#x20AC;&#x2122;s Hospital, Cape Town, South Africa Corresponding author: T Morgado (tiagoclementemorgado@gmail.com)

Hydrocephalus is one of the most common complications of spinal dysraphism. Although few patients require cerebrospinal fluid diversion immediately at birth or within the first few days of life, most patients with myelomeningocele, which comprises the most prevalent, clinically significant form of spina bifida, will eventually need surgical treatment for hydrocephalus at some point following closure of the spinal defect. Furthermore, symptomatic hydrocephalus needs to be dealt with timeously, as these patients not only face the usual ill-effects of raised intracranial pressure (ICP), but also have an increased risk of breakdown of the myelomeningocele repair. Poorly treated ICP may also cause the Chiari II malformation to become symptomatic.

and progressive disorder associated with increased ICP. Daily clinical assessment involves examination of the fontanelle and measurement of the head circumference. Symptoms such as poor feeding, lethargy or drowsiness should raise suspicion of a developing hydrocephalus.

Incidence

Cranial ultrasonography at birth is the usual method for diagnosing ventriculomegaly in the neonate. It is cheap, non-invasive, and both technically and logistically easier to perform than MRI. Routine MRI is seldom required prior to myelomeningocele repair, but may be useful in the postoperative period, providing very detailed information on both intracranial and spinal pathology. Computed tomography (CT) remains one of the most sensitive, widely available modalities to confirm hydrocephalus and plan treatment. However, there is growing concern about the radiation effects of CT on the developing brain in terms of cognitive development and induction of tumours.

Hydrocephalus is associated mainly with the open form of spina bifida and our article focuses specifically on this group of patients. Most children who develop symptomatic hydrocephalus do so within the first few days or weeks following myelomeningocele repair, with >80% ultimately requiring a surgical procedure to treat the condition.

Pathogenesis

The underlying developmental abnormalities and the exact pathogenesis of hydrocephalus remain subject to debate. Children with hydrocephalus virtually always have a Chiari II malformation, which is characterised by an abnormal posterior fossa and herniation of the cerebellar vermis across the foramen magnum. Several other structural and developmental abnormalities are usually present in association with the Chiari II malformation, but the hindbrain hernia is clinically the most important manifestation.

Clinical features

Careful physical examination with a high index of suspicion for hydrocephalus is essential in managing these patients. Ventriculomegaly may be diagnosed antenatally or postnatally with various imaging modalities. However, by definition hydrocephalus implies a dynamic

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Prenatal diagnosis

High-resolution fetal ultrasound scanning can reliably detect hydrocephalus in utero, assessing not just ventricular size but also typical skull vault abnormalities suggestive of the condition. Although more costly, fetal magnetic resonance imaging (MRI) is another non-invasive option in cases where ultrasound is not diagnostic or is inconclusive.

Postnatal diagnosis

Treatment options

The two main recognised definitive procedures to treat hydrocephalus in myelomeningocele patients are ventriculoperitoneal shunt (VPS) insertion and endoscopic third ventriculostomy (ETV). One has to manage hydrocephalus when it becomes clinically apparent. VPS insertion has a significant failure rate and the open nature of myelomeningocele increases the risk of shunt infection. ETV carries a smaller risk of infection. Even though hydrocephalus is common, it may be difficult to treat. If ventriculitis can be avoided, most of these children can achieve a fairly good cognitive outcome. S Afr Med J 2014;104(4):315. DOI:10.7196/SAMJ.8194

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ARTICLE SUMMARY

Occult spinal dysraphism N Mankahla, MB ChB; A Figaji, MB ChB, PhD, FCNeurosurg (SA) Paediatric Neurosurgery Unit, Division of Neurosurgery, University of Cape Town and Red Cross War Memorial Childrenâ&#x20AC;&#x2122;s Hospital, Cape Town, South Africa Corresponding author: N Mankahla (ncefactor@ananzi.co.za)

Occult spinal dysraphism (OSD) refers to a diverse group of congenital abnormalities resulting from varying degrees of disordered neuro-embryogenesis. Several terms have been used to describe these conditions, including spina bifida occulta and closed neural tube defects. By definition, OSD is characterised by intact overlying skin, although most patients have some form of cutaneous stigmata. Because the underlying pathology is so variable, the clinical presentation and course of the condition vary from severely disabling to asymptomatic throughout life. Management usually requires a multidisciplinary team comprising paediatricians, paediatric neurosurgeons, urologists, orthopaedic surgeons, occupational therapists, physiotherapists and geneticists. Although the spectrum of dysraphic abnormalities includes cranial anomalies (encephalocele), this article will focus on the spinal manifestations.

Epidemiology

normal. The primary concern, however, is late neurological deterioration (at any time from the first few months of life through to adulthood) as a consequence of mechanical stretch and ischaemic injury.

Clinical presentation

Often findings on examination of the newborn are apparently normal, but it must be remembered that neurological examination at this stage is relatively insensitive to subtle upper motor and lower motor neuron signs, both of which may reflect a static or progressive neurological deficit. Wasting of muscle groups is occasionally noticed, and the anus may demonstrate low external sphincter tone.

Cutaneous stigmata

Although it is termed occult, about 50 - 86% of patients with this disorder will have cutaneous stigmata of dysraphism. These are usually the presenting signs that initiate further investigation.

Unlike open dysraphism, the exact prevalence of occult dysraphic disorders is unclear, in part because many patients remain asymptomatic. The literature reports a combined incidence of spina bifida (open and closed) between 0.5 and 2.5/1Â 000 live births, varying among regions and populations. The incidence of OSD depends on how frequently relatively minor abnormalities are investigated and how often conditions are detected coincidentally.

Investigation and diagnostics

Embryology

Management

A clear understanding of the clinical and radio-pathological spectrum of OSD requires an appreciation of the basic embryology of the nervous system. This will be discussed briefly. The primary clinical problem in all these children is a tethered spinal cord, which is the key concept in understanding why they usually require treatment. The embryological problem occurs when the developing spinal cord lies low in the spinal canal. The conus of the spinal cord normally ascends in the spinal canal during fetal growth, as the vertebral column grows disproportionately in length. In OSD, however, the pathology (usually fat) attaches to the spinal cord low in the lumbosacral area, causing it to be tethered distally and progressively stretched. Often there is a neurological deficit related to failure of segmental development; however, sometimes the findings on neurological examination are

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If OSD is suspected, the child should be referred for neurosurgical evaluation, preferably by a paediatric neurosurgeon, and the diagnosis must be made with magnetic resonance imaging. Spinal ultrasound can be performed up to the age of 3 months, but it is unreliable as a stand-alone diagnostic tool because it is user-dependent and has a high false-negative rate.

Indications for surgery depend on the clinical presentation and the underlying pathology. The approach to tethering by an intradural lipoma depends on the presence of symptoms. Management of the asymptomatic patient who presents with cutaneous stigmata alone is controversial.

Conclusion

Although OSD is less apparent than the open variant, it has a significant impact on function and therefore on the lives of both patient and family. A high index of suspicion is needed in order to avoid a missed diagnosis. If OSD is suspected, the patient should be referred to a paediatric neurosurgeon. S Afr Med J 2014;104(4):316. DOI:10.7196/SAMJ.8196

April 2014, Vol. 104, No. 4

CONTINUING MEDICAL EDUCATION

ARTICLE SUMMARY

Beyond the operating theatre: Long-term quality of life in spina bifida Z Toefy, RN and volunteer Spinal Defects Clinic, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa Corresponding author: Z Toefy (zubeidatoefy@gmail.com)

Long-term quality of life in a person born with spina bifida, as in any disability, is dependent on the challenges of that disability being recognised, met and overcome, to prevent patients becoming handicapped.

Challenges Urine

Urinary incontinence may be one of the most difficult challenges for a person with spina bifida to manage effectively, as leakage and the subsequent odour may cause isolation in the home or workplace.

Bowel management

Faecal incontinence involves daily bowel washouts by way of water enemas. This process may be difficult to learn, is unpleasant and cumbersome, and may be painful.

Pressure sores

Pressure sores are a potential problem where there is diminished sensation, such as the pelvic area or the feet. The potential for developing pressure sores is increased in the pelvic area when urinary incontinence prevails.

Regular follow-up

A person with spina bifida should be regularly followed up at a hospital for various reasons.

Further education and employment

The overall development of a child with spina bifida is affected by physical, emotional, social and intellectual factors, and many children need special schooling and further education. Mainstream schools are reluctant to accept these children as they may be academically challenged and have problems (e.g. incontinence), and widespread stigmatisation is common. Ten years ago it was practically impossible for a young person with spina bifida to find employment. With the advent of Further Education Training (FET) colleges and organisations, such as the Siyaya Skills Institute, there are more opportunities for

317

young people with the condition to enter the open labour market.

Mobility

Access to many buildings and homes, as well as travelling, remains a challenge for a person in a wheelchair or on crutches, conferring the label ‘disabled’ to such a person. Society needs to adapt in a way that prevents the person from becoming ‘handicapped’ by the consequences of spina bifida.

Social integration

While there is ignorance about and prejudice towards people with spina bifida, a person who is disabled by the condition may effectively be ‘handicapped’ by society. Primary healthcare projects and community-based groups form an essential part of rooting out this misunderstanding and allowing people with the condition to become integrated into society.

Marriage and family life

The nature of this disability and developmental delay mean that most of these children rely on parental care for a long time, contributing to stressful situations in the family. However, young people less severely affected by spina bifida do marry and live a normal life, as their individual stories will illustrate in the article published online.

Successes

Understanding spina bifida and its management is vital. Often parents and carers of these children are uneducated and come from impoverished communities. Spina bifida patients in rural areas do not benefit from good schooling, owing to the distances they have to travel, particularly in wheelchairs and using crutches. Parents/carers must travel long distances to specialised and comprehensive healthcare services for their child’s needs. This often results in defaulting, which leads to deterioration of the child’s condition. S Afr Med J 2014;104(4):317. DOI:10.7196/SAMJ.8148

April 2014, Vol. 104, No. 4

CONTINUING MEDICAL EDUCATION

ARTICLE SUMMARY

The International Federation for Spina Bifida and Hydrocephalus: Priorities in developing countries L Bauwens, MA, MBA Secretary General, International Federation for Spina Bifida and Hydrocephalus, Brussels, Belgium Corresponding author: L Bauwens (lieven.bauwens@ifglobal.org)

The International Federation for Spina Bifida and Hydrocephalus (IF) is the global umbrella organisation for national and regional spina bifida and hydrocephalus associations. IF has 50 members, representing people with spina bifida and hydrocephalus from 46 countries. IF’s mission is to increase the quality of life of persons with these disabilities and to decrease the incidence of spina bifida and hydrocephalus by primary prevention. IF’s members share this mission and work locally to achieve these goals.

Primary prevention

Primary prevention involves fortifying flour with folic acid. Countries that have obligatory folic acid fortification of flour report an average of 46% reduction in the incidence of neural tube defects at a very favourable cost-benefit ratio. Other strategies involve publicising the importance of folic acid supplementation (400 µg daily), starting around 8 weeks prior to conception. However, compliance is generally low, particularly among women in developing countries. Reducing the incidence of spina bifida reduces the incidence of hydrocephalus, although primary prevention is difficult because of the multiple aetiology of the latter. In developing countries, around 60% of cases of hydrocephalus are the result of poorly treated ventriculitis; therefore, further research into preventing neonatal infection is required.

motivation of parents and caregivers and reinforce prejudices about the condition. Timely and affordable treatment is necessary to end stereotypical thinking about the disabilities associated with the condition. With visibly better outcomes, parents and caregivers are more motivated and the children become role models for similarly disabled children and their parents and carers. Disabled persons’ organisations, such as IF and its members, have become more important in the design, implementation and evaluation of programmes in developing countries. The United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) (especially Art. 25 on Health Care and Art. 26 on Habilitation and Rehabilitation) and the World Health Organization’s resolutions on birth defects (2010) and disabilities (2013) assign more importance to empowering people with disabilities and their families. IF started its programmes in developing countries in 1993 with the training of health workers in Kenya in the wake of the global conference held by Rehabilitation International. IF has learned much over these 20 years of experience. The four most important areas are: access to initial treatment with affordable shunts; access to life-long follow-up; access to healthcare (particularly continence management); and the importance of parents’ and children’s roles in the process.

Improving quality of life

Quality of life issues in developing countries depend on the availability and accessibility of healthcare services. Without access to good-quality, affordable care the prospects for newborns with spina bifida and hydrocephalus are grim. Poor outcomes will damage the

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• http://ifglobal.org/en/ • http://ifglobal.org/en/what-we-do/publications-and-downloads/international-solidarity

S Afr Med J 2014;104(4):318. DOI:10.7196/SAMJ.8202

April 2014, Vol. 104, No. 4

PULSE

Bayer’s Xarelto approved in South Africa across five additional indications

Bayer HealthCare’s oral anticoagulant Xarelto 15 and 20 mg (rivaroxaban) has been approved by the Medicines Control Council of South Africa (MCC) for use in five new indications in addition to prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs (10 mg), making it the only new oral anticoagulant approved in six indications across the world. The new indications are prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) (15 and 20 mg), treatment of deep-vein thrombosis (DVT) (15 and 20 mg), prevention of recurrent DVT (15 and 20 mg), treatment of pulmonary embolism (PE) (15 and 20 mg), and prevention of recurrent PE (15 and 20 mg). ‘The approval in these new indications by the MCC marks the culmination of years of intensive research, and underscores Bayer’s innovative strength,’ said Frans Labuschagne, CDH of Bayer HealthCare South Africa. ‘We are delighted to bring the benefits of rivaroxaban to patients and physicians in South Africa in need of a highly effective and convenient therapy against blood clots to prevent strokes and treat DVT and PE.’ The approval of rivaroxaban for the prevention of AF-related stroke is based on the important clinical benefits demonstrated in ROCKET AF, a rigorous, double-blind global phase III study that compared once-daily rivaroxaban with warfarin in more than 14 000 patients. The results from the ROCKET AF trial were published in the New England Journal of Medicine (NEJM) in August 2011. Its approval for the treatment of DVT and PE and the prevention of recurrent DVT and PE following an acute DVT and PE follows submission of data from the phase III EINSTEIN-DVT study and the phase III EINSTEIN-PE study (NEJM December 2010), and the phase III EINSTEIN-Extension study (NEJM April 2012). Rivaroxaban is the only oral anticoagulant that has consistently demonstrated superior efficacy over enoxaparin for VTE prophylaxis in adult patients undergoing total hip or total knee replacement surgery. The extensive clinical trial programme supporting rivaroxaban makes it the most studied and widely published oral direct factor Xa inhibitor. The studies, reported and ongoing, involve over 100 000 patients for the prevention and treatment of venous and arterial thromboembolic disorders across a broad range of both acute and chronic conditions. Anticoagulant medicines are potent drugs used to prevent or treat serious illnesses and potentially life-threatening conditions. Before initiating therapy with anticoagulants, doctors should carefully assess the benefit and risk for the individual patient. Responsible use of Xarelto is a very high priority for Bayer, and the company has developed a Prescriber’s Guide for doctors and a Xarelto Patient Card for patients to support best practice.

Enquiries: Anel Berning, Thrombosis Marketing Manager (anel. berning@bayer.com), Lionel Dobell, Xarelto Product Manager (lionel. dobell@bayer.com), Dr Naren Jairam, Xarelto Medical Advisor (naren. jairam@bayer.com). References available on request. For full prescribing information, refer to the package insert approved by the medicines regulatory authority (MCC).

Aspen helps preserve South African pharmaceutical history

Aspen has made a sizeable contribution to the Pharmaceutical Society of South Africa (PSSA) for the introduction of a state-ofthe-art electronic information system and the upgrade of the South African National Pharmacy Museum. ‘This Audio Guide system will significantly enhance the experience of visitors to the museum as they are able to view the wide range of displays while listening to an explanation of the items which interest them,’ commented Ray Pogir, Curator of the Museum. The Museum, established by two members of the PSSA National Executive in 1950, now houses what is arguably the most important documentation of the history of pharmacy in South Africa (SA). Its 1 000-plus artifacts, which are all listed electronically, include an extensive range of the equipment, dispensary bottles and instruments used by pharmacists in the preparation of medicines from as early as the 15th century. Of equal significance is its unique collection of original medicinal plant materials from all over the world, including over 850 samples of phytomedicines and other materials used by South African traditional healers. ‘SA has a rich pharmaceutical history and has been a leader in the formulation and manufacture of generic medicines. Aspen has played a significant role in the history and evolution of the pharmaceutical market, and a good case in point is the Lennon’s range of products, which were introduced by Dr Lennon in 1852 and subsequently the Lennon’s factory in Port Elizabeth which is more than 50 years old and in which the first SA generic medicines were manufactured. Today, the Lennon factory and its site have been transformed into a world-class manufacturing site housing world-class manufacturing across a number of dosage forms, with international accreditation from some of the most stringent regulators,’ commented Stavros Nicolaou, Aspen’s Senior Executive. The museum is visited by pharmacists, pharmacy students, historians and members of the general public who study the artifacts and consult the range of over 1 000 books dealing with pharmaceutical and medical subjects. ‘The main objective of this upgrade is to make this rich pharmacy history accessible to more people, including pharmacy students, pharmacists and the healthcare fraternity at large,’ concluded Pogir.

Enquiries: Aspen’s medical information hotline, 0800 118 088.

April 2014, Vol. 104, No. 4

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CPD

APRIL 2014

Effective in 2014, the CPD programme for SAMJ will be administered by Medical Practice Consulting: CPD questionnaires must be completed online at www.mpconsulting.co.za

True (A) or false (B): The safety of osteoporosis medication 1. Osteoporosis is a common, costly and serious disease with 1/5 patients dying within 1 year following a hip fracture. 2. Treatment of osteoporosis with calcium and vitamin D is associated with an impressive reduction in fracture risk. 3. In the absence of contraindications, the use of menopausal hormone (oestrogen without or without progestin) therapy in women aged 50 - 60 years is safe and appropriate to manage osteoporosis, and is the drug of choice if menopausal symptoms are present. The risks of gastrointestinal injury due to ingested magnetic beads 4. When multiple individual magnets are ingested, they can conglomerate in different segments of bowel causing pressure necrosis, perforation and/or fistula formation anywhere along the gastrointestinal tract. Acute porphyria 5. The symptomatic patient with an acute, severe porphyria typically presents with a sudden onset of a characteristic syndrome of acute abdominal pain, which may progress to a sudden onset of quadriparesis over the course of a few hours. High prevalence of cisplatin-induced ototoxicity 6. Cisplatin is one of the most widely used and effective cytotoxic agents currently available for the treatment of soft-tissue cancers, with a reported cure rate of up to 85%. 7. Cisplatin-induced ototoxicity is dependent on age at initiation of treatment, with those <5 years and those >40 years of age being most susceptible. Angiotensin converting enzyme inhibitors (ACEIs) v. angiotensin receptor blockers (ARBs) in the management of hypertension 8. Hypertension is the most prevalent chronic disease among medical aid members, affecting ~12%. 9. In the drug utilisation review process, managed-care companies should continue to recommend ACEIs, rather than ARBs, in the treatment of their hypertension patients.

Mammographic screening for breast cancer in a resource-restricted environment 10. After carcinoma of the cervix, breast cancer is the second most common female cancer in South Africa. Hydrocephalus in spina bifida 11. More than 80% of those who develop hydrocephalus ultimately require a surgical procedure to treat the condition. 12. Daily clinical assessment of hydrocephalus involves examination of the fontanelle and measurement of the head circumference. 13. Once a shunt has been placed, the later development of symptoms or signs of Chiari malformation or syringomyelia should raise suspicion of shunt failure. Occult spinal dysraphism 14. In occult spinal dysraphism, spinal lipomas and dermal sinus tracks are the most common disorders presenting as clinical problems. 15. About 50 - 86% of patients with occult spinal dysraphism will have cutaneous stigmata. 16. If a patient has an anorectal malformation it is routine to perform spinal magnetic resonance imaging to exclude an associated tethered spinal cord. The orthopaedic management of myelomeningocele 17. The primary goal of the orthopaedic management of myelo足 meningocele is mobility. 18. In the paraplegic group, spinal scoliosis usually develops by the age of 10 years. Beyond the operating theatre: Long-term quality of life in spina bifida 19. Incontinence of urine is managed effectively using a regimen of 3-hourly self-catheterisation, daily bowel washout and anticholinergic drugs three times per day. 20. The potential for pressure sores is increased in the pelvic area by urinary incontinence.

CPD questions include articles from CME. The full versions of each article can be found on the SAMJ website (http://www.samj.org.za)

A maximum of 3 CEUs will be awarded per correctly completed test.

INSTRUCTIONS 1. Read the journal. All the answers will be found there. 2. Go to www.mpconsulting.co.za to answer the questions. Accreditation number: MDB001/007/01/2014 (Clinical)

April 2014, Vol. 104, No. 4

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APRIL 2014

VOL. 104 NO. 4

275

Dangers of children swallowing magnetic beads

277

Safety of osteoporosis medication

279 blished by theociSoautiothn, the

Neurological manifestations of the acute porphyrias SciELO (SA) – enhancing visibility of SA research CME: Spina bifida

SAMF

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