SAMJ Vol 107, No 5 (2017) by HMPG

MAY 2017

PRINT EDITION

Skin Manifestations

Hypomelanotic macule (white patch)

Shagreen patch

Ungual fibroma

Facial angiofibromas

Fibrous cephalic plaques

GUEST EDITORIAL Brain Manifestations Undergraduate antibiotic stewardship training CME Tuberous sclerosis complex nodules Subependymal giant cell IN PRACTICE Subependymal (white arrows) astrocytoma (white arrow) The future of the voluntary active euthanasia OtherAfrica Manifestations debate in South Using social media: ethical and legal aspects

Cortical tubers (black arrows)

CASE REPORT Lead poisoning in shooting-range workers RESEARCH Bilateral renal angiomyolipomas Lymphangiolyomyomatosis (LAM) Critical care admission of South African surgical patients Influence of HIV on tuberculosis

Retinal hamartoma

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MAY 2017 PRINT EDITION

GUEST EDITORIAL 3

Undergraduate antibiotic stewardship training: Are we leaving our future prescribers ‘flapping in the wind’? A Brink, J Schoeman, G Muntingh

EDITOR’S CHOICE CORRESPONDENCE

A randomised controlled trial comparing laparoscopy with laparotomy in the management of women with ruptured ectopic pregnancy F Odejinmi, R Oliver; response from L C Snyman, T Makulana, J D Makin

EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB EDITORS EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) JP de V van Niekerk, MD, FRCR ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman, J M Pettifor, W Edridge, R P Abratt HMPG

Naude et al. avoid answering the essential question: Mistake or mischief? Z Harcombe, T Noakes

CEO AND PUBLISHER Hannah Kikaya Email: hannahk@hmpg.co.za

A skin test for latent tuberculosis C L Crawford

Serratia marcescens infection or hypoxic-ischaemic encephalopathy in neonates: Is magnetic resonance imaging a problem-solving tool? D Narese, C Auriti, D Longo

MANAGING EDITORS Ingrid Nye Claudia Naidu

IZINDABA 16

30 days in medicine B Farham

PRODUCTION MANAGER Emma Jane Couzens

CONTINUING MEDICAL EDUCATION

DTP AND DESIGN Clinton Griffin Travis Arendse

GUEST EDITORIAL Meeting the complex needs of individuals with rare genetic disorders in South Africa – lessons from tuberous sclerosis complex P J de Vries ARTICLE Diagnosis, monitoring and treatment of tuberous sclerosis complex: A South African consensus response to international guidelines P J de Vries, L Leclezio, J M Wilmshurst, G Fieggen, E Gottlich, L Jacklin, I P Naiker, R Newaj, D Shamley, B Schlegel, A Venter

IN PRACTICE 30 32

MEDICINE AND THE LAW Health research and safeguards: The South African journey A Dhai Assisted suicide and assisted voluntary euthanasia: Stransham-Ford High Court case overruled by the Appeal Court – but the door is left open D J McQuoid-Mason Human dignity and the future of the voluntary active euthanasia debate in South Africa D W Jordaan

Ethical and legal perspectives on use of social media by health professionals in South Africa B Kubheka

Biobanks in South Africa: A global perspective on privacy and confidentiality R Rheeder

Legal liability for failure to prevent pregnancy (wrongful pregnancy) L C Coetzee

CASE REPORTS Paraquat poisoning: Acute lung injury – a missed diagnosis S D Ntshalintshali, T C Manzini A rare case of massive hepatosplenomegaly due to acute lymphoblastic leukaemia in pregnancy R Gonçalves, R Meel

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May 2017, Print edition

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RESEARCH 54

Critical care admission of South African (SA) surgical patients: Results of the SA Surgical Outcomes Study* D L Skinner, K de Vasconcellos, R Wise, T M Esterhuizen, C Fourie, A Goolam Mahomed, P D Gopalan, I Joubert, H Kluyts, L R Mathivha, B Mrara, J P Pretorius, G Richards, O Smith, M G L Spruyt, R M Pearse, T E Madiba, B M Biccard; on behalf of the South African Surgical Outcomes Study (SASOS) investigators

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Factors associated with contracting malaria in Ward 29 of Shamva District, Zimbabwe, 2014* G Muchena, N Gombe, L Takundwa, M Tshimanga, D Bangure, N Masuka, T Juru

Members of the South African Medical Association receive the SAMJ only on request, as part of their membership benefit.

Predicting postoperative haemoglobin changes after burn surgery* P Slabber, Z Farina, N Allorto, R N Rodseth

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Influence of HIV and other risk factors on tuberculosis* S Mahtab, D Coetzee

Bacteria isolated from the airways of paediatric patients with bronchiectasis according to HIV status* C Verwey, S Velaphi, R Khan

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Obstructive pulmonary disease in patients with previous tuberculosis: Pathophysiology of a community-based cohort* B W Allwood, R Gillespie, M Galperin-Aizenberg, M Bateman, H Olckers, L Taborda-Barata, G L Calligaro, Q Said-Hartley, R van Zyl-Smit, C B Cooper, E van Rikxoort, J Goldin, N Beyers, E D Bateman

Validating the utilisation of venous bicarbonate as a predictor of acute kidney injury in crush syndrome from sjambok injuries* D L Skinner, G L Laing, J Bruce, B Biccard, D J J Muckart

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Codeine misuse and dependence in South Africa: Perspectives of addiction treatment providers* C D H Parry, E Rich, M C van Hout, P Deluca

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Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10* A Vorster, P Beighton, M Chetty, Y Ganie, B Henderson, E Honey, P Maré, D Thompson, K Fieggen, D Viljoen, R Ramesar

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MAY 2017

PRINT EDITION

Skin Manifestations

Background photo: Simão Magoma, a técnico de cirurgia (medical technician) at Caia District Hospital in Sofala Province, Mozambique, performs a C-section on Isabel Alfredo in the hospital’s operating theatre | Shaun Swingler Box photos: Script | Inked Pixels; Tuberous sclerosis, skin symptom | de Vries et al.; Twitter logo

May 2017, Print edition

Hypomelanotic macule (white patch)

Shagreen patch

Ungual fibroma

Facial angiofibromas

Fibrous cephalic plaques

Cortical tubers (black arrows)

Retinal hamartoma

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

GUEST EDITORIAL

Undergraduate antibiotic stewardship training: Are we leaving our future prescribers ‘flapping in the wind’? A multisite survey of South African (SA) medical students’ perceptions and knowledge of antibiotic resistance (ABR) and appropriate prescribing by Wasserman et al.,[1] published in this edition of the SAMJ, demonstrates that our final-year medical undergraduates are clearly inadequately prepared for practice. Moreover, crucial gaps in knowledge and poor understanding of antibiotic stewardship (AS) and infection control, vary geographically. This first-in-kind crosssectional survey of the preparedness of final-year medical students to prescribe antibiotics identified several enablers that necessitate alternative educational strategies and interventions that could decisively affect the prescribing by graduates. In keeping with a recent study of final-year SA pharmacy students,[2] by far the majority of respondents reported that they would prefer more education on appropriate antibiotic use. In fact, less than two-thirds reported being familiar with the term ‘antibiotic stewardship’. More disconcerting, only a third of respondents felt confident to prescribe antibiotics, with similar proportions across institutions. Prescribing confidence was significantly associated with several determinants, such as access to antibiotic prescribing guidelines, familiarity with AS, and more frequent contact with infectious diseases specialists. In contrast, the least perceived measures to improve preparedness were more contact with microbiologists, didactic lectures and the use of computer-based tutorials. Perhaps this suggests that however well-meaning, stewardship-related diagnostic or therapeutic teaching in lectures does not translate into clinical practice. No significant associations were found between knowledge scores and sources of educational information, except paradoxically, lower scores among those students who reported reading medical journals. While the majority of respondents agreed that antibiotics are overused and ABR is a significant problem in SA, for both of these determinants it was perceived to be less of a problem in their own institutions. However, the view of ‘not in my backyard’,[3] which suggests that others overprescribe antibiotics and drive resistance, may contribute to inappropriate prescribing behaviours.[4,5] The underlying cognitive bias for the students’ contradictory views need to be explored and may represent yet another enabler to affect behaviour. In this regard, we need to capitalise on undergraduate students’ perceptions as a matter of priority. While the study did not map AS education among the institutions,[6] existing education in SA medical schools may be augmented by standardisation, focusing on equipping young doctors with the necessary confidence and skills in appropriate antibiotic prescribing at an early stage of their careers, as well as implementing interventions to modify perceptions and behaviours. To mitigate the disparate education that our undergraduates are receiving, consideration should be given to establishing a national collaborative undertaking, similar to the Appropriate Prescribing for Tomorrow’s Doctors (APT) project, which was formed to address similar needs at undergraduate level in Scotland and the UK.[7] The formation of a joint SA working group can facilitate the process of employing standardised learning outcomes of a core consensus stewardship curriculum. Education within such a framework may permit flexibility of delivery, while allowing individual institutions to generate the methods by which the outcomes are achieved, without requiring rigid adherence to a set of standard teaching methods.[7] Ultimately, the principles of ABR and appropriate use are universal across a ‘one health’ platform. It is, therefore, important that other

cadres of healthcare professionals should be included. As a result, surveys to identify gaps in undergraduate education (for which a paucity of data exists internationally for veterinarians and dentists) are required to strengthen undergraduate training and ultimately improve prescribing practices of all healthcare providers in SA. The same applies to nurse practitioners, who are an important cadre of healthcare professional with a proven track record in antibiotic prescribing in SA communities,[8] in addition to intensive-care nurses, who already play a pivotal role in multidisciplinary hospital-based stewardship programmes.[9,10] Opportunities to improve baseline knowledge of pharmacists in SA have already been identified,[2,10] and work to assess barriers and enablers to reduce variability in stewardship education at the eight SA pharmacy schools has begun. Notably, dentists who are not a focus of formal stewardship programmes yet, prescribe a substantial proportion of antibiotics in the outpatient setting. In the UK, dentists prescribe ~10% of antibiotics dispensed in community pharmacies but, similarly to clinicians, they often do so against clear clinical guidelines.[11] Based on prescription data in Canada, dental prescribing increased by 62.2% (1996 - 2013), with proportionate contribution to community consumption increasing from 6.7% to 11.3% of antibiotic prescriptions over the same period.[12] Although data in terms of an SA perspective are not available yet, given the unique local healthcare challenges, there is no reason to believe that it will be much different. Therefore, targeting undergraduate dental students, including dental therapists, who have restricted prescribing privileges, is an important step in minimising overall antibiotic consumption. In animal health, the extensive, non-therapeutic use of antibiotics in food animals for growth promotion, metaphylaxis and prophylaxis raise serious concerns. This issue highlights the vital public health role and tremendous responsibility of veterinarians, who are often tasked with assessing and advising with regard to the conflicting objectives of upholding animal welfare and food security on the one hand, and keeping the interests of human health in mind on the other. Moreover, the major increase in the use of antibiotics in companion animals and recent evidence of the reciprocal transfer of resistant pathogens between pets and their owners should prompt urgent attention to AS in this context.[13] Consequently, the need for a structured curriculum regarding ABR to bridge a similar gap for veterinary students and practitioners is therefore also recognised. Once an outcome-based core curriculum is established, the question remains how and in what format it should be delivered. Based on the students’ responses in this survey regarding the usefulness of various educational modalities and sources, it appears that passive education to teach fundamental stewardship principles should be complemented with active educational approaches, such as interactive e-learning. For example, recognising the crucial role of veterinarians in mitigating ABR, the Centers for Disease Control and Prevention (CDC), USA, have funded the development of a suite of educational materials to promote the responsible veterinary use of antibiotics.[14] The format, an open-access, web-based multimedia curriculum regarding ABR in veterinary practice, was designed for integration into existing veterinary medical courses, but was also a resource for practising veterinarians. Such innovative teaching methods could be developed for SA and shared between medical, dental, pharmacy and nursing schools to standardise AS education with reliable and

May 2017, Print edition

GUEST EDITORIAL

effective sources of information, aiming to improve the overall use of antimicrobials and, as a result, attempt to reduce the current burden of ABR. A key strategy in facilitating appropriate antibiotic prescribing is the early introduction of the relevant knowledge, concepts and skills into undergraduate curricula. Findings from this study of undergraduate medical students promote the need for drastic educational measures in response. The promising enablers identified by Wasserman et al.,[1] combined with the considerable level of attention to ABR, may provide momentum in the right direction when it comes to setting our future stewards on a course of prescribing confidence for the rest of their careers. Adrian Brink Ampath National Laboratory Services, Milpark Hospital, Johannesburg; and Division of Infectious Diseases and HIV Medicine, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa brinka@ampath.co.za Johan Schoeman Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, South Africa George Muntingh Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa

1. Wasserman S, Potgieter S, Shoul E, et al. South African medical students’ perceptions and knowledge about antibiotic resistance and appropriate prescribing: Are we providing adequate training to future prescribers? S Afr Med J 2017;107(5):405-410. https://doi.org/10.7196/SAMJ.2017.v107i5.12370 2. Burger M, Fourie J, Loot D, et al. Knowledge and perceptions of antimicrobial stewardship concepts among final year pharmacy students in pharmacy schools across South Africa. S Afr J Infect Dis 2016;1(3):84-90. 3. Not in my backyard (NIMBY). http://dictionary.cambridge.org/dictionary/english/nimby?a=british (accessed 16 March 2016). 4. Abbo L, Sinkowitz-Cochran R, Smith L, et al. Faculty and resident physicians’ attitudes, perceptions, and knowledge about antimicrobial use and resistance. Infect Control Hosp Epidemiol 2011;32(7):714-718. 5. McCullough AR, Rathbone J, Parekh S, et al. Not in my backyard: A systematic review of clinicians’ knowledge and beliefs about antibiotic resistance. J Antimicrob Chemother 2015;70(9):2465-2473. https://doi.org/10.1093/jac/dkv164 6. Castro-Sánchez H, Drumright LN, Gharbi M, et al. Mapping antimicrobial stewardship in undergraduate medical, dental, pharmacy, nursing and veterinary education in the United Kingdom. PLoS ONE 2016;11(2):e0150056. https://doi.org/10.1371/journal.pone.0150056 7. Paterson Davenport AL, Davey PG, Ker JS; on behalf of the BSAC Undergraduate Education Working Party. An outcome-based approach for teaching prudent antimicrobial prescribing to undergraduate medical students: Report of a Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2005;56(1):196-203. https://doi.org/10.1093/jac/dki126 8. Brink AJ, van den Bergh D, Mendelson M, et al. Passing the baton to pharmacists and nurses: New models of antibiotic stewardship for South Africa? S Afr Med J 2016;106(10):947-948. https://doi. org/10.7196/SAMJ.2016.v106i10.11448 9. Olans RN, Olans RD, DeMaria A. The critical role of the staff nurse in antimicrobial stewardship – unrecognized, but already there. Clin Infect Dis 2016;62(1):84-89. https://doi.org/10.1093/cid/civ697 10. Schellack N, Pretorius R, Messina AP. ‘Esprit de corps’: Towards collaborative integration of pharmacists and nurses into antimicrobial stewardship programmes in South Africa. S Afr Med J 2016;106(10):973974. https://doi.org/10.7196/SAMJ.2016.v106i10.11468 11. Elouafkaoui P, Young L, Newlands R, et al. An audit and feedback intervention for reducing antibiotic prescribing in general dental practice: The RAPiD cluster randomised controlled trial. PLoS Med 2016;13(8):e1002115. https://doi.org/10.1371/journal.pmed.1002115 12. Marra F, George D, Chong M, et al. Antibiotic prescribing by dentists has increased. Why? J Am Dental Assoc 2016:147(5):320-327. https://doi.org/10.1016/j.adaj.2015.12.014 13. Wieler LH, Ewers C, Guenther S, et al. Methicillin-resistant staphylococci (MRS) and extendedspectrum β-lactamases (ESBL)-producing Enterobacteriaceae in companion animals: Nosocomial infections as one reason for the rising prevalence of these potential zoonotic pathogens in clinical samples. Int J Med Microbiol 2011;301(8):635-641. https://doi.org/10.1016/j.ijmm.2011.09.009 14. Gordoncillo MJN, Bender J, Noffsinger J, et al. Developing an open-access antimicrobial resistance learning site for veterinary medical students. J Vet Med Educ 2011;38(4):404-407. https://doi.org/10.3138/ jvme.38.4.404

S Afr Med J 2017;107(5):357-358. DOI:10.7196/SAMJ.2017.v107i5.12496

May 2017, Print edition

THE NEW MEDICAL OXYGEN CYLINDER THAT FACILITATES CARE AND IMPROVES SAFETY

EDITOR’S CHOICE

CME: Tuberous sclerosis complex

Every year, 28 February is Rare Disease Day around the globe. In many high-income countries, significant programmes of research and policy have been developed to understand and meet the needs of individuals who live with rare diseases. In South Africa (SA), rare diseases have unfortunately not reached the awareness of most policy-makers and health system planners. On the one hand, it seems relatively easy to understand why rare diseases have remained ‘rare’ in SA, given the very high burden of other diseases, both communicable and non-communicable. On the other hand, we may be able to learn a lot by studying and treating rare disorders, sometimes with profound clinical consequences. So, what about TSC? TSC is a rare genetic disorder, associated with very obvious ‘chronic multi-morbidity’.[1] The majority of individuals with TSC are diagnosed in the first few years of life, but some are not diagnosed until adolescence or adulthood. Most people with TSC will have involvement of the brain, skin and kidneys, and almost all will have some TSC-associated neuropsychiatric disorders (TAND), including a wide range of behavioural, psychiatric, neurodevelopmental, scholastic and psychosocial difficulties.[2] With a birth incidence of 1 in 6 000, TSC is relatively common for a rare disorder, but the majority of healthcare professionals will nevertheless see no or perhaps one case in their professional career. The majority of people with TSC in SA are probably cared for by general practitioners, and only a few by specialists. For that reason, the authors were keen to generate a broad and general document that they hope will assist general practitioners, specialists, families and individuals with TSC. As one of the anonymous reviewers of the article said, ‘The document is about creating awareness and clinical support to fellow clinicians.’ 15 May every year is Tuberous Sclerosis Complex Global Awareness Day. We sincerely hope that this CME article and editorial will help to raise awareness of TSC, while at the same time reminding doctors of the needs of all South Africans who live with chronic, multi-morbid rare genetic disorders.

Training antibiotic prescribers

Antibiotic resistance (ABR) is now an established threat to global health, and inappropriate prescribing behaviours by clinicians have been implicated as a major contributing factor. Antibiotic stewardship is a key intervention to improve prescribing practices at individual and facility levels. In SA, as elsewhere, antibiotic stewardship programmes have had success in reducing antibiotic consumption. However, the existing antibiotic stewardship infrastructure in SA has important limitations. The first is that existing antibiotic stewardship programmes target mainly postgraduate doctors in hospitals, leaving out outpatients and community settings. Second, existing programmes are usually led by infectious disease specialists, not commonly available in SA. Further, antibiotic prescribing is not a specialist task, usually being left to junior doctors and generalists. Education of medical students has been identified by the World Health Organization as an important aspect of antibiotic resistance containment. Formal pharmacology and microbiology lectures in medical school curricula have not been translated into clinical practice, leaving a gap in knowledge of the factors leading to antibiotic resistance. Wasserman et al.[3] did a cross-sectional survey of all final-year students at three medical schools, using a 26-item self-administered questionnaire recording basic demographic information, perceptions about antibiotic use and ABR, sources, quality and usefulness of current education about antibiotic use, and questions to evaluate knowledge. Hard-copy surveys were administered during whole-class lectures.

A total of 289 of 567 students (51%) completed the survey. Ninetytwo percent agreed that antibiotics are overused and 87% agreed that resistance is a significant problem in SA – higher proportions than those who thought that antibiotic overuse (63%) and resistance (61%) are problems in the hospitals where they had worked (p<0.001). Most reported that they would appreciate more education on appropriate use of antibiotics (95%). Only 33% felt confident to prescribe antibiotics, with similar proportions across institutions. Overall, prescribing confidence was associated with the use of antibiotic prescribing guidelines (p=0.003), familiarity with antibiotic stewardship (p=0.012), and more frequent contact with infectious disease specialists (p<0.001). Students who used antibiotic prescribing guidelines and found their education more useful scored higher on knowledge questionnaires. There are low levels of confidence with regard to antibiotic prescribing among final-year medical students in SA, and most students would like more education in this area. Perceptions that ABR is less of a problem in their local setting may contribute to inappropriate prescribing behaviours. Differences exist between medical schools in knowledge about antibiotic use, with suboptimal scores across institutions. The introduction and use of antibiotic prescribing guidelines and greater contact with specialists in antibiotic prescribing may improve prescribing behaviours. In a linked editorial, Brink et al.[4] suggest that our final-year medical undergraduates are clearly inadequately prepared for practice, with crucial gaps in knowledge and poor understanding of antibiotic stewardship. In fact, fewer than two-thirds knew the term ‘antibiotic stewardship’. These gaps in knowledge vary geographically and are in keeping with a recent study of final-year SA pharmacy students, of whom most reported that they would like more education on appropriate antibotic use. The keys, it seems, are access to antibiotic prescribing guidelines, familiarity with antibiotic stewardship, and more frequent contact with infectious disease specialists.

Use of social media by health professionals

Use of social media has increased exponentially throughout the world. Social media provides a platform for building social and professional relationships that can be used by all, including healthcare professionals. Alongside the benefits of creating networks and spreading information wider and faster than is possible with traditional communication channels, however, it presents ethical and legal challenges. For healthcare professionals, it poses a threat to the confidentiality and privacy due to patients, colleagues and employers. It is vital for healthcare professionals to acknowledge that the same ethical and legal standards apply both online and offline, and that they are accountable to professional bodies and the law for their online activities. The article by Kubheka[5] seeks to explore the ethical and legal pitfalls facing healthcare professionals using social media platforms. Importantly, it seeks to create awareness about the cyberpsychology phenomenon called the ‘online disinhibition effect’ responsible for lowering restraint during online activities. To date, the Health Professions Council of South Africa does not have ethical guidelines for the use of social media.

Health research and safeguards: The SA journey

Health research, as a social good, needs to be conducted in the interests of the common good.[6] Because of the unfortunate exploitation of research participants globally, safeguards for protection are necessary. Most international codes and guidelines originated as responses to the abuse and mistreatment of research subjects. By the 1890s, anti-

May 2017, Print edition

EDITOR’S CHOICE

vivisectionists were already calling for laws to protect children, as a result of the increasing numbers of institutionalised children being subjected to vaccine experiments in Europe and the USA. Just after the turn of the century, the first attempt to test a polio vaccine was thwarted after the American Public Health Association condemned the programme. In SA, medical scientists were busy with discoveries and innovations as far back as the 1800s. In December 1967, the historic first human heart transplant was undertaken in Cape Town. Although it is unclear how much research preceded this procedure, there is no doubt that the operation was done in a research setting, and it had a far-reaching impact.

Factors associated with contracting malaria in Shamva District, Zimbabwe

An increase in malaria cases, far surpassing the epidemic threshold, in the last week of December 2013 led to an investigation of the outbreak in order to identify risk factors and system weaknesses to improve epidemic preparedness and response in the region.[7] This unmatched case-control study was carried out in Ward 29 of Shamva District in Zimbabwe, and epidemic preparedness and response were assessed using the Zimababwe epidemic preparedness and response guidelines. Risk factors were not surprising – performing early morning chores, and water bodies and long grass near the home. Protective factors were also well known – staying indoors at night and living in a sprayed home. What was done wrong? There was no documentation of the outbreak response by the district health executive. Respraying (indoor residual spraying) did not cover 100% of rooms sprayed. Only one

nurse out of seven in the local clinic was trained in integrated disease surveillance and response, and malaria case management. District malaria thresholds were outdated and malaria commodities such as drugs and sprays did not have reorder limits. Why is this article of interest? This carefully conducted study is an excellent example of how simple research can improve public health measures – if, of course, officials listen. There were clear guidelines suggested as outcomes, such as emphasis on education about the simple measures required to prevent malaria in a community, how the lack of outbreak preparedness and response may have contributed to this outbreak, and, finally, that malaria interventions need to be tailored to locally prevailing determinants to prevent outbreaks – all of which needs ongoing surveillance, research, and analysis of the results of these measures. BF 1. De Vries PJ, Leclezio L, Wilmshurst JM, et al. Diagnosis, monitoring and treatment of tuberous sclerosis complex: A South African consensus response to international guidelines. S Afr Med J 2017;107(5):368-378. http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12447 2. De Vries PJ, Whittemore VH, Leclezio L, et al. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol 2015;52(1):25-35. http://dx.doi.org/10.1016/j. pediatrneurol.2014.10.00 3. Wasserman S, Potgieter S, Shoul E, et al. South African medical students’ perceptions and knowledge about antibiotic resistance and appropriate prescribing: Are we providing adequate training to future prescribers? S Afr Med J 2017;107(5):405-410. http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12370 4. Brink A, Schoeman J, Muntingh G. Undergraduate antibiotic stewardship training: Are we leaving our future prescribers ‘flapping in the wind’? S Afr Med J 2017;107(5):357-358. http://dx.doi.org/10.7196/ SAMJ.2017.v107i5.12496 5. Kubheka B. Ethical and legal perspectives on use of social media by health professionals in South Africa. S Afr Med J 2017;107(5):386-389. http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12047 6. Dhai A. Health research and safeguards: The South African journey. S Afr Med J 2017;107(5):379-380. http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12435 7. Muchena G, Gombe N, Takundwa L. Factors associated with contracting malaria in Ward 29 of Shamva District, Zimbabwe, 2014. S Afr Med J 2017;107(5):420-423. http://dx.doi.org/10.7196/SAMJ. 2017.v107i5.12204

Conﬁdence Through Clinical and Real World Experience1-3 #1 NOAC prescribed by Cardiologists* Millions of Patients Treated Across Multiple Indications4 REFERENCES: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fi brillation. N Engl J Med. 2011;365(10):883–91. 2. Tamayo S., Peacock W.F., Patel M.R., et al. Characterizing major bleeding in patients with nonvalvular atrial fi brillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8. 3. Camm A.J., Amarenco P., Haas S. et al. XANTUS: A Real-World, Prospective, Observational Study. 4. Calculation based on IMS Health MIDAS, Database: Monthly Sales December 2015. S4 XARELTO ® 15: Each film-coated tablet contains rivaroxaban 15 mg. Reg. No: 46/8.2/0111; Namibia S2 : 12/8.2/0006; Botswana S2 : BOT1302296 S4 XARELTO ® 20: Each film-coated tablet contains rivaroxaban 20 mg. Reg. No: 46/8.2/0112; Namibia S2 : 12/8.2/0007; Botswana S2 : BOT1302297 PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). HCR: Bayer (Pty) Ltd, Co. Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: +27 (0) 11 921 5044 Fax: +27 (0) 11 921 5041. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). L.ZA.MKT.GM.01.2016.1265 © Bayer January 2016 *Impact RX Data Oct - Dec 2015 NOAC: Non Vitamin K Oral Anticoagulant

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A randomised controlled trial comparing laparoscopy with laparotomy in the management of women with ruptured ectopic pregnancy

To the Editor: We read with interest the article that appeared in the March 2017 issue of SAMJ[1] and would like to commend the authors on the publication of this important topic, demonstrating the advantages of laparoscopic surgery for the management of women with ruptured ectopic pregnancy (REP). Even though the authors randomised the patients, in our opinion they failed to categorise the group of patients they refer to by not quantifying the haemoperitoneum. The description of such patients can be difficult, as there is no agreed standardisation. Do they refer to REP as including women in whom haemoperitoneum was demonstrated on an ultrasound scan and, if that was the case, what was the amount of blood in the peritoneal cavity? Does REP include the 30% of women who present with unquantified haemoperitoneum,[2] or the 6% of patients with significant haemoperitoneum (≥800 mL), as defined by Odejinmi et al.[3] Although the authors demonstrate the advantages of the operative laparoscopy approach to the management of ectopic pregnancy, particularly in the low-cost setting, in eliminating patients with an Hb 8 g/dL, a pulse rate 100 beats/minute, and a systolic blood pressure 90 mmHg, they may have been managing patients with minimal haemoperitoneum, whose outcomes would have been no different from women with unruptured ectopic pregnancies. This can also be inferred by the small difference in pre- and postoperative Hb levels in both groups of randomised patients. Furthermore, Snyman et al.[1] have highlighted that laparoscopy took significantly longer than laparotomy. Surely, the pivotal fact in a REP should be the time taken to haemostasis – not the total operating time. Moreover, the increased time is most probably a function of the experience of the operating surgeon, as there is ample evidence from units with experienced laparoscopic surgeons that laparoscopy is equally quick – if not quicker – compared with laparotomy. We fear that these data, if presented without qualification, might send a message reverting modern accepted practices. In our institution, we have been able to offer operative laparoscopy to nearly all women, irrespective of location of the ectopic pregnancy or haemodynamic status, but this has taken time, effort and education of all involved in the management of ectopic pregnancy.[4] It is hoped that, using their randomised study as a baseline, the authors will be able to update the academic community on their progress and changing trends in the laparoscopic management of ectopic pregnancy in a low-cost setting in a few years’ time.

The objective of our study was to include patients who, by definition, did not present with a diagnosis of unruptured ectopic pregnancy, as the trials referred to in the Cochrane Review were limited to patients with unruptured ectopic pregnancies.[1] We agree that the term ‘ruptured ectopic pregnancy’ does not accurately describe the cohort of women in our study, as many of these patients were bleeding into the peritoneal cavity without having demonstrable tubal rupture. The clinical diagnosis of a ruptured or bleeding ectopic pregnancy with any amount of haemoperitoneum was sufficient for inclusion in the study. Patients with unruptured ectopic pregnancies were excluded. The haemodynamic exclusion criteria were arbitrarily chosen after discussion with the anaesthetic department, as we were reluctant to include patients who were haemodynamically unstable, mainly owing to safety and ethical considerations. In our setting, laparoscopic management of these patients was not the standard of care at the time the study was conducted. We agree that these parameters did select for cases with less severe amounts of bleeding. The postoperative Hb values referred to did not reflect the severity of the cases, but demonstrated the quality of intraoperative resuscitation – evident from the statistically significant difference in blood transfusion requirements between the two groups. The laparotomy group required more blood transfusions (mainly commenced intraoperatively), and the postoperative Hb levels suggest that these transfusions were appropriate. We are, therefore, of the opinion that the group of patients described in our article are different from patients with unruptured ectopic pregnancies without haemoperitoneum. There is also enough other evidence supporting the view that patients with severe haemoperitoneum and even hypovolaemic shock can be safely managed by laparoscopic surgery.[2,3] We have shown (Table 4),[4] with multinomial logistic regression, that the increased operating time is a function of the procedure – not only the function of the operator. We do agree that with more experience the operating time can be shorter, but we do not think that the total theatre time will be the same or shorter as for the open procedure, as is the case in most laparoscopic operations. The reason for commenting on operating and theatre time is that in the context of a limited-resource setting, such as ours, theatre time is a scarce commodity, with several disciplines requiring and competing for after hours’ emergency theatre time. These theatre lists are managed and prioritised by the anaesthetic staff on call. In our experience, the time issue remains the main stumbling block in ensuring that all eligible women receive emergency laparoscopic surgery where indicated, as the dictum eloquently phrased by Dargent[5] that ‘we can do it faster open’ is still a reality in the minds of theatre nursing and anaesthetic staff. L C Snyman, T Makulana, J D Makin Department of Obstetrics and Gynaecology, Faculty of Health Sciences, School of

F Odejinmi, R Oliver

Medicine, University of Pretoria and Kalafong Provincial Tertiary Hospital, Pretoria,

Department of Gynaecology, Whipps Cross University Hospital, Barts Health NHS

South Africa

Trust, London, UK

leon.snyman@up.ac.za

reeba.oliver@gmail.com 1. Snyman LC, Makulana T, Makin JD. A randomised trial comparing laparoscopy with laparotomy in the management of women with ruptured ectopic pregnancy. S Afr Med J 2017;107(3):258-263. https:// doi.org/10.7196/SAMJ.2017.v107i3.11447 2. Falcone T, Mascha EJ, Goldberg JM, Falconi LL, Mohla G, Attaran M. A study of risk factors for ruptured tubal ectopic pregnancy. J Women’s Health 1998;7(4):459-463. 3. Odejinmi F, Sangrithi M, Olowu O. Operative laparoscopy as the mainstay treatment of haemodynamically unstable women with ectopic pregnancy. J Minim Invasive Gynecol 2011;18(2):179-183. https://doi. org/10.1016/j.jmig.2010.11.005 4. Odejinmi F, Rizzuto I, Oliver R, Alalade A, Agarwal N, Olowu O. Beyond guidelines: Effectiveness of a programme in achieving operative laparoscopy for all women requiring surgical management of ectopic pregnancy. Gynecol Obstet Invest 2015;80:46-53. https://doi.org/10.1159/000371763

Prof. L C Snyman et al. respond: Thank you for the opportunity to respond to the letter by F Odejinmi and R Oliver. We would like to thank them for their interest in our work and the important issues raised.

1. Hajenius PJ, Mol F, Mol BW, Bossuyt PM, Ankum WM, van der Veen F. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2007(1):CD000324. https://doi.org/10.1002/14651858.CD000324. pub2 2. Cohen A, Almog B, Satel A, Lessing JB, Tsafrir Z, Levin I. Laparoscopy versus laparotomy in the management of ectopic pregnancy with massive hemoperitoneum. Int J Gynaecol Obstet 2013;123(2):139-141. ttps://doi.org/10.1016/j.ijgo.2013.05.014 3. Rizzuto MI, Oliver R, Odejinmi F. Laparoscopic management of ectopic pregnancy in the presence of a significant haemoperitoneum. Arch Gynecol Obstet 2008;277(5):433-436. https://doi.org/10.1007/ s00404-007-0473-7 4. Snyman LC, Makulana T, Makin JD. A randomised trial comparing laparoscopy with laparotomy in the management of women with ruptured ectopic pregnancy. S Afr Med J 2017;107(3):258-263. https:// doi.org/10.7196/SAMJ.2017.v107i3.11447 5. Dargent DFG. Laparoscopic surgery in gynecologic oncology – some disputable applications and one fruitful indication. Gynecol Oncol 2005;97(3):725-726. https://doi.org/10.1016/j.ygyno.2005.03.046

S Afr Med J 2017;107(5):359. DOI:10.7196/SAMJ.2017.v107i5.12446

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Naude et al. avoid answering the essential question: Mistake or mischief?

To the Editor: It is common cause that the Naude/Stellenbosch University/University of Cape Town meta-analysis[1] played a decisive role in the multimillion rand prosecution of Prof. T Noakes by the Health Professions Council of South Africa (HPCSA), which has now been ongoing for more than 3 years. The complainant, Claire JulsingStrydom, referred to the importance of a meta-analysis generally and/or the Naude et al.[1] meta-analysis specifically on 12 separate occasions during her testimony. On 24 November 2015, under oath, she said of the Naude et al.[1] publication: ‘So before any media statements could be made we had to get that information and all these associations were waiting on that. It is not like the way you are saying it, it is not like everybody joined together to now make a statement against Prof. Noakes. We were all waiting for the evidence to be published.’ Another prosecution witness, Prof. H Vorster, referred to the Naude et al.[1] meta-analysis five times and quoted from it verbatim once. A third prosecution witness, Prof. A Dhansay, referenced the meta-analysis twice, using the term ‘Cochrane’ to ensure that it was afforded the appropriate esteem. Without the ‘correct conclusion’ from this meta-analysis, it is possible that the HPCSA trial against Noakes might never have happened. Therefore, the importance of the Naude et al.[1] meta-analysis extends far beyond any role purely as a neutral scientific publication. Had we realised the disproportionate consideration given to this ostensibly innocuous publication in the HPCSA trial, we would have examined it sooner. When we did examine it, we found the part used to claim that ‘Banting had been debunked’ to be replete with errors. We first presented these errors at the HPCSA/Noakes hearing on 24 October 2016, and then in the SAMJ.[2] Other than a misplaced article in the Cape Times, including comments from the authors on 20 December 2016,[3] the Naude et al.[4] letter published in the March 2017 edition of the SAMJ is the first response to our allegations. The authors cheaply suggest that we show a ‘lack of understanding’ of their protocol. We understand the Naude et al.[1] protocol only too well. Indeed, we appear to understand it rather better than do its authors: • We understand that the authors set isolcaloric as a criterion, which would mitigate the satiety advantage of low(er)-carbohydrate (CHO) diets. • We understand that the authors selected studies with an average CHO intake of 35% (35% fat, 30% protein) to represent ‘low CHO’ diets, which is substantially different from the 5% CHO (<50 g/day), moderate-protein and high-fat diet that is used for the therapeutic management of obesity and type 2 diabetes mellitus. • We understand that they set an inclusion criterion of 25 - 35% fat in the so-called balanced diet. This criterion was reiterated in Tables 2 and 3[1] and yet ignored by the authors, as they included two studies[5,6] that failed their own criterion. These errors remain unaddressed by the authors in any of their responses. • We understand that they set the key outcome measure as ‘total weight change’. They then used end weight, with no reference to start weight, in two studies,[7,8] which was in breach of their own protocol and absurd. These errors remain unaddressed by the authors. In their response to the SAMJ, the authors have accepted only one of the numerous errors that we documented in their article – their admission that they included a duplicate study.[9] This alone is grounds for retraction of the article.[10] The authors have not addressed any of the other numerous errors, material or otherwise, which we documented.[2]

They have not addressed their sub-grouping, which resulted in the protein intake in the diet groups of their so-called high-protein and high-fat studies averaging 31.5 - 32.5% and 28.4%, respectively, likely a biologically insignificant difference. We described this subgrouping as ‘not necessary, not justified and not robust’. The authors have not addressed their patently false claim that they used 52-week weight loss data for Wycherley et al.,[11] when they used data from 12 weeks instead. Use of the 52-week data would have favoured the lower-CHO intervention. The authors have not addressed using the wrong comparator diet for Krauss et al.,[12] which unnecessarily introduced a second variable and was to the advantage of the so-called ‘balanced’ diet. The authors have not explained from where they extracted the weight loss data of 2.65 kg for both the diet and control groups for Krauss et al.[12] Those specific data could not be found in the original publication. Instead, the actual data reported by Krauss et al.[12] slightly favoured the lower-CHO diet intervention. The authors have not addressed reporting the weight loss as 7.95 kg in the control diet rather than the 7.9 kg actually reported by Farnsworth et al.[13] Instead of addressing these errors in detail, point by point, the authors have informed us of new errors that we missed. They wrote: ‘We used data from intention-to-treat analyses (and only if not reported, we used data from per-protocol analyses).’ This was not declared in their original protocol. Intention-to-treat (ITT) is mentioned in only two places in their 30-page article. It first appears in Table 8, which is the table assessing risk of bias. It then re-appears on p. 14 in the ‘Results: Risk of bias’ section. This is where ITT should appear – it is a measure of attrition bias (incomplete outcome data). The authors reported: ‘Seven trials had low risk of attrition bias, with four reporting no attrition and three performing intention-to-treat analysis.’[1] The authors appear now to be confessing that they used ITT numbers instead of completers for some studies and not for others. A re-examination of their meta-analysis (Fig. 3), confirms that in three cases the participant numbers used differ to those extracted in Table 5, which in turn differ from the numbers used in the original publications on five occasions. ITT numbers have been used for Frisch et al.,[14] Klemsdal et al.[15] and Sacks et al.,[5] notwithstanding that Sacks should not have been included from the outset, having failed the authors’ inclusion criteria. These three studies favoured the low(er)-CHO diet, although the weight loss was reported the wrong way round by the authors for Sacks et al.;[5] therefore, it did not appear this way. The Cochrane Handbook for Systematic Reviews of Interventions[16] states that ‘ITT analyses tend to bias the results towards no difference …’ (section 16.2). This choice thus aided the authors’ conclusion that there is little or no difference between the diets. Frisch et al.[14] reported that ‘Missing data were replaced with baseline data in the intention-totreat analysis’. Klemsdal et al.[15] used the last observation carried forward (LOCF) technique and Sacks et al.[5] imputed an estimated weight gain of 0.3 kg/month for their ITT approach. But Cochrane warned of ‘A common, but potentially dangerous, approach to dealing with missing outcome data is to impute outcomes and treat them as if they were real measurements … Such procedures can lead both to serious bias and to confidence intervals that are too narrow … LOCF procedures can also lead to serious bias.’ In addition to this newly announced ITT methodology, which was not set out in their original protocol, the authors added another potential deflection, with an unsolicited reference to ‘standard mean difference’, which neither of us used. We used mean weight loss and standard deviations (SDs), as the authors did (apart from the De Luis et al.[7,8] studies, for which they used end weight). We converted standard error measurements to SDs where necessary, as

May 2017, Print edition

CORRESPONDENCE

the authors did, and we noted that we concurred with the authors’ conversion on four occasions, but found them to have erred with this calculation on three other occasions. These errors remain unaddressed by the authors. As regards the accusation of ‘common mistake’, the researchers will be well aware, as are we, that in meta-analysis significant means statistically significant. The size of the statistical significance is immaterial. What is significant, in the non-statistical use of the word, is that our repeat of the authors’ meta-analysis, using their methodology, but without the errors, produced a different result – a result that would not have given those keen to prosecute Prof. Noakes the ammunition they were ‘waiting for’. It is understandable that the authors chose rather to raise new issues (ITT, standard mean difference and significance) and to ignore the numerous errors that we identified in our critique, presumably because they have no cogent answers. As a result, those material errors have remained unanswered since October 2016 and unless addressed, they render the article worthless, other than of retraction. Given that only one error has been addressed and accepted (the duplication), we may never receive an answer to our research question: was this mistake or mischief? We may also never know if Prof. Noakes would have suffered for years in the way he has, had this article not made competence or conspiratorial errors. Declarations of interest. ZH receives income from writing and from two small self-employment businesses: The Harcombe Diet Co. and Columbus Publishing. TN is the author of the books Lore of Running and Waterlogged and co-author of The Real Meal Revolution, Raising Superheroes, The Banting Pocket Guide and Challenging Beliefs. All royalties from the sales of The Real Meal Revolution, Raising Superheroes and The Banting Pocket Guide and related activities are donated to the Noakes Foundation, of which he is the chairman and which funds research on insulin resistance, diabetes and nutrition as directed by its Board of Directors. Money from the sale of other books is donated to the Tim and Marilyn Noakes Sports Science Research Trust, which funds the salary of a senior researcher at the University of Cape Town, South Africa. The research focuses on the study of skeletal muscle in African mammals, with some overlap to the study of type 2 diabetes in carnivorous mammals and of the effects of (scavenged) sugar consumption on free-living (wild) baboons.

Zoë Harcombe Public Health Nutrition, Cardiff, UK

Tim Noakes Department of Human Biology, Faculty of Health Sciences, University of Cape Town, South Africa noakes@iafrica.com

1. Naude CE, Schoonees A, Senekal M, Young T, Garner P, Volmink J. Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: A systematic review and metaanalysis. PLoS ONE 2014;9(7):e100652. https://doi.org/10.1371/journal.pone.0100652 2. Harcombe Z, Noakes TD. The universities of Stellenbosch/Cape Town low-carbohydrate diet review: Mistake or mischief? S Afr Med J 2016;106(12):1179-1182. https://doi.org/10.7196/SAMJ.2016. v106i12.12072 3. Isaacs L. Noakes disputes diet study. Cape Times, 20 December 2016. 4. Naude CE, Schoonees A, Senekal M, Garner P, Young T, Volmink J. Reliable systematic review of low-carbohydrate diets shows similar weight-loss effects compared with balanced diets and no cardiovascular risk benefits: Response to methodological criticisms. S Afr Med J 2017;107(3):170. https://doi.org/10.7196/SAMJ.2017.v107i3.12382 5. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009;360(9):859-873. https://doi.org/10.1056/NEJMoa0804748 6. Keogh JB, Brinkworth GD, Clifton PM. Effects of weight loss on a low-carbohydrate diet on flowmediated dilatation, adhesion molecules and adiponectin. Br J Nutr 2007;98(4):852-859. https://doi. org/10.1017/s0007114507747815 7. De Luis DA, Aller R, Izaola O, et al. Evaluation of weight loss and adipocytokines levels after two hypocaloric diets with different macronutrient distribution in obese subjects with rs9939609 gene variant. Diabetes Metab Res Rev 2012;28(8):663-668. https://doi.org/10.1002/dmrr.2323

8. De Luis DA, Sagrado MG, Conde R, Aller R, Izaola O. The effects of two different hypocaloric diets on glucagon-like peptide 1 in obese adults, relation with insulin response after weight loss. J Diabetes Complications 2009;23(4):239-243. https://doi.org/10.1016/j.jdiacomp.2007.12.006 9. Luscombe ND, Clifton PM, Noakes M, Farnsworth E, Wittert G. Effect of a high-protein, energyrestricted diet on weight loss and energy expenditure after weight stabilization in hyperinsulinemic subjects. Int J Obes Relat Metab Disord 2003;27(5):582-590. https://doi.org/10.1038/sj.ijo.0802270 10. Senn SJ. Overstating the evidence – double counting in meta-analysis and related problems. BMC Med Res Methodol 2009;9(1):10. https://doi.org/10.1186/1471-2288-9-10 11. Wycherley TP, Brinkworth GD, Clifton PM, Noakes M. Comparison of the effects of 52 weeks’ weight loss with either a high-protein or high-carbohydrate diet on body composition and cardiometabolic risk factors in overweight and obese males. Nutr Diabetes 2012;2(8):e40. https://doi.org/10.1038/ nutd.2012.11 12. Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT. Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Am J Clin Nutr 2006;83(5):10251031 (quiz 1205). 13. Farnsworth E, Luscombe ND, Noakes M, Wittert G, Argyiou E, Clifton PM. Effect of a high-protein, energy-restricted diet on body composition, glycemic control, and lipid concentrations in overweight and obese hyperinsulinemic men and women. Am J Clin Nutr 2003;78(1):31-39. 14. Frisch S, Zittermann A, Berthold HK, et al. A randomized controlled trial on the efficacy of carbohydrate-reduced or fat-reduced diets in patients attending a telemedically guided weight loss program. Cardiovasc Diabetol 2009;8:36. https://doi.org/10.1186/1475-2840-8-36 15. Klemsdal TO, Holme I, Nerland H, Pedersen TR, Tonstad S. Effects of a low glycemic load diet versus a low-fat diet in subjects with and without the metabolic syndrome. Nutr Metab Cardiovasc Dis 2010;20(3):195-201. https://doi.org/10.1016/j.numecd.2009.03.010 16. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. http://handbook.cochrane.org (accessed 27 March 2017).

S Afr Med J 2017;107(5):360-361. DOI:10.7196/SAMJ.2017.v107i5.12454

A skin test for latent tuberculosis

To the Editor: Penn-Nicholson et al.[1] have suggested using a blood test for diagnosing early tuberculosis. It may be possible, however, to use a skin test to diagnose latent tuberculosis.[2,3] An autoimmune model of tuberculoid leprosy has been developed, using peripheral nerve as antigen. Rabbits were injected with a homogenate of human sensory nerve plus adjuvant. Some of the rabbits developed a state of granulomatous hypersensitivity; i.e. skin testing with a dilute solution of nerve in saline produced an epithelioid cell granuloma, in which the cytoplasm contained dilated rough endoplasmic reticulum filled with an electron-dense product.[4] The antigen is a non-myelin protein, active in doses of 1 µg. The ultrastructural appearances are similar to those in human tuberculoid leprosy. [5] The epithelioid cells in human tuberculoid leprosy are CD123positive, indicating that they are plasmacytoid dendritic cells.[6] In other models of granulomatous hypersensitivity using beryllium and sensitivity to zirconium, the antigen is specific.[7] Granulomatous hypersensitivity can be induced only in humans, and is unsuccesful even in non-human primates.[8] The epithelioid cells in both human tuberculosis and sarcoidosis are also ‘primarily biosynthetic rather than phagocytic’.[9] The Kveim reagent contains granulomatous tissue taken from the spleen of patients with sarcoidosis. Skin tests with this reagent produce secretory cells similar to those in sarcoidosis.[10] Results of skin tests with this reagent in patients with sensitivity to zirconium are negative,[7] suggesting that the antigen may be specific. In human tuberculous lymph nodes, plasmacytoid mononcytes are CD123-positive, indicating that they are plasmacytoid dendritic cells.[11] In view of the high mortality from tuberculosis in South Africa, it should be possible to obtain lymph nodes from dead patients and a Kveim-like reagent prepared that can be injected into rabbits, in an attempt to induce granulomatous hypersensitivity. If successful, the active antigen can be isolated according to the procedure adopted for sarcoidosis.[12] Adding phenol to the preparation and heating it to 60oC should make it sterile without losing its activity. A skin test which may be specific could be used to detect latent tuberculosis. C L Crawford London, UK clcraw66@outlook.com

May 2017, Print edition

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2016/04/06 4:43 PM

CORRESPONDENCE

1. Penn-Nicholson A, Scriba TJ, Hatherill M, White RG, Summer T. A novel blood test for tuberculosis prevention and treatment. S Afr Med J 2017;107(1):5-6. https://doi.org/10.7196/SAMJ.2017.v107i1.12230 2. Crawford CL. The epithelioid cell in tuberculosis is secretory and not a macrophage. J Infect Dis 2015; 201(7): 1172-1173. https://doi.org/10.1093/infdis/jiv155 3. Crawford CL. Diagnosis of latent tuberculous infection. Ann Intern Med 2016;165(6):447. https://doi. org/10.7326/L16-0193 4. Crawford CL, Hardwicke PMD, Evans DHL, Evans EM. Granulomatous hypersensitivity induced by sensory peripheral nerve. Nature 1977;265:223-225. 5. Nishuria M. The electron microscopic basis of the pathology of leprosy. Int J Lepr 1960;28:357-400. 6. Andrade PR, Amadeu TP, Nery JA, Pinheiro RO, Sarno EN. CD123, the plasmacytoid dendritic cell phenotypic marker is abundant in leprosy type 1 reaction. Br J Dermatol 2015;172(1):268-271. https:// doi.org/10.1111/bjd.13430 7. Epstein WL. Granulomatous hypersensitivity. Prog Allergy 1967;11:36-88. 8. Epstein WL. Metal-induced granulomatous hypersensitivity in man. Immunology and the skin. Adv Biol Skin 1971;11:313-333. 9. Jones Williams W, James VEM, Erasmus DA, Davies T. The fine structure of sarcoid and tuberculous granulomas. Postgrad Med 1970;46:496-500. 10. Sheffield EA, Mitchell DN, Dewar A, Corrin B. The ultrastructural features of developing Kveim test granulomas. Sarcoidosis 1989;6(Suppl1):S6-S7. 11. Cella M, Jarrosay D, Fachetti F. et al. Plasmacytoid monocyte migrate to inflamed lymph nodes and produce large amounts of type 1 interferon. Nat Med 1999;5(8):919-923. https://doi.org/ 10.1038/11360 12. Crawford CL, Hardwicke P. An experimental model of sarcoidosis using Kveim tissue. In: Connor MR, Stevens RS, eds. Sarcoidosis: Diagnosis, Epidemiology and Treatment Options. New York, NY: Nova Science Publishers, 2012; 145-153.

S Afr Med J 2017;107(3):362. DOI:10.7196/SAMJ.2017.v107i5.12176

Serratia marcescens infection or hypoxic-ischaemic encephalopathy in neonates: Is magnetic resonance imaging a problem-solving tool?

To the Editor: We read with great interest the retrospective case series by A Madide and J Smith,[1] describing brain ultrasound (US) findings of neonates with Serratia marcescens hospital-acquired infections. S. marcescens is a Gram-negative organism that frequently colonises neonatal intensive care units (NICUs). This bacterium can cause severe brain infections in neonates, with irreversible neurological damage and long-term neurodevelopmental impairment. The authors conclude that in babies with acute onset of the illness, US scans allow doctors to highlight pathological changes in the brain immediately before the microbiological diagnosis of infection, and to follow the evolution of those lesions. We are in complete agreement with their comments regarding the importance of accurate and timely diagnosis: early treatment, to minimise the bacterial load, seems to have a great impact on outcome. Moreover, it is important to underline that transfontanellar US scans remain the first-line modality of imaging because of their safety, low cost and especially because of their wide availability.[2] We would like to share our experience with a similar case, in a child with a prenatal diagnosis of partial agenesis of the corpus callosum and multiple intestinal atresia, born at 37 weeks’ gestational age, who developed postnatal hypoxic-ischaemic encephalopathy (HIE). The child underwent more than one surgical procedure to correct bowel atresia during the first week of life. During his stay in the NICU, he developed seizures and lethargy. In light of suspected

infection, the neonatologist performed microbiological cultures and started broad-spectrum antibiotics. Meanwhile, the child underwent a transfontanellar US scan that showed increased echogenicity of the subcortical white matter and extensive cystic periventricular leukomalacia, well-known findings interpreted as sequelae of HIE. Magnetic resonance imaging (MRI) of the brain confirmed severe periventricular cystic changes around the bodies of the lateral ventricles, and highlighted the presence of two focal lesions in the occipital lobes, with a hypointense centre on T1 weighted and a hyperintense on T2 weighted, and fluid attenuation inversion recovery (FLAIR) images with a rim, mildly hyperintense on T1 and hypointense on T2. The central core of the masses restricts strongly on the diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) map. MRI features are consistent with cerebral abscesses (Fig. 1). Neurosurgery and abscess drainage were immediately performed and the culture of the abscess fluid revealed S. marcescens. Confirmation of the brain US finding by MRI evaluation is very helpful in guiding therapy, especially when US scans usually do not allow a perfect distinction between the site of a previous haemorrhage and an abscess.[3] MRI has been gaining increasing importance in the evaluation of brain infections and abscesses because of its high sensitivity and specificity. A major disadvantage is that MRI requires the transport and possibly long sedation of critically ill patients, who are often haemodynamically unstable. D Narese Department of Radiology, Department of Pathobiology and Medical Biotechnology (DIBIMED), University of Palermo, Palermo, Italy; Neuroradiology Unit, Imaging Department, Bambino Gesù Children’s Hospital, Rome, Italy donatella.narese@virgilio.it

C Auriti Neonatal Intensive Care Unit, Department of Neonatology, Bambino Gesù Children’s Hospital, Rome, Italy

D Longo Neuroradiology Unit, Imaging Department, Bambino Gesù Children’s Hospital, Rome, Italy 1. Madide A, Smith J. Intracranial complications of Serratia marcescens infection in neonates. S Afr Med J 2016;106(4):36-38. https://doi.org/ 10.7196/SAMJ.2016.v106i4.10206 2. Messerschmidt A, Prayer D, Olischar M, et al. Brain abscesses after Serratia marcescens infection on a neonatal intensive care unit: Differences on serial imaging. Neuroradiology 2004;46(2):148-152. https://doi.org/10.1007/s00234-003-1140-8 3. Hirooka TM, Fontes RB, Diniz EM, et al. Cerebral abscess caused by Serratia marcescens in a premature neonate. Arq Neuropsiquiatr 2007;65(4A):1018-1021. https://doi.org/10.1590/S0004282X2007000600021

S Afr Med J 2017;107(5):363. DOI:10.7196/SAMJ.2017.v107i5.12345

Fig. 1. (A) Axial FLAIR images show two bilateral focal lesions (arrows) in the occipital lobes with a hyperintense centre and with a mildly hypointense rim. A significant amount of FLAIR hyperintense signal abnormality surrounds the lesions. The lesion’s content shows diffusion restriction, being bright signal in DWI (B) and low signal in ADC (C).

May 2017, Print edition

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The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the University of Cape Town’s Division of Clinical Pharmacologyyand the Health and Medical Publishing Group, University of Cape Town’s Division of Clinical Pharmacolog and the Health and Medical Publishing Group, publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines. 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines.

Go to www.samf12.org to download the order form or contact

Smith DianeSmith Please direct all order queries to:Diane Medical and Health Health and Medical Group Publishing Publishing Group

2069 4812069 012481 Tel:012 Tel: dianes@hmpg.co.za Email:dianes@hmpg.co.za Email: order dispatchofoforder postedonondispatch invoicetotobebeposted Taxinvoice Tax

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IZINDABA

30 days in medicine Measure blood pressure over 30 minutes to reduce treatment

Automated blood pressure monitoring over 30 minutes reduces not only the number of patients diagnosed with hypertension but also the number diagnosed as needing a change to existing hypertension treatment, according to a primary care study carried out on 201 consecutive patients (mean age 68.6 years) visiting a single primary healthcare centre in The Netherlands over 6 months in 2016. Researchers measured patients’ blood pressure every 5 minutes over 30 minutes using an automated blood pressure monitor. They compared the average readings with previous routine blood pressure measurements. The results, reported in the Annals of Family Medicine, showed that mean systolic blood pressure when measured over 30 minutes was 22.8 mmHg (95% confidence interval (CI) 19.8 - 26.1) lower than the mean found on standard measurement. The mean diastolic blood pressure on automated monitoring for 30 minutes was 11.6 mmHg (95% CI 10.2 - 13.1) lower. This backs up previous research showing that up to one-third of patients have white-coat hypertension, which falls to normal levels in other settings. Based on standard blood pressure measurement, GPs at the health centre said that they would have started or intensified hypertension treatment in 79.1% (73.6 - 84.6%) of patients in the study. With results from automated blood pressure monitoring for 30 minutes, this figure fell to only 24.9% (18.9 - 30.9%). Bos MJ, Buis S. 2017. Thirty-minute office blood pressure monitoring in primary care. Ann Fam Med 2017;15(2):120-123. http://dx.doi.org/10.1370/afm.2041

Insomnia linked with increased risk of stroke and myocardial infarction

Insomnia is associated with an increased risk of future myocardial infarction (MI) and stroke, according to a meta-analysis of prospective cohort studies published in the European Journal of Preventive Cardiology. The study included 15 prospective studies following up 160 876 adults aged >18 years for at least 2 years. The median follow-up ranged from 3 to nearly 30 years, during which time 11 702 adverse events were recorded. The results showed that non-restorative sleep and difficulty falling asleep and staying asleep were associated with an increased risk of future cardiovascular events, including incidences of or death due to acute MI, coronary heart disease, heart failure, stroke or combined events. Early-morning waking was not associated with an increased risk of adverse events. The underlying mechanism for the links is not understood, but the authors point out that sleep disorders are common in the general population and that sleep health should be included in a clinical risk assessment. He Q, Zhang P, Li G, Dai H, Shi J. The association between insomnia symptoms and risk of cardio-cerebral vascular events: A meta-analysis of prospective cohort studies. Eur J Prev Cardiol 2017 (epub 30 March 2017). http://dx.doi.org/10.1177/2047487317702043

Vitamin E, selenium do not prevent dementia

Kryscio RJ, Abner EL, Caban-Holt A, et al. Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADVISE). JAMA Neurol 2017 (epub 20 March 2017). http://dx.doi.org/10.1001/jamaneurol.2016.5778

Increased risk of cardiac arrest with commonly used non-steroidal antiinflammatory drugs

The non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and ibuprofen are associated with a significantly inreased risk of cardiac arrest, according to a Danish study published in the European Heart Journal: Cardiovascular Pharmacotherapy. Researchers used the Danish Cardiac Arrest Registry to identify all individuals who had a cardiac arrest out of hospital between 2001 and 2010. Of the 28 947 people identified, 3 376 had been treated with an NSAID up to 30 days before their cardiac arrest. Each case was matched with four controls from the Danish Patient Registry. Ibuprofen and diclofenac were the most commonly used NSAIDs, representing 51% and 22% of total NSAID use, respectively. The study found that use of any NSAID was associated with a 31% increased risk of cardiac arrest. Diclofenac was associated with a 50% increased risk of cardiac arrest (odds ratio (OR) 1.50, 95% confidence interval (CI) 1.23 - 1.82), and ibuprofen was associated with a 31% increased risk (OR 1.31, 95% CI 1.14 - 1.51). The study found no significant association between cardiac arrest and the COX-2 selective inhibitors celecoxib and rofecoxib, or with the unselective NSAID naproxen. However, these drugs are rarely used in Denmark so relatively few events occurred, leading to low statistical power. The authors say that the study is a stark reminder that NSAIDs are not harmless and should not be used without advice from a healthcare professional. Sondergaard K, Weeke P, Wissenberg M, et al. Non-steroidal anti-inflammatory drug use is associated with increased risk of out-of-hospital cardiac arrest: A nationwide case-time-control study. Eur Heart J Cardiovasc Pharmacother 2017;3(2):100-107. http://dx.doi.org/10.1093/ehjcvp/pvw041

Taking vitamin E or selenium supplements does not prevent dementia in asymptomatic older men, according to a study published in JAMA Neurology.

The Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE) trial was piggybacked onto a larger randomised controlled trial looking at the antioxidant effects of selenium and vitamin E on the incidence of prostate cancer. The parent trial started in 2002, but was stopped in 2009 after a planned futility analysis showed no effects on prostate cancer incidence. The trial recruited 7 540 men with a mean age of 67.5 years who were randomly assigned to receive vitamin E, selenium, vitamin E and selenium, or placebo. They were given antioxidant supplements for an average of 5.4 years and assessed using a cognitive screen. When the parent trial ended, a subset of 3 786 men received no additional supplements but continued to be observed for up to 6 more years. Although oxidative stress has been implicated in Alzheimer’s disease, the role of antioxidant supplements in disease prevention is not known. This study shows that using vitamin E and selenium supplements do not prevent dementia and should not be used for prevention.

B Farham Editor ugqirha@iafrica.com

May 2017, Print edition

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CME

GUEST EDITORIAL

Meeting the complex needs of individuals with rare genetic disorders in South Africa – lessons from tuberous sclerosis complex Every year, 28 February is Rare Disease Day around the globe. In many high-income countries, significant programmes of research and policy have been developed to understand and meet the needs of individuals who live with rare diseases. In South Africa (SA), rare diseases have unfortunately not reached the awareness of most policy-makers and health system planners. On the one hand, it seems relatively easy to understand why rare diseases have remained ‘rare’ in SA, given the very high burden of other diseases, both communicable and non-communicable. On the other hand, we may be able to learn a lot by studying and treating rare disorders, sometimes with profound clinical consequences. A careful look will identify many lessons we can learn from rare diseases.[1] Rare diseases are defined as conditions that have a prevalence less than 1/2 000. To date between 6 000 and 8 000 rare diseases have been identified, with characteristics that include a broad range of physical manifestations (e.g. renal, lung, cardiac and central nervous system involvement), neurodevelopmental manifestations (e.g. intellectual disability, autism, specific learning disorders) and mental health disorders (e.g. depression, psychosis and anxiety disorders). The first lesson, therefore, is that while these diseases are individually rare, they are collectively quite common, occurring in perhaps as many as 1 in 20 individuals at some point in their life. The second lesson is that many rare diseases share common pathophysiological mechanisms. A new discovery in one rare disorder may therefore also have a direct impact on another. The tuberous sclerosis complex (TSC) story is a case in point here. The third lesson is that the study of rare diseases can lead to improved understanding of common diseases.[1] A perfect example here is the relationship between trisomy 21 (Down syndrome) and high rates of Alzheimer’s disease, which led to the discovery of the molecular basis of familial Alzheimer’s.[2] An important feature of the majority of rare diseases is that they are chronic conditions, typically lifelong. Not only that, but many rare genetic disorders are also associated with multi-system involvement, sometimes referred to as ‘chronic multi-morbidity’. [3] There is global acknowledgement of the needs of individuals with chronic conditions, and a strong imperative from the World Health Organization for all countries to meet these chronic needs.[4] However, it is clear that, even with good policies, there is a mismatch between policy and implementation in the majority of low- and middle-income countries, including SA.[3,5,6] So, what about TSC? TSC is a rare genetic disorder, associated with very obvious ‘chronic multi-morbidity’ (see de Vries et al.[7] in this issue of SAMJ). The majority of individuals with TSC are diagnosed in the first few years of life, but some are not diagnosed until adolescence or adulthood. Most people with TSC will have involvement of the brain, skin and kidneys, and almost all will have some TSC-associated neuropsychiatric disorders (TAND), including a wide range of behavioural, psychiatric, neurodevelopmental, scholastic and psychosocial difficulties.[8] With a birth incidence of 1 in 6 000 TSC is relatively common for a rare disorder, but the majority of healthcare professionals will nevertheless see no or perhaps one case in their professional career. The disorder remained relatively obscure until the early 2000s, when the molecular mechanisms of TSC were

identified, showing that the two proteins directly affected, TSC1 and TSC2, are key regulators in a fundamental intracellular signalling pathway, the mTOR (mammalian target of rapamycin) pathway.[7] This pathophysiological discovery led remarkably rapidly to the identification of molecularly targeted treatments for TSC – medications that specifically and directly inhibit mTOR to reduce the overactivation resulting from deficits in TSC1 or TSC2 proteins. The mTOR proteins have since also been shown to be involved in neurofibromatosis type 1 and fragile X syndrome (two other rare genetic disorders), in response to cannabis (a rather common phenomenon), and in longevity.[9-12] The clinical challenges for individuals with TSC, however, remain. Given that most healthcare professionals will never have diagnosed or treated someone with TSC, people are undiagnosed, misdiagnosed or diagnosed very late. Treatment is often inadequate or wrong. For example, a recent case report[13] in the SAMJ was clearly a case of an adolescent with TSC, facial angiofibromas and a presumed fat-poor angiomyolipoma (a non-cancerous tumour that should be treated with an mTOR inhibitor). However, this would have been obvious only to professionals who have seen and treated numerous individuals with TSC. An interdisciplinary group of clinicians and TSC researchers have recognised the significant challenges of living with TSC in SA (and other low-resource countries). We acknowledge that these rare genetic disorders are not health priorities in SA, even though a systematic approach to the chronic multi-morbidity of rare diseases would probably lead to significant cost savings and improvements in quality of life for people with TSC. However, conscious that there were well-regarded international consensus guidelines for the diagnosis, monitoring and treatment of TSC,[14,15] we set out to draft a clinical update summarising an evidence-based and international consensus approach to the assessment and treatment of TSC.[7] We realised that the majority of people with TSC in SA are probably cared for by general practitioners, and only a few by specialists. For that reason, we were keen to generate a broad and general document that we hoped would assist general practitioners, specialists, families and individuals with TSC. As one of our anonymous reviewers said, ‘The document is about creating awareness and clinical support to fellow clinicians.’ 15 May every year is Tuberous Sclerosis Complex Global Awareness Day. We sincerely hope that this editorial and the CME article published in this issue of SAMJ will help to raise awareness of TSC, while at the same time reminding us of the needs of all South Africans who live with chronic, multi-morbid rare genetic disorders. Petrus J de Vries Division of Child and Adolescent Psychiatry, Faculty of Health Sciences, University of Cape Town, South Africa petrus.devries@uct.ac.za

May 2017, Print edition

CME

1. Roubertoux PL, de Vries PJ. From molecules to behavior: Lessons from the study of rare genetic disorders. Behav Genet 2011;41(3):341-348. http://dx.doi.org/10.1007/s10519-011-9469-y 2. Isacson O, Seo H, Lin L, Albeck D, Granholm AC. Alzheimer’s disease and Down’s syndrome: Roles of APP, trophic factors and ACh. Trends Neurosci 2002;25(2):79-84. http://dx.doi.org/10.1016/S01662236(02)02037-4 3. Oni T, McGrath N, BeLeu R, et al. Chronic diseases and multi-morbidity – a conceptual modification to the WHO ICCC model for countries in health transition. BMC Public Health 2014;14:575. http:// dx.doi.org/10.1186/1471-2458-14-575 4. World Health Organization. Innovative Care for Chronic Conditions: Building Blocks for Action. Geneva: WHO, 2002. 5. Hofman K. Non-communicable diseases in South Africa: A challenge to economic development. S Afr Med J 2014;104(10):647. http://dx.doi.org/10.7196/SAMJ.8727 6. Draper CA, Draper CE, Bresick GF. Alignment between chronic disease policy and practice: Case study at a primary care facility. PLoS One 2014;9(8):e105360. http://dx.doi.org/10.1371/journal. pone.0105360 7. De Vries PJ, Leclezio L, Wilmshurst JM, et al. Diagnosis, monitoring and treatment of tuberous sclerosis complex (TSC): A South African consensus response to international guidelines. S Afr Med J 2017;107(5):368-378. http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12447 8. De Vries PJ, Whittemore VH, Leclezio L, et al. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol 2015;52(1):25-35. http://dx.doi.org/10.1016/j. pediatrneurol.2014.10.00

9. Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA 2005;102(24):8573-8578. http://dx.doi. org/10.1073/pnas.0503224102 10. Sharma A, Hoeffer CA, Takayasu Y, et al. Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci 2010;30(2):694-702. http://dx.doi.org/10.1523/JNEUROSCI.3696-09.2010. 11. Gomez O, Sanchez-Rodriquez A, Le MQU, Sanchez-Caro C, Molina-Holgado F, Molina-Holgadi E. Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating PI3K/Akt in the mammalian target of rapamycin (mTOR) pathways. Br J Pharmacol 2011;163(7):1520-1532. http:// dx.doi.org/10.1111/j.1476-5381.2011.01414.x 12. Ehninger D, Neff F, Xie K. Longevity, aging and rapamycin. Cell Mol Life Sci 2014;71(22):4325-4346. https://dx.doi.org/10.1007%2Fs00018-014-1677-1 13. Rood JW, Mokhobo KP. A case of renal cell carcinoma and angiomyolipoma in an adolescent girl. S Afr Med J 2016;106(8):795-796. http://dx.doi.org/10.7196/SAMJ.2016.v106i8.10519 14. Northrup H, Krueger DA, Roberds S, et al. Tuberous sclerosis complex diagnostic criteria update: Recommendations from the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49(4):243-254. http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.001 15. Krueger DA, Northrup H, Roberds S, et al. Tuberous sclerosis complex surveillance and management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49(4):255-265. http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.002

S Afr Med J 2017;107(5):366-367. DOI:10.7196/SAMJ.2017.v107i5.12488

May 2017, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

CME

Diagnosis, monitoring and treatment of tuberous sclerosis complex: A South African consensus response to international guidelines P J de Vries,1 MB ChB, MRCPsych, PhD; L Leclezio,1 MSc (Med) Neurosci; J M Wilmshurst,2 MB BS, MRCP, FC Paed (SA), MD; G Fieggen,3 MB ChB, MSc (Neurosci), FCS (SA) Neurosurgery, MD; E Gottlich,4,5,6 MB BCh, DCH (SA), FC Paed (SA), Cert Nephrology (SA) Paed; L Jacklin,7 MB BCh, FCP (SA), MMed (Paed); I P Naiker,8 MB ChB, FRCP (Lond), FCP (SA); R Newaj,9 MB BCh, FC Derm (SA); D Shamley,10 MB BCh, FCP (SA); B Schlegel,2,11 MB ChB, FC Paed (SA); A Venter,12 MB ChB, MMed, PhD, DCH (SA), FC Paed (SA) Division of Child and Adolescent Psychiatry, Faculty of Health Sciences, University of Cape Town, South Africa Tuberous Sclerosis Complex Clinic, Department of Paediatric Neurology, Red Cross War Memorial Children’s Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 3 Division of Neurosurgery, Faculty of Health Sciences, University of Cape Town, South Africa 4 Paediatric nephrologist, private practice, Johannesburg, South Africa 5 Department of Paediatric Nephrology, Faculty of Health Sciences, University of Pretoria, South Africa 6 Clinical specialist, Discovery Health, South Africa 7 Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 8 Nephrologist, private practice, Durban, South Africa 9 Dermatologist, private practice, Johannesburg, South Africa 10 Neurologist, private practice, Johannesburg, South Africa 11 Paediatric neurologist, private practice, Cape Town, South Africa 12 Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 1 2

Corresponding author: P J de Vries (petrus.devries@uct.ac.za)

Tuberous sclerosis complex (TSC) is a genetic disorder with multi-system manifestations and a high burden of disease. In 2013, an international panel of TSC experts revised the guidelines for the diagnosis, surveillance and treatment of the disorder. In South Africa (SA), a local multidisciplinary group of healthcare professionals and TSC researchers reviewed the international guidelines to generate an SA consensus clinical update on the identification, diagnosis, treatment and lifelong monitoring of individuals who live with TSC. We strongly endorse dissemination and use of the international guidelines for the assessment, monitoring and treatment of TSC. In addition, we strongly support access to genetic testing and to mTOR (mammalian target of rapamycin) inhibitors to treat subependymal giant cell astrocytomas not amenable to surgery and renal angiomyolipomas larger than 3 cm, and as adjunctive treatment for refractory focal seizures. We await with interest results from mTOR inhibitor trials of skin and TSC-associated neuropsychiatric disorders (TAND). With regard to training, we recommend the inclusion of TSC in undergraduate and postgraduate medical and health sciences curricula, and the promotion of other continuing professional development events to raise awareness about TSC. We also support the development of a TSC user/carer/parent organisation to provide an informal support network for families across SA. We acknowledge that some progress has been made in recent years in SA, but much remains to be done. We hope that this SA consensus clinical update based on the international guidelines will make a positive contribution to increase knowledge and improve clinical care for all patients who live with TSC in SA, and their families. S Afr Med J 2017;107(5):368-378. DOI:10.7196/SAMJ.2017.v107i5.12447

Tuberous sclerosis complex (TSC) is a multi-system genetic disorder with a birth incidence around 1:5 800.[1,2] It affects ~1.5 million people around the globe with no obvious differences in prevalence based on gender or ethnicity, although epidemiological data from Africa, including South African (SA) populations, are lacking.[1,2] TSC can affect almost any organ system in the body, including the brain, heart, skin, kidneys and lungs. The greatest morbidity and mortality is associated with neurological, neuropsychiatric and renal manifestations.[2] To reduce the morbidity and mortality in TSC, evidence-based management and co-ordination of care across medical specialties is crucial throughout the lifespan of the patient.[2,3] TSC was first described in 1880 by the French neurologist Bourneville at the Salpetriere Hospital in Paris. Bourneville had a 15-year-old patient with severe intellectual disability and intractable

epilepsy. After the death of the child, postmortem examination revealed unusual white, hard lesions on the cortical surface of the brain, and multiple small nodules lining the ventricular surface of the brain. Bourneville described these white, hard lesions as ‘sclereuse tubereuse’ (white, potato-like lesions) of the cerebral cortex. [2] Previously used terms for TSC include ‘Bourneville’s disease’ and ‘epiloia’, but use of these terms is now strongly discouraged. The early diagnostic criteria, first documented in 1979, were based purely on the systematic clinical observations of Dr Manuel R Gomez, a physician at the Mayo Clinic in Rochester, USA. [4,5] Gomez identified that patients with TSC had a wide range of physical manifestations across almost all organ systems, including the brain, skin, heart, eyes, kidneys and lungs, and that multi-system involvement was highly variable between patients. He also recognised (in contrast to

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CME

the late 19th-century descriptions, where all patients were believed to have intellectual disability) that the intellectual abilities of individuals with TSC were extremely varied, ranging from normal intellectual ability to profound intellectual disability. Gomez’s observations remain at the heart of the diagnostic criteria and treatment guidelines for TSC, even in the most recent international revisions.[3,6] Very little was understood about the pathophysiology of TSC until the 1990s and 2000s. The TSC1 gene (on chromosome 9q34) and the TSC2 gene (on chromosome 16p13.3) were identified in 1993 and 1997, respectively, but it remained unclear how their protein products functioned intracellularly. [1,2] We now know that the TSC1 and TSC2 proteins form an intracellular complex in all cells, upstream to a protein called the mammalian target of rapamycin, typically referred to by its abbreviation mTOR. Two of the key intracellular functions of mTOR are protein synthesis and regulation of cell migration and proliferation. In a situation where either the TSC1 or TSC2 gene is affected due to a mutation, the TSC1-TSC2 complex is therefore not able to inhibit or ‘put the brakes’ on the mTOR complex, leading to overgrowth in specific cells, causing the benign tumours that are seen in individuals with TSC.[2,7,8] Recognition of this fundamental role of the TSC proteins in cells has also led to the discovery of molecularly targeted treatments for TSC in the form of mTOR inhibitors. These agents reduce the ‘overactivation’ of mTOR that results from disruption of the TSC1-TSC2 complex. [2,7,8] Fig. 1 shows a graphic representation of intracellular signalling in TSC, indicating where the mTOR inhibitors have their molecular treatment target. In about 70% of cases, TSC occurs due to ‘sporadic’ mutations (de novo). In the remaining 30% of cases, the mutation is inherited in an autosomal dominant fashion, and is therefore ‘familial’. Individuals with TSC have a 50% chance of passing the mutated TSC gene on to their children. Unaffected parents with one child with TSC have an approximately 1% chance of having another child with TSC.[1-3]

The clinical presentation and needs of individuals with TSC

Patients with TSC can have a complex and changeable clinical presentation. Firstly, many different organ systems can be involved, but in a variable way, termed variable expression. For instance, some patients may have significant skin involvement but few brain manifestations; others may have little skin involvement but significant renal and brain involvement. Secondly, TSC manifestations may present at different ages, termed age-related expression. For instance, cardiac rhabdomyomas may be identified with antenatal fetal ultrasound or in the first year of life. After that they tend to regress and disappear. In contrast, skin and renal manifestations are typically not present at birth, but gradually appear over the first 5 - 15 years of life.[1,2] Given the variability of manifestations and the age-related expression, individuals with TSC may present to a range of healthcare professionals with signs and symptoms of possible TSC. Table 1 shows a list of clinical manifestations that may suggest possible TSC in a new patient. In the antenatal period, a fetus is most likely to be identified with possible TSC when cardiac rhabdomyomas are identified on ultrasound. There are also cases where central nervous system manifestations (such as cortical tubers) are identified antenatally. In the first few years of life, the most typical presentation of TSC is likely to be with seizures, in particular focal seizures and infantile (epileptic) spasms, often with an onset in the first 12 months of life. Many parents notice unusual jerky movements in their 2 - 9-monthold infant, and these spasm-like movements are often confused with

Ras ERK1/2

p38MAPK MK2

LKB1

AMPK REDD1

HIF1α

PI3K

Akt

TSC2TSC1

NF1

PTEN

GSK3β

Rheb mTORC1

eIF4E

4E-BP1

mTOR inhibitors

S6K1

Cell growth and proliferation

Fig. 1. The pathophysiology of TSC. The figure shows the intracellular signalling pathways involved in TSC. Under normal conditions the TSC1-TSC2 complex inhibits mTOR, thereby regulating cell growth and proliferation. When a TSC1 or TSC2 mutation exists, the TSC1-TSC2 complex is disrupted, which removes the inhibition on mTOR, leading to over-activation of mTOR signalling. This mTOR overactivation results in tumour formation, with cell growth and proliferation, as seen in the disorder. mTOR inhibitors counteract the overactive mTOR signalling, thus reducing inappropriate cell growth and proliferation. (Arrowhead = activating protein; flat head = inhibitory protein; 4E-BP1 = eukaryotic initiation factor 4E binding protein 1; AKT = protein kinase B; AMPK = adenosine monophosphate activated protein kinase; eIF4E = eukaryotic translation initiation factor 4E; ERK1/2 = extracellular signal regulated kinase 1 and 2; GSK3β = glycogen synthase kinase 3-beta; HIF1α = hypoxia-inducible factor 1-alpha; LKB1 = serine/threonine kinase 1; MK2 = MAPK-activated protein kinase 2; mTORC1 = mammalian target of rapamycin complex 1; NF1 = neurofibromin, protein product of NF1 gene; p38MAPK = p38 mitogen-activated protein kinase; PI3K = phosphoinositide 3 kinase; PTEN = phosphatase and tensin homolog; Ras = Rat sarcoma, a small GTPase protein; REDD1 = REgulated in Development and DNA Damage responses 1; Rheb = Ras homologue enriched in brain; S6K1 = ribosomal p70 S6 kinase 1; TSC1 = tuberous sclerosis complex 1 protein (hamartin); TSC2 = tuberous sclerosis complex 2 protein (tuberin). Different colours indicate different signalling pathways.)

colic. Clear-cut seizures typically lead to hospitalisation, neurological work-up and clinical diagnosis of TSC in the presence of at least two major diagnostic criteria of TSC (see later in the article). After the first few years of life, children may present with skin manifestations such as facial angiofibromas or hypomelanotic macules (white patches), or with developmental or behavioural concerns. Autism spectrum disorder is seen in 40 - 50% of individuals with TSC, and TSC is seen in as many as 4% of children with autism spectrum disorder. For this reason, all children with autism spectrum disorder and epilepsy should be evaluated for possible TSC. Individuals with mild physical manifestations of TSC may present with skin, academic or mental health problems, or be identified when renal manifestations are picked up on an ultrasound/magnetic resonance imaging (MRI) scan by chance. Individuals with TSC may develop a benign brain tumour called a subependymal giant cell astrocytoma (SEGA) that almost invariably arises in the lateral ventricle adjacent to the foramen of Monro and may present with raised intracranial pressure due to obstructive

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Table 1. When to suspect TSC: Some suggestive clinical signs and symptoms Family history • A family history of TSC may lead to comprehensive physical work-up and diagnosis of the disorder Antenatally • Cardiac rhabdomyoma on fetal ultrasound or fetal MRI • Cortical dysplasias such as cortical tubers or SENs on fetal ultrasound or fetal MRI First 5 years of life • Hypomelanotic macules (white patches) on the skin (distinct from vitiligo in that melanocytes are present in normal numbers in TSC hypomelanotic macules) (Fig. 3) • Epilepsy, particularly infantile spasms (infantile spasms do not have to be accompanied by hypsarrhythmia) • Cortical dysplasias such as cortical tubers, SENs or white-matter migration lines on MRI scan (these are unlikely to be visible on CT scan) (Fig. 3) • Global developmental delay, particularly when accompanied by epilepsy • Autism spectrum disorder, particularly when accompanied by epilepsy • Treatment-resistant epilepsy 5 - 15 years • SEGAs typically present in the 5 - 15-year age group. They may present with signs of raised intracranial pressure, but very often present with more subtle changes such as in behaviour, sleep or epilepsy control (Fig. 3) • Facial angiofibromas (often diagnosed as acne) around the sides of the nose, but also on the chin, cheeks and forehead (Fig. 3) • Renal angiomyolipomas on renal ultrasound or MRI scan (Fig. 3) • Sudden deterioration in academic skills and onset of challenging behaviours such as aggression • Specific learning disorders in school (particularly mathematics) • Presentation of mood disorder or anxiety symptoms 15 - 25 years • By now many of the clinical characteristics of TSC have developed. Young people identified for the first time at this age may present for a range of reasons, including skin concerns, epilepsy or epilepsy control, learning-related problems, emerging mental health problems, or increasing challenging behaviours in those with intellectual disability • Ungual fibromas (on the fingers or toes) may present at this age (Fig. 3) • Liver hamartomas may be identified for the first time at this age • Visual problems associated with retinal hamartomas also have a slight increase in this age range (Fig. 3) Adulthood • Many mildly affected adults are only diagnosed with TSC when they have a child diagnosed with the disorder • Adults who may have lived in more rural areas with less access to healthcare may present for the first time with any of the diagnostic characteristics of TSC, e.g. renal angiomyolipoma presenting with haemorrhage • Adults with intellectual disability who move into care homes may be noted to have some of the physical characteristics of TSC, such as the facial angiofibromas or white patches (Fig. 3) • Onset of mood and anxiety disorders in adulthood may lead to a mental health assessment where clinical features of TSC may be identified Older adults • Very little is known about the natural history of TSC in older adults • It is unknown whether older adults with TSC have an increased risk of dementias or other neurocognitive disorders • Older adults may be diagnosed when a grandchild with TSC is born, and a multi-generation clinical work-up is performed Note: It is often a combination of features that raise suspicion of TSC, e.g. learning disorder in a child with a facial rash. Please note that this is not an exhaustive list of clinical presentations of TSC. SENs = subependymal nodules; MRI = magnetic resonance imaging; CT = computed tomography; SEGA = subependymal giant cell astrocytoma.

hydrocephalus. It is therefore possible that presentation and diagnosis of a SEGA will

lead to comprehensive clinical work-up and diagnosis of TSC.

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Adolescent boys or young men with TSC are sometimes diagnosed when they have a skin rash (often misdiagnosed as acne) that causes profuse bleeding during shaving. Some young people and adults present with ungual growths on their hands or feet that cause embarrassment or discomfort. A proportion of mildly affected individuals with TSC are only diagnosed when they have a child diagnosed with TSC, or when there is a family history of TSC and a child receives comprehensive physical work-up.[1-3,6,8] Given the variability of manifestations and the age-related onset, it is clear that individuals with TSC have both clinically complex and multi-system needs that will require input from a range of healthcare professionals across their lifespan. Patients therefore require a multidisciplinary diagnostic, monitoring and treatment approach using evidence-based intervention strategies. [2,3,8] In SA, the majority of patients with TSC are likely to present to and be managed by general practitioners rather than by specialists. For this reason, it is of utmost importance for generalist and primary care teams to be aware of the best-practice guidelines for the assessment, monitoring and treatment of TSC.

Revision of the international diagnostic criteria and consensus guidelines for monitoring and treatment of TSC

As listed above, the first set of diagnostic criteria were generated by Gomez in 1979, based on his observations at the Mayo Clinic. By 1998, the TSC clinical and research community had grown, and a decision was made to have a conference in the USA with the aim of revising and generating international consensus on diagnostic criteria and treatment. The meeting was attended by 23 TSC experts from four countries, and recommendations were based on majority views of expert opinion. The meeting resulted in publication of the first set of consensus diagnostic criteria,[4] often referred to as the ‘Roach criteria’. In addition, a consensus document on treatment and monitoring was published.[5] The genes for TSC had been identified by the time of the 1998 consensus conference, but little more was known about the biology of TSC, and no disorder-specific treatments were available. In 2003, the link between TSC1-TSC2 and mTOR was established, which rapidly led to clinical trials of mTOR inhibitors for TSC. In 2006, David

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Franz and colleagues in Cincinnati showed that rapamycin (the prototypical mTOR inhibitor) could shrink SEGAs in TSC.[2] By 2012, everolimus, another mTOR inhibitor, had received Federal Drug Administration and European Medicines Agency approval for the treatment of brain (SEGAs) and renal (angiomyolipoma) lesions in TSC.[2] With the support of the National Institutes of Health (a research funding agency of the US Department of Health) and the Tuberous Sclerosis Alliance (a US advocacy and support organisation), a second consensus conference was convened in 2012, attended by 79 TSC clinicians, researchers, individuals with TSC and parents, from 14 countries. The majority of the recommendations were based on evidence from peer-reviewed publications. This meeting resulted in a revised set of diagnostic criteria[6] and an enhanced set of management and surveillance guidelines.[3] Full details of the processes and procedures to generate relevant literature, review and weigh up (grade) evidence were presented clearly in the two core publications.[3,6] To summarise in brief, 12 subcommittees were organised to focus on specific disease areas. Subcommittees included a range of clinicians, researchers and parents/individuals with TSC. Each subcommittee had about 12 months to identify relevant questions, review the relevant literature, evaluate and weigh up the strength of data, and present an initial set of recommendations. Where consensus recommendations could not be made based on conflicting or lack of evidence, subcommittees were asked to provide recommendations for future research to answer these unresolved questions. A centralised literature search was performed for all subcommittees to use. The search included PubMed and Scopus databases between 1997 and 2012 (the year of the review). A total list of 2 692 articles were retrieved and provided to subcommittees. Subcommittees were also encouraged to add additional key literature based on specific subcommittee questions, if data provided in the central literature were insufficient. Evidence was evaluated and weighed up (graded) using the evidencebased framework of the National Comprehensive Cancer Network Clinical Guidelines (all details provided in references).[3,6] Category 1 recommendations were based on high-level evidence and uniform consensus, category 2 recommendations were based on lower-level evidence and consensus, and category 3 recommendations were made where consensus could not be reached, regardless of evidence. All subgroups presented their recommendations at a 2-day overall consensus workshop where final consensus recommendations were made, from which the international guidelines were drawn up. All final recommendations were graded in the international publications. Interested readers are encouraged to read these documents.[3,6] The diagnostic criteria and management guidelines were adopted internationally by TSC parent/user organisations and clinical groups, but the international consensus panel encouraged regional and national groups to consider the application and implementation of guidelines in local settings.

TSC in South Africa

Based on birth incidence and prevalence estimates for TSC and a midyear population estimate of 54 million South Africans in 2014, there are likely to be somewhere between 5 000 and 10 000 people with TSC in SA. While these numbers may not sound significant in the context of our many other health challenges, the complex, lifelong and multisystem nature of TSC leads to an extremely high burden of disease, a high burden of care and treatment, and a very significant impact on disability and health economics.

However, very little is known about TSC in SA. There are no epidemiological data on the prevalence or incidence of TSC in this country, and no national registry or national organisation exists. Red Cross War Memorial Children’s Hospital in Cape Town has, to our knowledge, the only dedicated TSC clinic in the country, which includes ~80 - 100 patients. Collectively, the TSC experts and consensus working group members who drafted this consensus clinical update are involved in the monitoring and treatment of no more than 200 patients across SA. This observation suggests that the majority of individuals with TSC in SA are cared for in either general practice or non-specialist settings in the state or private sector, or may not even have reached medical services to receive diagnosis and treatment. It is unclear how much healthcare professionals in SA know about TSC. Given the fact that it is a rare disease, many healthcare professionals may not be exposed to patients with TSC during their undergraduate or clinical training, or even during specialisation. Many nurses, psychologists, occupational and speech and language therapists, and other community-based practitioners are unlikely to receive training on recognition of the clinical manifestations of TSC. There is a great need for multidisciplinary teams in SA for the assessment, monitoring and treatment of the disorder. Two of the key changes in the 2013 diagnostic and treatment guidelines for TSC involved the introduction of molecular genetic testing as a ‘genetic diagnostic criterion’ for TSC, and introduction of mTOR inhibitors for the treatment of specific manifestations of the disorder.[3,6] There are at present no clinical laboratories in SA that can do mutation analysis to establish a molecular diagnosis of TSC. Samples have to be sent to the USA, the UK or Europe for clinical molecular genetic testing. No mTOR inhibitors have received marketing authorisation in SA for any TSC-related indications to date. We are, however, aware of a number of individuals with TSC who are currently receiving mTOR inhibitors ‘off-label’ for various specific TSC indications. The primary purpose of this SA consensus response to the international guidelines was to promote awareness of TSC among colleagues at primary healthcare level and specialists who may be involved in the care of affected individuals. Given that a wellconsidered set of international guidelines had already been drawn up and published, we elected not to generate our own guidelines but rather to prepare a consensus clinical update in response to the internationally adopted guidelines.[3,6]

SA consensus clinical update in response to the 2013 revised diagnostic criteria and international guidelines for TSC

Given the clinical need of patients with TSC and the relative lack of expertise on TSC in SA, a decision was made to convene an SA consensus panel with the aim of developing a formal response to the international guidelines. The panel was led by PJdV, an international TSC expert, and included healthcare professionals with experience in the management of TSC from across SA. In the context of the two-tier healthcare system in the country, we deliberately included clinicians from both the state and private sectors. All panel members were provided with the two consensus articles[3,6] and were asked to review all recommendations. Each panel member was asked to indicate agreement or disagreement with each of the recommendations independent of other experts, and the results were collated by one of the authors (LL). A face-to-face consensus meeting took place on 17 July 2014 in Johannesburg, with all the authors except one (BS) present. At the consensus meeting, the background and rationale of the

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meeting was presented by PJdV, all areas of consensus and disagreement were discussed, and a plan of action for next steps was generated. Overall, the SA consensus group endorsed the two articles, with comments and caveats about resource implications and implementation into practice as outlined below.

A clinical flowchart for the diagnosis, monitoring and treatment of TSC (Fig. 2)

Once the first clinical suspicion of TSC has presented (see Table 1 for examples), patients require a comprehensive physical work-up as outlined in Table 2.[3] The primary purpose of clinical assessment is to determine whether a patient with ‘possible’ TSC has sufficient clinical manifestations to meet criteria for ‘definite’ TSC. The diagnostic criteria are presented in Table 3.[6] As highlighted above, a molecular diagnosis of TSC can now be made when an accredited clinical laboratory identifies a disease-associated mutation in TSC1 or TSC2. Many mutations identified in clinical molecular laboratories around the world are of unclear significance, and may represent non-diseaseassociated polymorphisms (i.e. changes in the DNA sequence with an unclear consequence with regard to protein structure and/or function). Given that SA has no clinical laboratories that can do mutation analysis for TSC, the consensus panel recommended that efforts should be made to introduce molecular genetic testing into a suitable SA clinical laboratory. In the meantime, SA clinicians should use the clinical diagnostic criteria to determine whether a patient meets the criteria for the disorder. A patient meets the criteria when they have clinical evidence of two major diagnostic criteria for TSC (Table 3) or if they meet one major and two or more minor criteria. Fig. 3 illustrates some of the common diagnostic characteristics of TSC. Once a patient has been diagnosed with TSC, they will require appropriate treatment based on their clinical manifestations and needs. Table 4 sets out the international treatment guidelines for TSC.[3] The SA expert panel recognised that a number of the treatment and monitoring recommendations may be hard to access in a

Clinical suspicion of TSC (see Table 1)

Perform a clinical work-up for TSC (see Table 2) TSC confirmed using diagnostic criteria (see Table 3) Implement appropriate evidence-based treatment (see Table 4)

Monitor manifestations of TSC as recommended (see Table 5)

Fig. 2. A clinical flow-chart for the diagnosis, monitoring and treatment of TSC.

resource-limited SA setting, such as in accessing annual MRI scans of the brain, or electro-encephalograms. However, we were encouraged to hear that some SA centres were able to follow the international consensus recommendations. We therefore agreed that these international guidelines should be seen as an aspirational set of recommendations. Ongoing monitoring of all patients with TSC is required, even if they had no overt problems or concerning manifestations at a previous clinic visit. Given the known age-related expression, patients may develop a range of clinical difficulties over a relatively short period of time. The international guidelines for regular monitoring of patients with TSC are presented in Table 5.[3] Rapid assessment and treatment is required where patients present with sudden changes in clinical presentation. Examples of ‘change’ may include changes in seizure control or pattern, appearance of focal neurological signs, deterioration in school performance, or behavioural change (e.g. an individual who has a change in sleep or mood or becomes disruptive without obvious reason). Physical work-up should be prioritised and careful consideration given to the possibility of a SEGA, renal complications or other physical or metabolic abnormality.

Frequently asked clinical questions about diagnosis, monitoring and treatment in SA

During the preparation of this article, a number of questions emerged from within the consensus panel and from other clinical stakeholders in SA. We address some of the key questions here. • Do we need to do MRI scans of the abdomen every 1 - 3 years, or is there a safe alternative in SA? Given that the majority of patients with TSC will develop renal angiomyolipomas associated with hypertension, pain and risk of haemorrhage, early identification and treatment of renal lesions is essential. Identification of renal lesions is therefore the primary reason for abdominal imaging. In order to understand and treat the renal lesion, we need to know what is there and how big it is. TSC renal lesions are often of odd shapes and fat-poor, making it very difficult to visualise and measure their size accurately. Ultrasound has been assessed in the literature, and has been shown not to be sufficiently accurate for use in TSC and polycystic disease. Apart from renal lesions, it is also important to detect additional TSC-related findings in the liver, aorta/blood vessels, spleen, pancreas, etc., all of which can be identified in patients with TSC during MRI surveillance of the kidneys. These TSC manifestations are not detected or evaluated with renal ultrasound. For these reasons, the evidencebased recommendation for renal and abdominal monitoring is abdominal MRI every 1 - 3 years. • Do we need an MRI scan of the brain every 1- 3 years, or will a computed tomography (CT) scan be sufficient? CT scans are not recommended in TSC for two reasons: (i) the need for serial imaging from early childhood into adulthood poses real concern about unnecessary cumulative exposure to ionising radiation when a non-exposure alternative (MRI) exists; and (ii) MRI is superior to CT at detecting soft-tissue components of SEGAs, especially when tumours are only partially calcified. While a SEGA may be diagnosed on a CT scan, especially if there is a calcified component, MRI with post-contrast sequences is better able to define the tumour margin and the relationship to important structures such as the foramen of Monro, fornix and blood vessels, and is also a more reproducible means of measuring and monitoring tumour size over time.

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Table 2. Consensus guidelines for baseline work-up of newly identified patients with possible TSC (modified from Krueger et al.,[3] with permission) Organ system or specialist area Genetics

Recommendation • Obtain a three-generation family history to assess for additional family members at risk of TSC • Offer genetic testing and family counselling • Genetic testing is not available in SA. However, where a TSC diagnosis is in question but cannot be clinically confirmed, genetics services could consider requesting genetic testing from an international clinically accredited laboratory Brain • Regardless of the age of the patient at diagnosis, perform MRI of the brain (with or without gadolinium enhancement) to assess for presence of cortical/subcortical tubers, SENs, migrational defects and SEGAs • If MRI is not available or cannot be performed, CT or head ultrasound (in neonates or infants with open fontanelles) may be used, although results are considered suboptimal and will not always be able to detect abnormalities revealed by MRI • For parents with infants, educate parents to recognise infantile spasms, even if none have occurred at the time of first diagnosis • Obtain baseline routine EEG, even in the absence of recognised or reported clinical seizures. If baseline EEG is abnormal, especially if features of TAND are also present, follow up with a 24-hour video EEG to assess for subclinical seizures, wherever possible TAND • Evaluate for TAND. All patients should receive a comprehensive assessment at diagnosis as a baseline for future evaluations and to identify areas requiring immediate or early intervention • Comprehensive evaluation should include detailed neurodevelopmental assessment, and assessment for behavioural, psychiatric, learning, neuropsychological and psychosocial concerns • In particular, ensure evaluation for intellectual disability, autism spectrum disorder, ADHD, anxiety and depressive disorder • Comprehensive assessment is likely to require multidisciplinary involvement • Clinical teams should maintain a low threshold to initiate early intervention and other management strategies • Patients of school-going age should be considered for an IEDP Kidneys • MRI of the abdomen to assess for the presence of angiomyolipoma and renal cysts • Many angiomyolipomas are fat-poor and hence missed on CT or ultrasound • Screen for hypertension by obtaining accurate blood pressure • Evaluate renal function by determining GFR. Paediatric GFR can be derived from a calculated Schwartz formula Lungs • Perform baseline lung function testing (including a 6-minute walk test) and HRCT in patients at risk of LAM, even if asymptomatic. At-risk patients are typically females over the age of 18 years. Symptomatic male adult patients should also undergo testing • Aim to use low-radiation HRCT protocols wherever possible • VEGF-D level may be helpful to establish a baseline for future LAM development or progression in at-risk patients at around the age of 18 years • Provide counselling to adolescent and adult females on the adverse impact of smoking and oestrogen use (such as oral contraceptives) on LAM Skin • Perform a detailed clinical dermatological examination to look for angiofibromas, fibrous cephalic plaques, hypomelanotic macules or confetti lesions, ungual fibromas and shagreen patch Teeth • Perform a detailed clinical dental examination to look for defects in tooth enamel and intraoral fibromas Heart • Where rhabdomyomas are identified during prenatal testing, consider fetal echocardiography to detect individuals at high risk of heart failure after delivery • Obtain an echocardiogram and ECG in paediatric patients, especially aged <3 years, to assess for rhabdomyomas and arrhythmia, respectively • Obtain an ECG in all ages to assess for underlying conduction defects that may be present, and may influence medication choice and dosing Eyes • Perform a comprehensive opthalmological examination, including dilated fundoscopy, to assess for hamartomas or hypopigmented lesions of the retina, and for visual field defects Other • Although vascular aneurysms, gastrointestinal polyps, bone cysts and various endocrinopathies may be seen in TSC, there is insufficient evidence to recommend routine evaluation at the time of diagnosis, unless clinical symptoms or a concerning history warrants specific additional investigations Note: All the investigations listed above should be performed by appropriately qualified professionals acting within their field of competence. The table outlines the need for multidisciplinary, multiprofessional work in TSC. SENs = subependymal nodules; CT = computed tomography; EEG = electroencephalogram; TAND = TSC-associated neuropsychiatric disorders; ADHD = attention deficit hyperactivity disorder; IEDP = individual education development plan; GFR = glomerular filtration rate; HRCT = high-resolution chest CT; LAM = lymphangioleiomyomatosis; VEGF-D = serum vascular endothelial growth factor type D; ECG = electrocardiogram.

• Can we combine MRI of the abdomen and brain in a single session? We strongly recommend that MRI of the abdomen and brain is co-ordinated between neurology, nephrology and radiology teams to ensure that patients only need to come for a single MRI session. This may be particularly useful for patients who require sedation or an anaesthetic for the procedure.

• How important are neurodevelopmental assessments in TSC? Many people with TSC have neurodevelopmental difficulties, but many do not receive regular and detailed assessments. For this reason, we strongly support the international recommendations to perform annual screening for neurodevelopmental difficulties as part of a

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Table 3. Revised diagnostic criteria for TSC (Northrup et al.,[6] reproduced with permission) A. Genetic diagnostic criteria The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of TSC. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 protein (e.g. out-of-frame indel or nonsense mutation), prevents protein synthesis (e.g. large genomic deletions), or is a missense mutation the effect of which on protein function has been established by functional assessment (see the LOVD databases for TSC1 (http://www.lovd.nl/TSC1) and TSC2 (http://www.lovd.nl/ TSC2)). Other TSC1 or TSC2 variants with less certain effects on function do not meet these criteria, and are not sufficient to make a definite diagnosis of TSC. Note that 10 - 20% of TSC patients have no mutation identified by conventional genetic testing, and a normal result does not exclude TSC or have any effect on the use of clinical diagnostic criteria to diagnose TSC. Where genetic testing is not available, the clinical criteria are used to diagnose TSC. B. Clinical diagnostic criteria Major features • Hypomelanotic macules (≥3, at least 5 mm diameter) • Angiofibromas (≥3) or fibrous cephalic plaque • Ungual fibromas (≥2) • Shagreen patch • Multiple retinal hamartomas • Cortical dysplasias (these include tubers and cerebral white matter radial migration lines) • SEN • SEGA • Cardiac rhabdomyoma • LAM* • Angiomyolipomas (≥2)* Minor features • ‘Confetti’ skin lesions • Dental enamel pits (>3) • Intraoral fibromas (≥2) • Retinal achromic patch • Multiple renal cysts • Non-renal hamartomas Definite diagnosis: Two major features or one major feature plus ≥2 minor features Possible diagnosis: Either one major feature or ≥2 minor features SEN = subependymal nodule; SEGA = subependymal giant cell astrocytoma; LAM = lymphangioleiomyomatosis. *A combination of these two major features without other features does not meet criteria for a definite diagnosis of TSC.

broader evaluation of all TSC-associated neuropsychiatric disorders (TAND).[3,9] We also strongly support the international recommendation to perform regular detailed neurodevelopmental and mental health assessments at key timepoints, as shown in Table 5. • Is it important to screen for and assess for autism spectrum disorder? TSC is the medical condition most strongly associated with autism spectrum disorder. Almost 50% of people with TSC meet criteria for autism spectrum disorder, and many have socialcommunication difficulties even if they do not meet criteria for autism spectrum disorder. For this reason, it is very important to screen for autism spectrum disorder from early on, and to do a comprehensive diagnostic work-up if there are any concerns. The TAND Checklist[9,10] was designed as a simple pen-and-paper tool to help clinicians screen for autism spectrum disorder and other TAND. • Are formal assessments required to assist with school placements for children with TSC? Even though children with TSC can have a huge range of intellectual abilities, the rates of scholastic difficulties are very high.[2,9] Many children with TSC, even when they have normal or above-average IQs, have specific learning disorders that will affect their ability to achieve in school. It is also important to remember that any aspect of TAND can affect a child’s ability to access learning, e.g. attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety or depressive disorders, specific neuropsychological deficits, and psychosocial factors. For this reason, we strongly support the international

recommendations that all school-aged children should be assessed for their educational needs and for the potential need for an individual education development plan (IEDP) (Table 4).

Recommendations for next steps to support individuals with TSC in SA

Given the discrepancy between needs of patients with TSC and available resources and expertise in SA, the SA consensus panel made a number of recommendations for implementation in SA (Table 6). We strongly endorsed the dissemination and use of the international guidelines for the assessment, monitoring and treatment of TSC. In addition, we strongly support access to genetic testing, which is increasingly used around the world in clinical genetics settings to do preimplantation testing, and to examine the association between genotype and phenotype. At present, there are no clinical recommendations regarding differences between TSC1 and TSC2 mutations, but there is significant research interest in the use of genotypic information to predict phenotype and potential for treatment response.[11,12] We also strongly advocate for the relevant regulatory bodies in SA to provide marketing authorisation and reimbursement to support access to mTOR inhibitors for patients in SA for all internationally approved indications. Everolimus, one of the mTOR inhibitors, received marketing authorisation in the USA and Europe for the treatment of SEGAs not amenable to surgery, and for renal angiomyolipomas larger than 3 cm.[3] Recently, everolimus also received marketing authorisation

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Skin manifestations

Hypomelanotic macule (white patch)

Facial angiofibromas

Shagreen patch

Ungual fibroma

Facial angiofibromas

Fibrous cephalic plaques

Brain manifestations

Cortical tubers (black arrows)

Subependymal nodules (white arrows)

Subependymal giant cell astrocytoma (white arrow)

Other manifestations

Retinal hamartoma

Bilateral renal angiomyolipomas

Lymphangioleiomyomatosis (LAM)

Fig. 3. Clinical manifestations of TSC. The images are reproduced with the permission of Dr J Chris Kingswood (UK) and Dr Raj Newaj (SA).

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Table 4. Consensus guidelines for the treatment of TSC (modified from Krueger et al.[3] and adapted for the SA context) Organ system or specialist area Genetics

Brain

TAND

Kidneys

Lungs

Skin

Teeth

Heart Eyes

Recommendation • Individuals with TSC who reach reproductive age should be offered genetic assessment and genetic counselling • First-degree relatives of affected individuals should be offered clinical assessment, and where a mutation has been identified in the index case, genetic testing should be offered • There is no direct access to genetic testing for TSC in SA at present. Specific requests should be discussed directly with clinical genetics experts, who may be able to explore access to international, clinically accredited laboratories • Acutely symptomatic SEGA. Surgical resection should be performed for acutely symptomatic SEGAs. Cerebrospinal fluid diversion (shunt) may also be necessary • Growing but otherwise asymptomatic SEGA. Either surgical resection or medical treatment with mTOR inhibitors may be used. The shared decision-making process with families should consider complication risks, adverse effects, cost of treatment, expected length of treatment, potential impact of TAND and family preference • Infantile (epileptic) spasms. Vigabatrin is recommended as the first-line treatment for infantile (epileptic) spasms. ACTH may be considered when treatment with vigabatrin is unsuccessful • Other seizure types. Antiepileptic drug therapy should follow that of other epilepsies • Refractory seizures. Epilepsy surgery and VNS may be considered for children with medically refractory seizures. Special consideration should be given to children at young ages with neurological regression. Epilepsy surgery and VNS are best performed at epilepsy centres with experience and expertise in TSC. Ketogenic and related diets may have a place in management, but the evidence is limited.[2] mTOR inhibitors have recently been approved as adjunctive treatment for partial-onset seizures.[13] • Management strategies should be based on the TAND profile of each patient and should be based on evidence-based, good practice guidelines/practice parameters for individual disorders (e.g. autism spectrum disorder, ADHD, anxiety disorder) • All school-aged children should be considered for an IEDP • Sudden change in behaviour should prompt medical/clinical evaluation to look at potential medical causes (e.g. SEGAs, seizures, renal disease) • Acute haemorrhage. Embolisation followed by corticosteroids is first-line treatment for angiomyolipomas presenting with acute haemorrhage • Asymptomatic, growing angiomyolipomas >3 cm. An mTOR inhibitor is recommended as first-line treatment. Selective embolisation or kidney-sparing resection are acceptable second-line therapy for asymptomatic angiomyolipomas • Nephrectomy should be avoided at all costs • mTOR inhibitors may be used to treat LAM patients with moderate to severe lung disease or rapid progression • TSC patients with LAM are candidates for lung transplantation, but the comorbidities of TSC may affect suitability for transplant. Lung transplantation for TSC has not been performed in SA • Rapidly changing, disfiguring or symptomatic TSC-associated skin lesions should be treated as appropriate for the lesion and clinical context. Approaches may include surgical excision, laser(s) or topical mTOR inhibitors • Systemic mTOR inhibitors also have an impact on TSC-associated skin lesions, but are not recommended for skin lesions as a primary indication. Clinical trial evidence is awaited to inform recommendations regarding topical mTOR preparations • Symptomatic or deforming dental lesions, oral fibromas and bony jaw lesions should be treated with surgical excision, curettage, or lasers • Enamel defects (dental pits) can be treated with restorative treatments if the patient is at high risk for cavities, although they rarely cause symptoms or an increased rate of dental decay • Patients with clinical symptoms, including conduction defects and rhythm disturbances such as Wolff-Parkinson-White syndrome, may require more frequent monitoring and appropriate intervention • Intervene as appropriate when clinical concern arises regarding visual symptoms and visual field defects

TAND = TSC-associated neuropsychiatric disorders; ACTH = adrenocorticotrophin hormone; VNS = vagus nerve stimulation; ADHD = attention deficit hyperactivity disorder; LAM = lymphangioleiomyomatosis.

in Europe for the adjunctive treatment of refractory focal seizures, following results of an international multi-centre trial.[13] In addition, topical preparations are used for facial angiofibromas and other skin manifestations with very positive outcomes. There is also evidence that systemic mTOR inhibition improves skin manifestations in patients who take mTOR inhibitors for SEGAs or angiomyolipomas. A number of clinical trials are underway exploring the potential for mTOR inhibitors to improve TAND such as autism, intellectual disability, academic difficulties or specific neuropsychological deficits.[2] Apart from clinical aspects of TSC, we also recommend its inclusion in undergraduate and postgraduate medical and health

sciences curricula, and the promotion of other continuous professional development events to raise awareness about it. We support the development of a TSC user/carer/parent organisation that can develop into an informal support network for families across SA. TSC International (TSCi) is a worldwide network of user/carer organisations (http://www.tscinternational.org), and it would be a very powerful strategy to connect the SA TSC community to TSCi. We strongly support ongoing research on TSC in SA and other African countries, given the clear need, but lack of local research data. In high-income settings, it is standard practice for an individual with TSC to be seen by a range of specialists, including paediatric neurology,

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Table 5. Consensus guidelines for ongoing monitoring of individuals with TSC (modified from Krueger et al.,[3] with permission) Organ system or specialist area Genetics

Brain

TAND

Kidneys

Lungs

Skin Teeth Heart

Eyes

Recommendation • If individuals with TSC reach reproductive age, or if a first-degree relative would like to consider having children, referral to a clinical genetics service should be made • In families where there is an individual with TSC, other family members, including new ones, should be considered for the possibility of TSC • At present, no genotype-phenotype correlations warrant any clinical recommendations • Perform an MRI scan of the brain every 1 - 3 years in asymptomatic patients aged <25 years to look for possible emerging SEGAs • Asymptomatic patients with large or growing SEGAs causing ventricular enlargement should undergo MRI scans more frequently, and their families should be educated about potential new symptoms • Patients with asymptomatic SEGAs in childhood should continue to be imaged periodically as adults to ensure that there is no growth • Screen for TAND at least annually. A free, downloadable TAND Checklist has been developed for this purpose[9] • Formal evaluation for TAND should be performed at five key developmental time points: infancy (0 - 3 years), preschool (3 - 6 years), in the middle school years (6 - 9 years), in adolescence (12 - 16 years), in early adulthood (18 - 25 years), and as required after that • Formal evaluation should include detailed neurodevelopmental assessment and assessment for behavioural, psychiatric, learning, neuropsychological and psychosocial concerns • Perform an MRI scan of the abdomen every 1 - 3 years from diagnosis, regardless of age, throughout the lifespan to assess the progression of angiomyolipomas and renal cystic disease • Assess renal function (including GFR) and blood pressure annually • Perform urinalysis for haematuria at each clinical visit • Perform clinical screening for LAM symptoms (including exertional dyspnoea and shortness of breath) at each clinic visit • Perform HRCT every 5 - 10 years in asymptomatic individuals at risk of LAM • Individuals with lung cysts at baseline HRCT should have annual lung function tests and HRCT every 2 - 3 years • Perform a detailed clinical skin examination annually • Perform a detailed clinical dental examination every 6 months • Perform a panoramic radiograph by the age of 7 years, if not performed earlier • Perform an echocardiogram every 1 - 3 years in asymptomatic paediatric patients until regression of cardiac rhabdomyoma • Symptomatic patients may require more frequent echocardiogram • Perform an ECG every 3 - 5 years in asymptomatic patients of all ages to monitor for conduction defects • More frequent or advanced diagnostic assessment (e.g. ambulatory and event monitoring) may be required for symptomatic patients • Perform annual ophthalmological examination in patients with previously identified eye lesions or vision symptoms • More frequent assessment (including of patients on vigabatrin) appears to be of limited benefit and is not recommended unless new clinical concerns arise

TAND = TSC-associated neuropsychiatric disorders; GFR = glomerular filtration rate; LAM = lymphangioleiomyomatosis; HRCT = high-resolution chest computed tomography; ECG = electrocardiogram.

Table 6. Recommendations of the SA TSC consensus meeting 1. Endorse the Revised Diagnostic Criteria as recommended by the 2012 International Tuberous Sclerosis Complex Consensus Conference 2. Endorse the Surveillance and Management Guidelines as recommended by the 2012 International Tuberous Sclerosis Complex Consensus Conference 3. Support access to mutation analysis for TSC in SA 4. Support access to mTOR inhibitor treatments for patients with TSC in SA in the state and private sectors 5. Encourage inclusion of TSC into undergraduate and postgraduate medical and health sciences curricula 6. Facilitate continuing professional development activities to raise awareness and knowledge about TSC 7. Promote establishment of a user/carer/parent non-profit organisation for TSC in SA 8. Promote establishment of an SA registry of TSC patients 9. Promote research on TSC in SA and across the African continent 10. Support development of specialist TSC multidisciplinary teams

dermatology, paediatric nephrology, psychiatry, psychology and so on. In an SA setting, we acknowledge that, owing to resource limitations, many patients with TSC may currently be cared for in primary or secondary care settings. We would, however, like to encourage referral to and appropriate liaison with tertiary services, particularly to teams

with a particular interest in and experience working with individuals who have TSC. Patients with SEGAs, angiomyolipomas, hypertension, dermatological manifestations, epilepsy and neuropsychiatric disorders should always be referred to specialists and, wherever possible, to tertiary settings. While general practitioners in SA may have a central

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role in the overall co-ordination of care, we do not recommend that a general practitioner be expected to carry out clinical management of an individual with TSC in isolation. In SA, a shared-care approach with clear communication and liaison between generalists and specialists to build a virtual ‘team around the family’, with families as active and equal partners in this process, would be ideal. We acknowledge that some positive progress has been made in recent years. A number of talks on TSC have been presented at local and national fora, and a number of SA-based publications have been produced. [10,14,15] In addition, SA is a participating country in the International Natural History Study of TSC, referred to as TOSCA (TuberOus SClerosis Registry to increase disease Awareness).[16] We sincerely hope that these SA guidelines will also make a positive contribution to increase knowledge and improve clinical care for all patients who live with TSC in SA, and their families.

JMW is PI for the Red Cross War Memorial Children’s Hospital (RCWMCH) site for the TOSCA study sponsored by Novartis. Proceeds from this study are used to support the RCWMCH TSC service. JMW is also chair of the Pediatric Commission for the International League Against Epilepsy, secretary of the International Child Neurology Association, education officer for the Commission on African Affairs and executive board member of the African Child Neurology Association and the Paediatric Neurology and Developmental Association of Southern Africa. EG is a part-time employee of Discovery Health, where he is responsible for the development and implementation of the KidneyCare Programme aimed at managing members of the scheme with chronic kidney disease. AV is an advisory board member for ADHD medications, funded by Novartis. GF, EG, LJ, IPN, RN, DS and BS did not declare any additional conflicts of interest.

Acknowledgements. The SA consensus meeting was sponsored by Novartis. We are grateful to Novartis colleagues Dr Michelle Blou, Medical Director, and Dr Chris Nathaniel, Oncology Medical Advisor, for funding and logistic support for the meeting. The sponsors did not play any role in the content or conduct of the meeting, and had no influence on or input in the consensus clinical update manuscript prepared by the consensus working group. No science writers were used to produce the manuscript. Author contributions. All authors contributed to the consensus meeting and to generation of the outline for the article. PJdV prepared the first draft of the article. All authors contributed to drafts of the article and to reviewer comments. All authors approved the final version of the article. Funding. The manuscript was written without any financial support from Novartis or any other organisation. Conflicts of interest. All the authors were members of the consensus meeting sponsored by Novartis and received honoraria and travel for participation. PJdV is a study steering group member of three clinical trials of mTOR inhibitors, sponsored by Novartis, and a co-principal investigator on two investigator-initiated phase II clinical trials of mTOR inhibitors, partfunded by Novartis, Autism Speaks, the TS Alliance, Tuberous Sclerosis Association and the Wales Gene Park. PJdV is also a member of the Working Committee and Scientific Advisory Board of the TOSCA natural history study, sponsored by Novartis. He was chairman of the Neuropsychiatry Panel at the 2012 International Consensus Conference and contributed to the two manuscripts produced by the meeting. LL has a Career Development Studentship funded by the Tuberous Sclerosis Association (UK).

1. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008;372(9639):657-668. http:// dx.doi.org/10.1016/S0140-6736(08)61279-9 2. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 2015;14(7):733-745. http://dx.doi.org/10.1016/S1474-4422(15)00069-1 3. Krueger DA, Northrup H, Roberds S, et al. Tuberous sclerosis complex surveillance and management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49(4):255-265. http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.002 4. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: Revised clinical diagnostic criteria. J Child Neurol 1998;13(12):624-628. http://dx.doi.org/10.1177/088307389801301206 5. Roach ES, DiMario FJ, Kandt RS, et al. Tuberous Sclerosis Consensus Conference: Recommendations for diagnostic evaluation. J Child Neurol 1999;14(6):401-407. http://dx.doi.org/10.1177/088307389901400610 6. Northrup H, Krueger DA, Roberds S, et al. Tuberous sclerosis complex diagnostic criteria update: Recommendations from the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49(4):243-254. http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.001 7. De Vries PJ, Howe CJ. The tuberous sclerosis complex proteins – a GRIPP on cognition and neurodevelopment. Trends Mol Med 2007;13(8):319-326. http://dx.doi.org/10.1016/j.molmed.2007.06.003 8. De Vries PJ. Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex. Neurotherapeutics 2010;7(3):275-282. http://dx.doi.org/10.1016/j.nurt.2010.05.001 9. De Vries PJ, Whittemore VH, Leclezio L, et al. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol 2015;52(1):25-35. http://dx.doi.org/10.1016/j. pediatrneurol.2014.10.004 10. Leclezio L, Jansen A, Whittemore VH, et al. Pilot validation of the tuberous sclerosis-associated neuropsychiatric disorders (TAND) checklist. Pediatr Neurol 2015;52(1):16-24. http://dx.doi.org/10.1016/j. pediatrneurol.2014.10.006 11. Van Eeghen AM, Black ME, Pulsifer MB, et al. Genotype and cognitive phenotype of patients with tuberous sclerosis complex. Eur J Hum Genet 2012;20(5):510-515. http://dx.doi.org/10.1038/ejhg.2011.241 12. Wong HT, McCartney DL, Lewis JC, et al. Intellectual ability in tuberous sclerosis complex correlates with predicted effects of mutations on TSC1 and TSC2 proteins. J Med Genet 2015;52(12):815-822. http://dx.doi.org/10.1136/jmedgenet-2015-103154 13. French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): A phase 3, randomized, double-blind, placebocontrolled study. Lancet 2016;388(10056):2153-2163. http://dx.doi.org/10.1016/S0140-6736(16)31419-2 14. Samia P, Donald KA, Schlegel B, et al. Parental understanding of tuberous sclerosis complex. J Child Neurol 2015;30(10):1281-1286. http://dx.doi.org/10.1177/0883073814558121 15. Lachman A, van der Merwe C, de Vries P. Cognitive and functional outcomes after a trial of an mTOR inhibitor in an adolescent with neuropsychiatric sequelae of TSC. Eur Psychiatry 2016;33:S355. http:// dx.doi.org/10.1016/j.eurpsy.2016.01.1265 16. Kingswood JC, Bruzzi P, Curatolo P, et al. TOSCA – first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex. Orphanet J Rare Dis 2014;9:182. http://dx.doi.org/10.1186/s13023-014-0182-9

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Health research and safeguards: The South African journey A Dhai, PhD, MB ChB, FCOG, LLM, PG Dip (Int Res Ethics) Steve Biko Centre for Bioethics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: A Dhai (ames.dhai@wits.ac.za)

Health research, as a social good, needs to be conducted in the interests of the common good. Because of the unfortunate exploitation of research participants globally, safeguards for protections are necessary. Most international codes and guidelines originated as responses to the abuse and mistreatment of research subjects. By the 1890s, antivivisectionists were already calling for laws to protect children, as a result of the increasing numbers of institutionalised children being subjected to vaccine experiments in Europe and the USA. Just after the turn of the century, the first attempt to test a polio vaccine was thwarted after the American Public Health Association condemned the programme. In South Africa, medical scientists were busy with discoveries and innovations as far back as the 1800s. In December 1967, the historic first human heart transplant was undertaken in Cape Town. Although it is unclear how much research preceded this procedure, there is no doubt that the operation was done in a research setting, and it had a far-reaching impact. S Afr Med J 2017;107(5):379-380. DOI:10.7196/SAMJ.2017.v107i5.12345

The social and scientific worth of health research is indisputable. South Africa (SA)’s journey in this sphere is interesting, and dates back to the early 19th century. Health research needs to be conducted in the interests of the common good. Safeguards are instituted to facilitate ethical research because of the unfortunate global history of the exploitation of vulnerable individuals and groups enrolled in research. It must be emphasised that vulnerability is associated with the strong potential for exploitation. The fact that research participants require protection from exploitation highlights a highly disturbing issue in this context: that the researcher, sponsor and others may see an opportunity to capitalise on and take unfair advantage of the situation, to an individual’s or group’s detriment.[1] Most of the international codes and guidelines originated as responses to disaster, disgrace and dishonour as a result of the abuse and mistreatment of research subjects. However, in SA, the protectionist approach started off in the sixties in individual institutions, not because of scandals and tragedies in the country’s research sites, but because morally, it was the right thing to do. This article, the first of a series of three, briefly considers health research in SA from a historical perspective, and discusses the need for and global response to protectionism and safeguards.[2]

History of health research in SA

In SA, medical scientists were busy with discoveries and innovations as far back as the 1800s. Ova of parasites that cause bilharzia were discovered in the urine of a patient from Uitenhage by Dr John Harley in 1864. About 30 years later, in 1895, the cycle of nagana, a disease of cattle spread by a species of tsetse fly, was uncovered by Sir David Bruce of the British Royal Army Medical Corps, in Zululand. Because of this, he was able to associate the disease with human sleeping sickness caused by a related parasite and transmitted by other tsetse flies. In 1912, the SA Institute for Medical Research (SAIMR) was established as a joint venture between the SA government and the Chamber of Mines, represented by the Witwatersrand Native Labour Association. While some research was conducted at the SAIMR, a major aspect of its activities was directed at routine screening and diagnostic work.[3] It has been argued that early medical research

in SA was established to keep the mines in production, rather than to protect the population of mine workers from the high incidence of serious tropical diseases to which they were succumbing. It is suggested that the goal of medical research in SA at that time was based on narrow economic rather than humanitarian interests,[3] undoubtedly a utilitarian view. The SAIMR played a substantial role in research involving pneumococci, which subsequently resulted in the development of the pneumococcal vaccine. In addition, the SAIMR researchers determined the transmission cycle of plague, and identified two species of Anopheles mosquito principally responsible for the transmission of malaria. As a result of rapid scientific and industrial development during the Second World War, research in many fields gained momentum in SA, especially at the University of Cape Town (UCT). In 1944, Dr Basil Schonland from the University of the Witwatersrand (Wits) was requested by General Jan Smuts, then Prime Minister and Minister of Defence of the country, to create the legislative basis for scientific research, and the Scientific Research Council Act No. 33 was promulgated in 1945. This Act established the principle of overall government control of research, and led to the establishment of the Council for Scientific and Industrial Research (CSIR) soon thereafter. The CSIR controlled the practical administration of research in the country. Although the CSIR’s brief, while broad, did not include medicine, it established a co-ordinating committee (the Committee for Research in Medical Sciences) within the organisation, to take medical research forward. It was this committee that established several research units and sponsored research programmes in medical schools. It also participated in collaborative research with institutes outside SA. The established and fully fledged universities at that time were UCT, Wits, Stellenbosch University and the University of Pretoria.[3] In December 1967, the historic first human heart transplant was carried out in Cape Town. Although it is unclear how much research preceded this procedure, there is no doubt that the operation was done in a research setting,[4] and it had a far-reaching impact. Spurred by this dramatic feat in therapy, Senator Walter Mondale of the USA

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that year introduced a bill in congress, the Senate Joint Resolution (S.J.Res 145), which called for a National Commission on Health, Science and Society to ‘evaluate the integrity and direction of research and to assess the impact of the technological advances on society, including issues of social justice generated by research’.[4] While only a few aspects of the bill were incorporated into legislation some years later, Mondale’s attempts did succeed in changing the research terrain.[4] Following the heart transplant, although most people around the world showered praise on SA, there were some objections, albeit somewhat muffled, that research could have been better channelled in other directions, towards the greater good for a greater number of South Africans, and that the research was only possible because of SA’s oppressive apartheid policies.[3] However, Barnard’s heart transplant was undoubtedly a major medical achievement. It also underscored the need for order in the organisation of medical research in the country. This requirement led to the enacting of the Medical Research Act No. 19 of 1969, and the establishment of the Medical Research Council (MRC) in 1969. Its most important mandate was to promote the improvement of health and the quality of life of the people of SA through research, development and technology transfer. The MRC was funded solely by an annual government grant. Initially, there was no provision for the acceptance of funds from other sources. The council was to co-ordinate medical research within the country, and to determine the distribution of government funding for such research.[3] It is interesting to note that, while legislation promulgating medical research was enacted, there was legislative and regulatory silence at that time on the protection of participants involved in these studies.

The historical origins of protectionism

Without doubt, even very early experiments with humans had positive outcomes. According to Sands, Murray and Cochran, in the 1700s James Lind, a British surgeon, studied scurvy in sailors over a 6-year period aboard the HMS Salisbury. He used an interventional study design in which some sailors were provided with a diet that included fresh fruits and vegetables, while others were given the ‘standard of care’ sailor diet that did not include the fresh products (the control group, as in contemporary research methodologies). In so doing, he was able to demonstrate that sailors in the control group were more likely to develop scurvy compared with those who received fresh fruits and vegetables.[5] Two-and-a-half decades later, Edward Jenner tested the cowpox vaccine on his children and other children in the area where he resided. These children did not get smallpox, and this was the origin of the smallpox vaccine.[5] While these research successes were being celebrated, abuse and exploitation, resulting in violations of human dignity and disrespect for morality, were starting to surface in the field, and by the 1890s, antivivisectionists were already calling for laws to protect children because of the increasing numbers of institutionalised children being subjected to vaccine experiments in Europe and the USA. Therefore, just after the turn of the century, the first attempt to test a polio vaccine was thwarted after the American Public Health Association condemned the programme.[6] In 1897, Sanarelli, an Italian bacteriologist, injected five people with an organism that he had isolated to prove his postulation that it caused yellow fever. His action, which resulted in severe harm being suffered by the five, was widely criticised and remembered for some time thereafter.[5] By the end of the 19th century, research rules were imposed by the Prussian State,[7.8] and according to Lederer and Grodin, the US Congress contemplated the prohibition of medical experiments for particular groups, such as pregnant women, in the District of Columbia.[6] The Prussian Ministry of the Interior issued a regulation in 1891 that would not allow the treatment of tuberculosis with tuberculin against

the patient’s will, and although this was specific to the treatment and not to research, it was among the first initiatives towards clearly defining medical ethics regulations.[8] It also preceded research ethics regulation in Prussia, where in 1900, the Prussian Ministry of Religious, Educational and Medical Affairs issued a legal directive that ‘absolutely prohibited’ non-therapeutic interventions in humans if the subject did not consent to this unequivocally. In addition, proper explanation of the potential adverse consequences of the intervention was necessary before the subject could consent. This legal directive affirmed that voluntary informed consent as a requirement was fundamental to ethically sound experimentation.[8] In the wake of the Sanarelli scandal, when Walter Reed was commissioned to identify the cause of yellow fever, a raging epidemic in Cuba at that time, he developed ethical guidelines to act as safeguards for the research, which was to be overseen by the US Army’s Yellow Fever Board. This board could be described as the forerunner to what is today known as the research ethics committee. The guidelines included: self-experimentation by members on the board; written contracts that clearly explained the risks involved in the experimentation for locals who were not members of the board (the precursor to written informed consent forms); payment in gold for locals who volunteered; USD100 compensation for those who became ill with yellow fever; enrolment to be restricted to adults >24 years of age; children to be excluded; and all journal publications on the research to use the phrase ‘with his full consent’.[5] The safeguards utilised by the Yellow Fever Board, the contract process for obtaining explicit consent and the heroism of the board members who participated as research subjects helped legitimise health research in the aftermath of emerging scandals.[5] It also led to medical researchers being ‘largely inoculated against regulation by the legendary status of self-experimentation by the Yellow Fever Board members’.[6]

Conclusion

The importance of health research must be acknowledged, and moreover, celebrated, right from the outset. SA has a rich history of research in the health environment, dating back to the early 1800s. It is beyond doubt that studies in the healthcare context have improved wellbeing for people globally. This global progress has not been without cost to human dignity, however, resulting in both physical and social harms to enrolled subjects. The birth of protectionism that followed in the late 1800s is therefore not surprising. The next article will focus on the emergence of exploitation of the vulnerable in research, and will begin the discussions on protectionism in SA. Acknowledgements, funding, conflicts of interest. None. 1. Macklin R. After Helsinki: Unresolved issues in international research. Kennedy Inst Ethics J 2001;11(1):17-36. 2. Dhai A. A study of vulnerability in health research. PhD thesis. Johannesburg: University of the Witwatersrand, 2015. 3. Medical Research Council. Thirty years of the MRC – A history. (Undated). http://www.mrc.ac.za/ history/history.pdf (accessed 20 August 2013). 4. McCarthy CR. The evolving story of justice in federal research policy. In: Kahn PJ, Mastroianni AC, Sugarman J, eds. Beyond Consent. Seeking Justice in Research. 1st ed. New York: Oxford University Press, 1998:11-31. 5. Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C. Scandals and tragedies of research with human participants. In: Emanuel EJ, Crouch RA, Arras JD, Moreno JD, Grady C, eds. Ethical and Regulatory Aspects of Clinical Research. Baltimore: Johns Hopkins University Press, 2003:1-5. 6. Moreno JD. Protectionism in Research Involving Human Subjects (Research Involving Human Subjects V2). Online Ethics Centre for Engineering, 2006. http://www.onlineethics.org/Topics/ ResResearch/ResResources/nbachindex/hmoreno.aspx (accessed 20 July 2012). 7. Tröhler U. The long road of moral concern: Doctors’ ethos and statute law relating to human research in Europe. In: Schmidt U, Frewer A, eds. History and Theory of Human Experimentation. Germany: Franz Steiner Verlag, 2007:29-54. 8. Engelhardt D. The historical and philosophical background of ethics in clinical research. In: Schmidt U, Frewer A, eds. History and Theory of Human Experimentation. Germany: Franz Steiner Verlag, 2007:55-70.

Accepted 17 March 2017.

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Assisted suicide and assisted voluntary euthanasia: Stransham-Ford High Court case overruled by the Appeal Court – but the door is left open D J McQuoid-Mason, BComm, LLB, LLM, PhD Centre for Socio-Legal Studies, University of KwaZulu-Natal, Durban Corresponding author: D J McQuoid-Mason (mcquoidm@ukzn.ac.za)

Whether persons wishing to have doctor-assisted suicide or voluntary active euthanasia may make a court application based on their rights in the Constitution has not been answered by the Appeal Court. Therefore, if Parliament does not intervene beforehand, such applications can be made – provided the applicants have legal standing, full arguments are presented regarding local and foreign law, and the application evidence is comprehensive and accurate. The Appeal Court indicated that the question should be answered by Parliament because ‘issues engaging profound moral questions beyond the remit of judges to determine, should be decided by the representatives of the people of the country as a whole’. However, the Government has not implemented any recommendations on doctor-assisted suicide and voluntary active euthanasia made by the South African Law Commission 20 years ago. The courts may still develop the law on doctor-assisted death, which may take into account developments in medical practice. Furthermore, ‘the possibility of a special defence for medical practitioners or carers would arise and have to be explored’. S Afr Med J 2017;107(5):381-382. DOI:10.7196/SAMJ.2017.v107i5.12450

The decision in Stransham-Ford v Minister of Justice and Correctional Services and Others[1] by the North Gauteng High Court held that a terminally ill patient with intractable suffering was entitled to commit suicide with the assistance of his doctor, whose conduct would not be unlawful. The evidence was that the applicant was a highly qualified lawyer with terminal stage 4 cancer and had tried several traditional and other forms of medication, including palliative care, without alleviating his suffering. He was fully mentally competent and had only a few weeks left to live. The application was heard on 29 April 2015, and two hours before the judge was due to make his order, Mr Stransham-Ford ‘died of natural causes’. At this time, neither the judge nor Mr Stransham-Ford’s lawyers knew that he had died. The judge gave his reasons for his judgment on 4 May 2015, knowing of the applicant’s death, but not recalling his order as he could have done in terms of the Uniform Rules of Court.[2] In Minister of Justice and Correctional Services and Others v Estate Late Stransham-Ford and Others,[2] the Appeal Court overruled the decision of the court below on three grounds: (i) when Mr StranshamFord died ‘his cause of action ceased to exist’; (ii) there was ‘no full and proper examination’ of the current local and international legal position in the light of the Constitution; and (iii) the order was based on ‘an incorrect and restricted factual basis’. However, the Appeal Court left the door open by concluding that assisted suicide is not ‘in all circumstances unlawful’.[2] A similar application may therefore still be made to the courts, based on proper facts and a full analysis of local and international law in the light of the Constitution.

Death of Mr Stransham-Ford

The Appeal Court held that the death of Mr Stransham-Ford after the arguments had been heard by the judge, but before the judge gave his order, meant that the ‘his cause of action ceased to exist’.[2] This was because Mr Stransham-Ford’s application ‘concerned only his personal situation in seeking relief to enable him to die’. Once he died,

therefore, ‘no further purpose could be served by granting that relief ’. High Court judges cannot ‘make orders on causes of action that have been extinguished, merely because they think that their decisions will have broader societal implications’.[2] Had the applicant brought the action in the ‘general public interest or as a member of a group or class of persons’, different allegations would have to have been made and other potentially interested parties would have to have been cited,[2] on which basis the case might have proceeded.

No full and proper examination of local and international law

The Appeal Court’s second reason for overruling the decision of the court was that ‘there was no full and proper examination of the present state of our law in this difficult area, in the light of authority, both local and international, and the constitutional injunctions in relation to the interpretation of the Bill of Rights and the development of the common law’.[2] Suicide and attempted suicide are not crimes; patients are entitled to refuse medical treatment (which does not constitute suicide), and in ‘double-effect’ situations the conduct of doctors is not unlawful where the doctor knows that ‘palliative treatment for pain … will have the effect of hastening the patient’s death’.[2] After analysing the South African cases, the Appeal Court held that the main authority cited in the court[3] did not indicate ‘that a criminal offence is committed whenever a person encourages, helps or encourages someone to commit suicide or to attempt to do so’. [2] Furthermore, each case must be decided on its merits and the principles governing assisted suicide ‘should be applied and adapted to the present day’.[2] This was particularly so as the ‘background would be markedly different, given changes in medical circumstances in the nearly 50 years that have passed since the judgment was given’.[2] Any development of the common law would have to decide whether to take a different view of causation, intention or

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unlawfulness. ‘The possibility of a special defence for medical practitioners or carers would arise and have to be explored’.[2] Without dealing with these issues, the question of whether the constitutional rights of persons in Mr Stransham-Ford’s position had been violated could not be considered. The Court listed the kinds of issues that must be addressed when considering the constitutional guarantees in the Bill of Rights, such as: (i) whether ‘the right to life includes a right to die’, or does it mean that active voluntary euthanasia must be criminalised; (ii) whether the right to dignity includes ‘a right to die when and in the manner we choose’; (iii) whether ‘the rights of patients warrant a change in existing criminal law as it affects doctors’; (iv) whether the right to healthcare includes ‘the provision and possible administration of lethal agents, or does it by necessary implication exclude this’; and (v) what the implications for palliative care are if ‘a person’s dignity is infringed by their inability to terminate their own life or have it terminated’.[2] In terms of the development of foreign law regarding doctorassisted suicide, the Appeal Court found that while a minority of countries allowed it, their mechanisms for doing so varied. Only in two US lower court cases and one Canadian Supreme Court case have the courts found that a constitutional right was unjustifiably infringed by prohibiting doctor-assisted death and doctor-assisted suicide.[2] However, the Appeal Court’s decision implies that these issues should be fully canvassed in a future case where the applicant has legal standing and the case is based on correct and relevant facts.

Court order based on incorrect and restricted facts

The Appeal Court also found that all the available evidence had not been properly placed before the court, and that a true picture of Mr Stransham-Ford’s position and condition was not given. The evidence of a doctor who treated him was that on 20 April 2015 (nine days before the court application), Mr Stransham-Ford had indicated to

his former wife that he was concerned about whether he could change his mind about consenting to doctor-assisted death.[2] Furthermore, by 28 April 2015 (the day before the application), he had lapsed into a coma.[2] When he died – contrary to the fears expressed in his court application – he was provided with palliative care at his ex-wife’s home that managed his symptoms ‘effectively enough for him to be able to die in a homely atmosphere surrounded by family and friends who cared for him’.[2] The judge was unaware of any of these changes in Mr Stransham-Ford’s condition that might have ‘render[ed] the whole application unnecessary’.[2] The Appeal Court indicated that the question of doctor-assisted suicide and voluntary active euthanasia is best answered by Parliament.[2] However, as the Government has not implemented any of the recommendations on doctor-assisted suicide and voluntary active euthanasia made by the South African Law Commission 20 years ago,[4] it is likely that this will have to be done by the courts. The courts to date have not had an opportunity to deal with an appropriate case based on correct and relevant facts to determine whether doctor-assisted suicide and voluntary active euthanasia should be allowed in South African law. Acknowledgements. None. Author contributions. Sole author. Funding. None. Conflicts of interest. None. 1. Stransham-Ford v Minister of Justice and Correctional Services and Others 2015 (4) SA 50 (GP). 2. Minister of Justice and Correctional Services and Others v Estate Late James Stransham-Ford and Others (531/2015). http://www.saflii.org/za/cases/ZASCA/2016/197.html (accessed 23 February 2017). 3. Ex parte Die Minister van Justisie: In re Grotjohn 1970 (2) SA 355 (A). 4. South African Law Commission. Euthanasia and the Artificial Preservation of Life. Project 86. Pretoria: South African Law Commission, 1997.

Accepted 15 March 2017.

MEDICINE AND THE LAW This open-access article is distributed under CC-BY-NC 4.0.

Human dignity and the future of the voluntary active euthanasia debate in South Africa

D W Jordaan, PhD School of Law, Howard College, University of KwaZulu-Natal, Durban, South Africa Corresponding author: D W Jordaan (mail@donrichjordaan.law.za)

The issue of voluntary active euthanasia was thrust into the public policy arena by the Stransham-Ford lawsuit. The High Court legalised voluntary active euthanasia – however, ostensibly only in the specific case of Mr Stransham-Ford. The Supreme Court of Appeal overturned the High Court judgment on technical grounds, not on the merits. This means that in future the courts can be approached again to consider the legalisation of voluntary active euthanasia. As such, Stransham-Ford presents a learning opportunity for both sides of the legalisation divide. In particular, conceptual errors pertaining to human dignity were made in Stransham-Ford, and can be avoided in future. In this article, I identify these errors and propose the following three corrective principles to inform future debate on the subject: (i) human dignity is violable; (ii) human suffering violates human dignity; and (iii) the ‘natural’ causes of suffering due to terminal illness do not exclude the application of human dignity. S Afr Med J 2017;107(5):383-385. DOI:10.7196/SAMJ.2017.v107i5.12339

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During 2015, Mr Stransham-Ford, who was terminally ill at the time, approached the Pretoria High Court on an urgent basis.[1] The relief that he sought was nothing short of a medicolegal earthquake: Mr Stransham-Ford requested the Court to develop the common law to legalise voluntary active euthanasia – at least in his specific case. The case was opposed by, among others, the Minister of Health and the Health Professions Council of South Africa (HPCSA). The legal arguments of both sides centred on constitutional rights – in particular, the right to human dignity, the right to life, and the right to control one’s body. In a judgment that caused much sensation and controversy, the Pretoria High Court decided in Mr Stransham-Ford’s favour. However, in a Shakespearean twist of fate, Mr Stransham-Ford died of his illness a few hours before the judgment. This twist of fate proved to be decisive in the subsequent appeal,[2] as it raised the question: Was the Pretoria High Court competent to adjudicate the matter after Mr StranshamFord’s death? The Supreme Court of Appeal answered this question with a definite ‘no’, and upheld the appeal against the Pretoria High Court’s judgment primarily on this technical ground. Consequently, the Supreme Court of Appeal did not engage with the arguments for and against the legalisation of voluntary active euthanasia. As such, the figurative jury is still out on the merits of the various legal arguments for and against voluntary active euthanasia. The Supreme Court of Appeal judgment is probably the end of the road for the Stransham-Ford lawsuit, as the death of Mr StranshamFord is an obstacle that will also stand in the way of a possible appeal to the Constitutional Court. Yet this may only be the first chapter in a longer saga of voluntary active euthanasia legal reform in South Africa (SA). One possibility for chapter two is that Parliament may take up the issue and initiate new legislation – this was held by the Supreme Court of Appeal as the ideal solution. However, the ruling party may prefer to avoid getting entangled in this issue and therefore rather decide to leave it to the courts. Whether or not Parliament decides to take up this issue, nothing prohibits civil society organisations that favour the legalisation of voluntary active euthanasia from initiating public interest litigation in an attempt to succeed where Mr Stransham-Ford as (deceased) private litigant has ultimately failed. It might even be that a future Minister of Health and HPCSA management may change their position on the subject and simply abide by the decision of a future court. However, what is certain is that a number of civil society organisations will oppose the legalisation of voluntary active euthanasia, and take up the gauntlet of litigation. Although the issue of legalisation of voluntary active euthanasia was not finally adjudicated in Stransham-Ford, the case provided a forum for a comprehensive rights-based debate on the issue. As such, Stransham-Ford can serve as a learning opportunity for future discourse on the subject of voluntary active euthanasia. In this article, I intend to make use of this opportunity. From the papers filed with the Supreme Court of Appeal in the Stransham-Ford appeal, I identify three pertinent conceptual errors concerning human dignity, and in each instance propose a corrective principle to guide future discourse. I focus on human dignity because of its central position in the discourse on voluntary active euthanasia in general, and the special attention that it received in the High Court judgment and in the papers filed with the Supreme Court of Appeal. My focus on human dignity should not be interpreted as denigrating any other relevant right. The purpose of this article is not to advocate any final position on the issue of voluntary active euthanasia, or to consider factual questions such as the efficacy of palliative care in managing pain in some or all cases. Instead,

my purpose is more confined, namely to contribute to greater conceptual clarity regarding human dignity. In the following paragraphs, I first present a brief analysis of the meaning of human dignity, before I analyse the conceptual errors pertaining to human dignity and suggest corrective principles.

What is human dignity?

A conceptual distinction must be made between ‘human dignity’ and ‘dignity’. Human dignity is best understood as a specific species of dignity that denotes the objective value inherent to all humans. Other notable species of dignity in Western philosophy are the following: Firstly, dignity as subjective self-value; secondly, a behavioural conception of dignity, which denotes the objective value that an individual possesses based on certain behavioural qualities that are associated with dignity, such as composure, calmness, and a noble manner; and thirdly an aspirational conception of dignity that denotes the objective value that an individual possesses based on his or her accomplishments in life. The species of dignity that is relevant to human rights analysis – and therefore discourse on the legalisation of voluntary active euthanasia – is human dignity. Our Constitutional Court has refrained from specifically defining human dignity, but the meaning of human dignity has gradually crystallised through the Constitutional Court’s jurisprudence, as entailing the following inter-related components:[3] • An individual is an end in himself or herself. • All individuals are entitled to equal concern. • An individual is entitled to a space for self-actualisation. • An individual is entitled to self-governance or autonomy. • Individuals are collectively responsible for the material conditions for individual agency. The component of human dignity that stands out as relevant to the voluntary active euthanasia debate is an individual’s entitlement to autonomy. The High Court in Stransham-Ford relied heavily on human dignity, and adhered to the meaning of human dignity qua autonomy. In the following paragraphs, I analyse the conceptual errors concerning human dignity made in the papers filed with the Supreme Court of Appeal, and propose corrective principles.

Principle: ‘Inherent’ does not mean ‘inviolable’

The first conceptual error that emerges in the papers filed with the Supreme Court of Appeal in the Stransham-Ford appeal is the interpretation of the inherent status of human dignity as meaning that human dignity is inviolable. The relevance to the debate about voluntary active euthanasia is that if human dignity is inviolable, it follows that human dignity would not be affected by illness, restraints on autonomy, etc. The interpretation of human dignity as being inviolable is incorrect. The inherent nature of human dignity means that all humans can claim protection of their dignity by virtue of being human; however, the inherent nature of human dignity does not mean that human dignity is incapable of violation. One can recognise that a person’s human dignity is violated by a certain event, while simultaneously holding that the person has human dignity. Recognising a violation of human dignity does not equate to postulating a person-without-humandignity. This analysis and conclusion is implicit in constitutional cases that dealt with the violation of the human dignity of a person (or, depending on the case, a group of persons).[4-6]

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Principle: Human suffering violates human dignity

The second conceptual error does not insist on the inviolability of human dignity in general, but asserts that suffering in particular does not violate human dignity. The assertion is typically stated as ‘suffering is not undignified’ (expert opinion by Dr Cameron, filed in Stransham-Ford[2]). This assertion confuses human dignity with other philosophical species of dignity. A terminally ill patient might carry herself with great composure despite her suffering – an instance of behavioural dignity. However, in the context of a human rights analysis, the species of dignity that is relevant is not behavioural dignity, but human dignity. Human dignity entails that an individual is entitled to autonomy. Autonomy, in turn, means that every person should be able to pursue his or her own idea of the ‘good life’,[7] but while there may be a great many ideas of the ‘good life’, it can safely be stated that suffering is nobody’s idea of the ‘good life’, and hence that suffering is antithetical to autonomy. Accordingly, as a general rule, suffering violates human dignity.

Principle: ‘Nature’ is no immunisation against human dignity

The third conceptual error is that human dignity as a normative construct does not – and cannot – protect persons against nature. The argument proceeds as follows: Given that terminal illness and the suffering associated with it are natural occurrences, human dignity has no application to such illness and suffering, and cannot be used to justify voluntary active euthanasia in such context. While some aspects of nature are indeed beyond human control, other aspects are well within our power to control. To the extent that an aspect of nature is within human control, it enters the normative sphere. One aspect that is within our power to control is to provide palliative care; another aspect that is within our power to control is to allow voluntary active euthanasia. Accordingly, the context of terminal illness and suffering at the end of human life is appropriate for the application of human dignity.

Excursus on ‘nature’ and ‘natural’

In Stransham-Ford, the arguments against voluntary active euthanasia were often based on the implicit notion that dying of a ‘natural’ death has moral value, or is at least morally superior to self-determining the time and way of one’s death. This implicit notion is a version of the belief that ‘natural’ is morally good, while ‘unnatural’ is morally bad, or at least morally inferior. The logical conclusion of this belief is that the entire enterprise of medical science amounts to an immoral attempt to counter the natural course of pain and death caused by nature in the form of illnesses. After all, it is natural for cancer to be painful. Clearly, this belief that ‘natural’ is morally good, and ‘unnatural’ is morally bad is a fallacy. The philosopher Karl Popper states as follows in his book The Open Society and Its Enemies:[8] ‘Nature consists of facts and of regularities, and is in itself neither moral nor immoral. It is we who impose our standards upon

nature, and who in this way introduce morals into the natural world, in spite of the fact that we are part of this world.’ Accordingly, the fact that death occurs ‘naturally’ due to a terminal illness has no inherent moral content. But the human decision to force terminally ill persons to die a ‘natural’ death – despite the suffering caused in the process of ‘natural’ dying to the patients and their loved ones – does have moral content. Furthermore, any argument that juxtaposes the palliative care approach with voluntary active euthanasia, and posits the palliative care approach – and in particular, continuous sedation – as moral, and voluntary active euthanasia as immoral, based on the fact that the former allows nature to run its course regarding the timing of death, while the latter allows human determination of the time of death, is fallacious. Care should be taken that future discourse on the legalisation of voluntary active euthanasia should not relapse into the appealto-nature fallacy. If the palliative care approach is to be preferred above voluntary active euthanasia – even contrary to a patient’s autonomous desire for euthanasia – logically valid reasons must be provided.

Conclusion

The focus of this article was on human dignity in the discourse on voluntary active euthanasia. It bears repetition that human dignity is not the only right that is relevant to this complex discourse. The question of whether or not voluntary active euthanasia is required by SA’s human rights system must be answered by carefully balancing all rights that are relevant to the subject. Still, human dignity remains essential to any rights-based analysis of voluntary active euthanasia. Accordingly, conceptual clarity regarding human dignity is important, and the post-Stransham-Ford voluntary active euthanasia discourse would be enhanced by avoiding the conceptual pitfalls of the past. Acknowledgements. This article is based in part on the author’s (unpublished) amicus curiae submission to the Supreme Court of Appeal in the Stransham-Ford appeal. Author contributions. Sole author. Funding. None. Conflicts of interest. None. 1. Stransham-Ford v Minister of Justice and Correctional Services & Others 2015 (4) SA 50 (GP). 2. Minister of Justice and Correctional Services and Others v Estate Late James Stransham-Ford & Others (531/2015) [2016] ZASCA 197. 3. Woolman S. Dignity. In: Woolman S, Bishop M, eds. Constitutional Law of South Africa. 2nd ed. Cape Town: Juta & Co., 2005. 4. National Coalition of Gay and Lesbian Equality and Another v Minister of Justice and Others 1999 (1) SA 6 (CC). 5. Government of the Republic of South Africa and Others v Grootboom and Others 2001 (1) SA 46 (CC). 6. Khosa and Others v Minister of Social Development and Others, Mahlaule and Another v Minister of Social Development 2004 (6) SA 505 (CC). 7. Ferreira v Levin NO and Others; Vryenhoek and Others v Powell NO and Others 1996 (1) SA 984 (CC). 8. Popper K. The Open Society and Its Enemies. London: Routledge, 1945.

Accepted 7 March 2017.

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

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MEDICINE AND THE LAW

Ethical and legal perspectives on use of social media by health professionals in South Africa B Kubheka, MB ChB, Dip Project Management, MBA Health IQ Consulting, Johannesburg, South Africa; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: B Kubheka (brenda.k@wol.co.za)

Use of social media has increased exponentially throughout the world. Social media provides a platform for building social and professional relationships that can be used by all, including healthcare professionals. Alongside the benefits of creating networks and spreading information wider and faster than is possible with traditional communication channels, however, it presents ethical and legal challenges. For health professionals, it poses a threat to confidentiality and privacy owed to patients, colleagues and employers. It is vital for health professionals to acknowledge that the same ethical and legal standards apply both online and offline, and that they are accountable to professional bodies and the law for their online activities. This article seeks to explore the ethical and legal pitfalls facing health professionals using social media platforms. Importantly, it seeks to create awareness about the cyberpsychology phenomenon called the ‘online disinhibition effect’, responsible for lowering restraint during online activities. S Afr Med J 2017;107(5):386-389. DOI:10.7196/SAMJ.2017.v107i5.12047

Social media refers to forms of electronic communication that enable individuals and communities to gather, communicate, share personal messages, share various types of information, and in some cases collaborate or play.[1,2] Examples of social media include Twitter, Facebook, YouTube, LinkedIn and blogs, among others. [2] Social media litigation is still new in South Africa (SA), and the 2013 Isparta v Richter case[3] is the first case in SA where damages were awarded to the plaintiff for defamatory statements made on Facebook. Traditionally, health service managers worried about breaches of confidentiality or violations of patients’ rights occurring during inappropriate discussions in canteens, hospital corridors or elevators.[4] Social media has taken these concerns to new levels, where there is no control on how fast or far information shared on its platforms can spread.[2,4] To date, the Health Professions Council of South Africa (HPCSA) does not have ethical guidelines for the use of social media. The South African Medical Association (SAMA) published on its website a guide titled ‘Practical and ethical guidance for doctors and medical students’,[5] which provides practical recommendations for avoiding most ethical and legal pitfalls facing professionals and medical students on social media. This article presents an overview of the findings of an analysis of ethical and legal issues facing professionals on social media.

Legal framework

The Bill of Rights in chapter 2 of the Constitution of the Republic of South Africa[6] affirms the democratic values of human dignity, equality and freedom. It further confers the right of natural or juristic persons to approach the court to enforce their rights when they are threatened or violated. The rights relevant to this article are the rights to: (i) have dignity protected and respected; (ii) physical and psychological integrity; (iii) equality; (iv) privacy; and (v) freedom of expression. Many of the rights are not absolute, but their infringement ought to be justifiable and reasonable in an open and democratic society.[7] The right to freedom of speech is not absolute, but limited to avoid violation of other people’s rights. Notably, the

patient-professional relationship is characterised by an imbalance of power, patients being more vulnerable than the professionals treating them.[8,9] Limitations to freedom of speech are seen in the Isparta v Richter case,[3] where the plaintiff was awarded damages after the first defendant, the partner of the former spouse, posted comments about the plaintiff ’s parenting skills on Facebook and tagged the former spouse, the second defendant. The plaintiff felt belittled and found one of the posts to be malicious and damaging to her reputation. The post attracted negative comments for allegedly allowing a teenage stepson to bath the plaintiff ’s younger daughter. Although the second defendant did not comment on the post, he did not remove the tag, therefore failing to distance himself from the defamatory posts. The judge found both defendants guilty of defamation.[3] The National Health Act (Act No. 61 of 2003)[10] ratifies the patient’s right to confidentiality, and this is consistent with the right to privacy stated in the Bill of Rights.[6] Patients have a right to expect information shared with health professionals to be treated as privileged information and to be held in confidence.[11,12] Breaching confidentiality erodes the public’s trust in the medical profession.[9]

Ethical framework

Morality and ethical principles ought to guide the professional’s disclosure of patient information, both online and offline. The principles are: (i) autonomy – respect for self-determination; (ii) beneficence – promoting the interests of others; (iii) non-maleficence – avoiding or minimising harm; and (iv) justice – fair distribution of benefits and burdens.[8] Professionalism is the foundation of the social contract with patients, and society expects professionals to behave empathically and professionally.[12] The HPCSA’s General Ethical Guidelines[13] state that professionals ought to act quickly to protect patients from risk due to any reason, and to report violations and seek redress in circumstances where they have a good or persuasive reason to believe that the rights of a patient are being violated. Professionals therefore have the moral obligation to

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bring inappropriate online behaviour of colleagues to their attention in a discreet manner, and even to ask them to take down any inappropriate posts.[5,9,12] Ethical codes have no legal precedent, but hold professionals to a higher moral obligation in serving the public, and they can be enforced through professional standards.[14] Virtues depicting traditional medical practice are care, compassion, discernment, trustworthiness, integrity, conscientiousness, respectfulness, benevolence, truthfulness and justice.[8] Professionals ought to conscientiously exercise both reasoning and moral judgement on social media. Importantly, patients ought not to be treated as a means to an end but with dignity, and their rights ought to be protected.[8] The HPCSA guidelines provide guidance for disclosures that benefit patients directly or indirectly, protect the patient and others, and are linked with judicial or statutory proceedings.[11] Any other disclosure in the absence of express consent is neither legally nor morally defensible and threatens the profession’s reputation.

Discussion

Double identity: Social and professional self

The new generation of medical students have joined medical training with digital footprints and established social media habits unimaginable to their seniors.[1] It is relevant that one study found that 52% of undergraduate medical students admitted to having embarrassing photos on Facebook.[1] In another study conducted on male pharmacy students, most of them indicated that they viewed Facebook as a social domain separate from their professional lives. [1] Professionals ought to think carefully before accepting friend requests from their patients or sending friend requests to them, because of the risk of blurring professional and personal lives.[5,12] Importantly, professionals ought to have a reliable character, good moral sense, and an appropriate emotional responsiveness.[8] Some users are naive and believe social media to be platforms for self-expression without legal restraint. The Isparta v Richter case[3] is a good example proving that online communication is subject to legal rules and that there are limitations to freedom of expression. The same laws and codes of conduct apply in the real world and cyberspace.[12] Users of Facebook must be extremely careful not only about what they post but also with regard to posts on which they may be ‘tagged’, because if they do not ‘un-tag’ themselves or if they ‘like’, it will be construed that the they agree with the shared content, as seen in the Isparta v Richter case.[3]

The patient-professional relationship and its boundaries

Trust is the foundation of the patient-professional relationship.[8,11] Information shared in confidence for the purpose of healthcare ought to be protected, because failure to do so violates the patient’s rights and undermines the patient-professional fiduciary relationship. Professionals ought to uphold ethical standards and act in an ethical and legally defensible manner both offline and online, because it is the right thing to do. Failure to uphold ethical standards on social media exposes patients to embarrassment and psychological harm, thus undermining the principles of beneficence and non-maleficence. Another area of concern is dissemination of patients’ pictures on social media that might constitute invasion of privacy, defined as a situation in which someone fails to respect a person's right to keep certain personal information from being known.[15] This could be for information sharing, educational purposes, or other reasons. Professionals are also warned against taking pictures without obtaining signed informed consent from their patients, especially if the patient is identifiable.[2] Patients ought to explicitly give informed consent for the taking of pictures and for the dissemination of

their pictures on any media platform. Valid informed consent is characterised by: (i) disclosure of the nature and extent of the risks and benefits; (ii) appreciation and understanding of the risks and benefits; (iii) ability to make decisions and communicate them; (iv) voluntariness; and (v) authorisation to proceed with sharing pictures and other patient information.[8,11,12,15,16] Professionals ought to acknowledge the imbalance of power between themselves and patients when facilitating informed consent, and this imbalance might compromise free will.[8,11] In this instance, informed consent fulfils the legal role of protecting patients against violation of their dignity, privacy, and bodily and psychological integrity. Studies assessing the use of social media by medical professionals have included reviewing content on medical blogs and other social media platforms.[2,17] The findings confirmed a large number of cases in which it was easy for patients to identify their doctors, or even themselves.[1] In one of the studies, the use of negative language describing patients was evident in 57% of cases.[1] This is contrary to the professional’s moral obligation to protect patients and the profession’s reputation. Trust, non-maleficence, beneficence and transparency are important characteristics of a relationship between two or more parties. Relationships can be irrevocably severed because of breach of trust.[18]

Social media as a work tool and professionalism

The workplace benefits from the use of group-based communication channels, and these include WhatsApp groups used to share information in clinical settings lacking sophisticated communication technologies. Work interaction groups on WhatsApp are becoming commonly used by professionals to communicate availability for shift work, traffic issues, and pictures of patients when requesting second opinions from colleagues – the list is endless. There are, however, challenges associated with some of these platforms because they may not be secure and messages may get sent to wrong recipients, thus compromising privacy and confidentiality. Sending pictures and requesting second opinions via these platforms permeate into the practice of telemedicine, posing further ethical and legal challenges, including storage and ownership of shared information. The use of uncontrolled and open-access social media platforms to share patient information may expose professionals to violation of ethical standards and the law. Social media also presents a challenge of blurring boundaries in the patient-professional relationship,[2,12] as seen in the Prof. Tim Noakes HPCSA disciplinary hearing. The incident was triggered by dietary advice provided by Noakes via Twitter to a breastfeeding mother advising her to wean her child on a low-carbohydrate and high-fat diet.[19] It is advisable that professionals share generic information online, and avoid responding with direct medical advice to individuals. Further, as a standard precaution, it should be mandatory that any medical discussion professionals enter into on social platforms be accompanied by the advice that patients must consult their practitioners.[12] Information shared online is accessible to the public, and employers may use it to screen potential employees. Inappropriate content may affect one’s professional standing.[9,12] Societal expectations often go beyond the professional role and into the daily activities of professionals, and poor judgement demonstrated even in a personal capacity reflects negatively on both the individual and the profession. [5,12] Interestingly, research conducted on medical students showed that frequent users of social media perceived regulating personal use of social media as an infringement of privacy, but still believed that the users ought to conduct themselves professionally.[20] Facebook has the ability to create closed groups of selected participants

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with common interests. The users are ‘approved’ by the administrator or other members of the page before they can gain access to the content and are able to contribute to discussions. Administrators should keep in mind that they do not own these social platforms, and owners may change security settings without consulting the users. In the future, information classified as private today might be opened to the public. Administrators have additional responsibilities of ensuring that information shared on their page does not violate ethical standards and laws, since they are ultimately accountable for the content.[3] Making negative comments about colleagues, patients and others on social media can be viewed as bullying and unprofessional, and has a corrosive effect on the affected person and others around them. Such comments may attract charges from the HPCSA and, worse, legal action from the complainant for defamation[5,9,12] and other legally quantifiable losses. Defamation is the act of making statements about a person or organisation through publication of information considered harmful to their reputation.[3,12] The HPCSA’s General Ethical Guidelines[13] state that ‘a professional shall not cast reflections on the probity, professional reputation or skill of another person registered under the Health Professions Act or any other Health Act’. [13] Professionals therefore ought to refrain from making negative and defamatory comments about colleagues on social media, but rather address issues of concern with the relevant individuals. Professionals ought to acknowledge benefits and weaknesses stemming from digitalisation of communication. Crucially, information shared online is in the public domain and has relative permanence, even after it has ostensibly been deleted. [12] Employers and professional bodies can use this information for disciplinary proceedings if it is deemed to have brought a profession or an organisation into disrepute.[2,18] Disclosing work-related information can undermine the employee-employer relationship and violate employer policies, and may have negative consequences. [17] In countries such as the USA and the UK, medical professionals who have violated ethical principles on social media have faced academic dismissal, termination of employment, and worse fates such as deregistration from professional boards.[2,9] In most cases, such violations are not intentional but due to lapses in judgement.[2,17] To offset the potential minefield of negative occurrences, social media has potent benefits. It has the capacity to reach more people faster, and therefore has become a great tool for health promotion, education[12] and professional networking.

Cyberpsychology and the disinhibition effect

The online disinhibition effect is defined as the lowering in the online social environment of the psychological restraints that normally serve to regulate behaviour.[21,22] Disinhibitions are influenced by various factors ranging from invisibility, personality type and intensity of feelings to the type of social media platform being used.[21] Like any other person, professionals are susceptible to disinhibition and will loosen up, communicate more freely and experience fewer inhibitions and behavioural boundaries online.[12,22] Others disaggregate their online self, detaching it from the rest of their lives and, disturbingly, minimising personal accountability for their online actions to professional bodies and the law.[21] This is a logical fallacy, because the same ethical standards and laws applicable offline also apply online. The fallacy facilitates temporary suspension of moral cognitive processes, triggering undesirable effects. Crucially, disinhibition is not the only factor influencing how professionals behave online, but it is a significant factor.[22] Raising professionals’ awareness of the disinhibition effect could play a significant role in

avoiding the ethical and legal pitfalls associated with the use of social media.

Conclusions

Professionals ought to ask themselves before posting on social media whether sharing certain information is legally and morally defensible, whether it reflects the professional conduct expected of them and whether it will benefit their patients, and importantly question their own intention for posting. Current medical training includes training on communication skills, but it does not address the benefits and risks of digitalisation of communication, especially social media. The HPCSA needs to develop social media guidelines and train medical trainers in this specific area. Medical schools need to address social media issues during new student induction briefings, and this should continue to advance in sophistication until graduation. Health establishments ought to develop social media policies and train staff on risks associated with the use of social media. While social media has made it easier for professionals to communicate and share information, it holds the potential to threaten patients’ rights and undermine professional and employer relationships if its use by professionals is not guided. Professionals should monitor what information they share and how they share it, and take precautionary measures to protect themselves from online dangers. Finally, social media is not immoral, but the intentions of professionals and how they use such platforms may lead to actions that are not morally or legally defensible. Acknowledgements. The author thanks Dr Graham Howarth and Prof. Mncedisi Maphalala for their insightful guidance. She also appreciates the assistance of Lizeka Tandwa and Ayanda Simelane in proofreading the manuscript. Author contributions. Sole author. Funding. None. Conflicts of interest. None.

1. Von Muhlen M, Ohno-Machado L. Reviewing social media use by clinicians. JAMIA 2012;19(5):777781. http://dx.doi.org/10.1136/amiajnl-2012-000990 2. Basevi R, Reid D, Godbold R. Ethical guidelines and the use of social media and text messaging in healthcare: A review of literature. N Z J Physiother 2014;42(2):68-80. 3. Roos A, Slabbert M. Defamation on Facebook: Isparta v Richter SA 529 (GP). Potchefstroom Electron Law J 2014;17(6):2485-2868. http://dx.doi.org/10.4314/pelj.v17i6.18 4. Snyder Y. Online professionalism: Social media, social contracts, trust and medicine. J Clin Ethics 2011;22(2):173-175. 5. South African Medical Association. Using social media: Practical and ethical guidance for doctors and medical students. https://www.samedical.org/files/Guideline%20for%20Drs%20Using%20Social%20 Media%20febr015.pdf (accessed 12 January 2017). 6. South African Government. Constitution of the Republic of South Africa, 1996. Chapter 2: Bill of Rights. http://www.gov.za/documents/constitution/chapter-2-bill-rights (accessed 12 January 2017). 7. McQuoid-Mason D, Dada M. The A-Z of Medical Law. 1st ed. Cape Town: Juta, 2011. 8. Beauchamp TL, Childress JF. Principles of Medical Biomedical Ethics. 7th ed. New York: Oxford University Press, 2013. 9. Australian Medical Association. Social media and the medical profession: A guide to online professionalism for medical practitioners and medical students. https://ama.com.au/sites/default/files/ Social_Media_and_the_Medical_Profession_FINAL.pdf (accessed 20 January 2017). 10. Republic of South Africa. National Health Act (Act No. 61 of 2003). http://www.saflii.org/za/legis/ consol_act/nha2003147/ (accessed 29 August 2016). 11. Health Professions Council of South Africa. Confidentiality: Protecting and Providing Information. Booklet 10. Pretoria: HPCSA, 2008. http://www.hpcsa.co.za/Uploads/editor/UserFiles/downloads/ conduct_ethics/rules/generic_ethical_rules/booklet_10_confidentiality_protecting_and_providing_ information.pdf (accessed 1 February 2017). 12. Grobler C, Dhai A. Social media in healthcare context: Ethical challenges and recommendations. S Afr J Bioethics Law 2016;9(1):22-25. http://dx.doi.org/10.7196/SAJBL.2016.v9i1.464 13. Health Professions Council of South Africa. General Ethical Guidelines for the Health Care Professions. Booklet 1. Pretoria: HPCSA, 2008. http://www.hpcsa.co.za/Uploads/editor/UserFiles/ downloads/conduct_ethics/rules/generic_ethical_rules/booklet_1_guidelines_good_prac.pdf (accessed 14 January 2017). 14. Littleton V, Meemon, N, Breen G, et al. An ethical analysis of professional codes in health and medical care. Ethics Med 2010;26(1):25-48. 15. Merriam-Webster Dictionary. https://www.merriam-webster.com/dictionary/invasion%20of%20 (someone's)%20privacy (accessed 15 January 2017). 16. Health Professions Council of South Africa. Seeking Informed Consent: Ethical Considerations. Booklet 9. Pretoria: HPCSA, 2008. http://www.hpcsa.co.za/Uploads/editor/UserFiles/downloads/ conduct_ethics/rules/generic_ethical_rules/booklet_9_informed_consent.pdf (accessed 14 January 2017).

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17. Knudson E. Social media presents unique risks for healthcare professionals. AORN J 2012;97(1):5-6. http://dx.doi.org/10.1016/S0001-2092(12)00619-9 18. Shange N. Yes, your boss can fire you for social media posts – attorney. 2016. http://www.heraldlive. co.za/news/2016/02/02/yes-boss-can-fire-social-media-posts-attorney/ (accessed 24 August 2016). 19. Genever S. Noakes in hot water over Twitter diet advice. 2015. http://www.sabreakingnews. co.za/2015/04/22/noakes-in-hot-water-over-twitter-diet-advice/ (accessed 28 August 2016). 20. Farnan JM, Higa JT, Paro JAM, et al. Training physicians in the digital age: Use of digital media among medical trainees and views on professional responsibility and regulation. AJOB Prim Res 2010;1(1):310. http://dx.doi.org/10.1080/21507711003697527

21. Suler J. The online disinhibition effect. Cyberpsychol Behav 2004;7(3):321-326. http://dx.doi. org/10.1089/1094931041291295 22. Lapidot-Lefler N, Barak A. The benign online disinhibition effect: Could situational factors induce selfdisclosure and prosocial behaviors? J Psychosoc Res Cyberspace 2015;9(2). http://dx.doi.org/10.5817/ cp2015-2-2:20-38

Accepted 13 February 2017.

MEDICINE AND THE LAW This open-access article is distributed under CC-BY-NC 4.0.

Biobanks in South Africa: A global perspective on privacy and confidentiality

R Rheeder, ThD Department of Theology, School of Ecclesiastical Studies, North-West University, Potchefstroom, South Africa Corresponding author: R Rheeder (riaan.rheeder@nwu.ac.za)

The Universal Declaration of Bioethics and Human Rights (UDBHR) of the United Nations Educational, Scientific and Cultural Organization (UNESCO) was adopted unanimously in 2005 by the world community as a universal guideline, according to which members of the global community were accountable to each other. Research results from UNESCO show that the UDBHR has had little or no impact in South Africa (SA). The primary objective of this article is to promote awareness of the UDBHR in SA and Africa by focusing on Article 9 of the Declaration, which accepts the right to privacy and confidentiality. For this objective to be relevant in the SA context, depends on whether the guidelines of the National Department of Health’s Ethics in Health Research: Principles, Processes and Structures of 2015 acknowledge biobanks of the universally accepted ethical guidelines on privacy and confidentiality of autonomous persons and whether these guidelines are broadly in accordance with global bioethical guidelines. S Afr Med J 2017;107(5):390-393. DOI:10.7196/SAMJ.2017.v107i5.12004

In this study, Article 9 of the Universal Declaration on Bioethics and Human Rights (UDBHR) of the United Nations Educational, Scientific and Cultural Organization (UNESCO) is investigated to understand and promote the global bioethical norms of privacy and confidentiality. Under the heading ‘Privacy and confidentiality’, Article 9 reads as follows: ‘The privacy of the persons concerned and the confidentiality of their personal information should be respected. To the greatest extent possible, such information should not be used or disclosed for purposes other than those for which it was collected or consented to, consistent with international law, in particular international human rights law.’[1] The UDBHR is, in my opinion, one of the most important instruments in the development of human rights and bioethics, as the international community, comprising 191 member states, accepted it unanimously in 2005. This means that the declaration was the first global political and bioethical text to which all the governments in the world, including South Africa (SA), committed themselves. It is the only bioethical document that is so widely accepted.[2-4] The primary aim of this article is to promote awareness of the UDBHR in SA and Africa. Article 23 of the UDBHR makes an appeal to states that have signed the Declaration to promote the principles of Article 9 by means of education in all areas. Mathooko and Kipkemboi,[5] two UDBHR researchers from Africa, are convinced that bioethical teaching is necessary on this continent. The research focus arises from UNESCO research results, showing that the UDBHR has had little or no impact in SA.[6] To bring the primary objective of creating

awareness of the UDBHR in SA into effect, UNESCO’s understanding of respect for the principle of privacy and confidentiality is explained briefly. It is also important to consider that the promotion of human rights awareness in SA depends on all citizens’ understanding of and concurrence with the fundamental content of the UDBHR. With regard to the latter, in contrast to all other bioethical instruments, the UDBHR is definitely aimed at developing countries.[1] Several biobanks that function globally have come into existence, also in SA. In June 2010, the National Institutes of Health (USA) and Wellcome Trust (UK) lodged a project, Human Heredity and Health in Africa (H3Africa), with four biobanks in SA. Biobanks are repositories that store human biological materials for research purposes specifically. These banks do not only store organised collections of human biological materials (usually from a large number of donors), but also associated data, including individual health records and information derived from their analysis.[1,2] Several ethical issues are closely related to the phenomenon of biobanks, i.e. informed consent, privacy and confidentiality, sharing of benefits, and many other ethical challenges. It is surmised that there are >12 biobanks of different sizes in SA,[7-9] but there is currently no national instrument that focuses exclusively on the ethics of biobanks. The National Health Act No. 61 of 2003 offers no ethical guidelines for biobanks;[9] therefore, the only national document that is currently directional in this regard is the Ethics in Health Research: Principles, Processes and Structures of 2015, updated from the 2004 guidelines[7,10] of the Department of Health (DoH). In

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the Foreword and Acknowledgements, this document expresses its status as the national policy for conducting research responsibly and ethically, as mandated by Section 72 of the National Health Act No. 61 of 2003.[10] To make the primary goal of the article relevant to the SA context, I discuss whether the guidelines of the DoH with regard to biobanks incorporate the universally acknowledged ethical guidelines on privacy and confidentiality (of autonomous persons) and whether these guidelines are broadly in accordance with global bioethical guidelines. Commentators of the UDBHR also discuss biobanks in the light of Article 9.[11] In the Handbook of Global BioEthics,[5] which uses the UDBHR as a frame of reference, it is stated that legislation or bioethical instruments in Africa (and by implication in SA) do not conform to international bioethical standards. Consequently, attention is given to Article 9 of the UDBHR; thereafter, the ethical guidelines of the DoH are discussed briefly to determine whether they are broadly in accordance with global bioethical guidelines.

Global guidelines

In the first instance, the UDBHR relates human dignity and privacy/ confidentiality to each other. According to Article 3 of the UDBHR, respect for privacy and confidentiality gives expression to human dignity; where these principles are respected, people are treated with human dignity.[12-15] From the following statement it is clear that UNESCO wanted to formalise these principles: ‘Nevertheless, in order to use “dignity” in our lives, some practical principles were established.’[13] In the second instance, privacy or confidentiality is the direct outcome of autonomy, which deals (according to Article 5 of the UDBHR) with the global recognition that a human being has the right to determine the content of his life.[12] In the third instance, what is UNESCO’s interpretation of the concept of ‘privacy of the persons’? In their explanation of Article 9, both Stiennon[14] and Martin,[15] who analyse the UDBHR, use the definition of the International Bioethics Committee (IBC) of UNESCO as found in UNESCO’s Explanatory Memorandum on the Elaboration of the Preliminary Draft Declaration on Universal Norms on Bioethics[4] of June 2005: ‘A right to privacy guarantees a control over personal information in many ways. It restricts access to personal and medical information and it provides a claim of non-interference in various private spheres of the individual. Privacy extends beyond data protection, as certain private spheres of the individual that are not manifested in data processing can also be protected by the right to privacy.’ The first fundamental distinguishing norm of the right to privacy is the recognition or confirmation that every individual has a personal space in which he or she has an autonomous decision-making right.[11,14] This personal space includes the whole person (including biological, psychological, social, cultural and spiritual dimensions and all types of data; see Foreword of the UDBHR[1,13]) and no one has the right to enter the personal space (the claim of non-interference) and remove and use any material or information of the person.[12] Only the person has the right to free his or her space from privacy. This private space of persons (who have the capacity to make autonomous decisions) is protected or held private by the right of (informed) consent, which can be summarised as follows (Article 6 of the UDBHR): ‘Any preventive, diagnostic and therapeutic medical intervention … as well as scientific research … is only to be carried out with the prior, free and informed consent of the person concerned, based on adequate information.’[1,14,15] The second fundamental distinguishing guideline of the right to privacy is the recognition that every individual also has within his or her personal space multiple spaces over which he or she has an

autonomous, decision-making right (see the abovementioned definition on private spheres). Article 9 of the UDBHR restricts the scope of consent or space. This is deduced from the norm that regulates privacy, confidentiality and information: ‘The privacy of the persons concerned and the confidentiality of their personal information should be respected. To the greatest extent possible, such information should not be used … for purposes other than those for which it was collected or consented to.’[1,14] From this explanation, it is clear that consent can or must be clearly aimed at a specific goal (‘for purposes other than those for which it was … consented to’). Consent is very specifically applicable to an exact space or spaces within the larger space and does not open up the total personal space.[12,14,15] The following two examples serve as explanation: (i) consent to use blood samples doesn’t automatically open the space to psychological information; and (ii) consent to use biological spaces for researching diseases doesn’t mean that biological material may be used for creating human embryos.[9] Currently, it seems (in line with the draft Declaration on Ethical Considerations Regarding Health Databases and Biobanks of the World Medical Association (WMA)[16] and in light of the UDBHR’s Article 9) as if a concept such as broad informed consent could be problematic, as it cannot be specific. Broad consent permits donor use of biological materials for future studies, subject only to further prior ethics review and approval.[10,13] In the fourth instance, what is UNESCO’s understanding of the concept of confidentiality? In their discussion of this concept, both Stiennon[14] and Martin[15] use the definition in the abovementioned explanatory memorandum of the IBC: ‘Confidentiality refers to a special and often fiduciary relationship, such as that between researcher and research subject, or doctor and patient, and provides that the shared information shall remain secret, confidential and shall not be disclosed to third persons, unless a strictly defined, compelling interest justifies disclosure under domestic law.’[4] The first basic norm with regard to the concept of confidentiality is that the person is and remains the lawful and autonomous owner of all information that has been attained and moved from the private space.[14] This ownership is quite clear from the following UNESCO statement: ‘Individuals “own” their information: it is essential to their personal integrity.’[12,13] It also means that a person has the right not to know and may request not to be informed about a certain situation. After death, a person also has the right to privacy and confidentiality.’[15] The second basic norm is that if a person or persons want to share information with others outside the initial consent situation, he, she or they have to obtain consent to or exemption from specific confidentiality again. Article 9 states clearly that ‘information should not be used or disclosed for purposes other than those for which it was collected or consented to’.[1] From this, it is clear that consent consists of two phases. In a ‘first consent’, information that has a specific purpose is entrusted to a very clear, demarcated space. If someone wants to move this information from the first space for which consent has been given (whatever the reason might be), a ‘second consent opportunity’ is necessary.[14,15] Currently, it also seems (in line with the WMA Draft Declaration on Ethical Considerations Regarding Health Databases and Biobanks[16] and in light of the UDBHR’s Article 9) as if a concept such as broad informed consent could be contentious in this case. In the fifth instance, UNESCO recognises that the abovementioned norm is not absolute in all respects and exceptions are possible. The golden rule is that before any confidentiality may be breached, the consent of the patient or substitute must be received.[12] Article 9 regulates that confidentiality should be respected to ‘the greatest extent possible’.[1] It means that in exceptional cases, it is permissible

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that the right to confidentiality could be infringed upon. These exceptions are described as follows in Article 27 of the UDBHR: ‘If the application of the principles of this Declaration is to be limited, it should be by law, including laws in the interests of public safety, for the investigation, detection and prosecution of criminal offences, for the protection of public health or for the protection of the rights and freedoms of others. Any such law needs to be consistent with international human rights law.’[1,14] Martin[15] asserts that the interest and wellbeing of the community may not easily be used as an argument to justify unlawful infringement of the right to privacy and confidentiality. Article 3.2 of the UDBHR motivates this truth in the following way: ‘The interests and welfare of the individual should have priority over the sole interest of science or society.’[1] It means that the respect for privacy and confidentiality of the person has greater weight than the interests of science and the community. For now, it would appear as if the UDBHR’s possible exception only considers public safety, crime tracing and protection of public health (e.g. a highly infectious disease) to infringe upon the right to privacy and confidentiality, and does not really leave room for the argument of broad consent with a view to research or the promotion of the common good of the community. In the sixth instance, what is the implication of Article 9 as universal bioethical principle and human right? Article 9 states clearly that the right to privacy and confidentiality must be respected.[1] The concept of ‘respect’ has the meaning of ‘protection’ within the framework of the Declaration and Article 9.[14] These meanings are confirmed by one of the objectives of the UDBHR, i.e. ‘to promote respect for human dignity and protect human rights by ensuring respect for the life of human beings and fundamental freedoms, consistent with international human rights law’ (Article 2, c).[1] This protection can be by means of legislation, policy, instruments in the field of bioethics (Article 2), ethics committees (Article 19) and education in bioethics (Article 23).[1] These guidelines refer to both the subject (participant) and the object (researcher) in the context of medical care and research.[1,14]

Department of Health guidelines

The DoH’s ethical guidelines with regard to biobanks, privacy and confidentiality are discussed briefly. In paragraph 3.5, which deals with special topics, the DoH pays attention to the following issues: databases, registries and repositories, including biobanks (3.5.2.2). As paragraph 3.5 deals very concisely with biobanks (repositories), relevant information is collected from the entire document.[10] The following conclusions can be drawn: 1. The DoH states clearly in Chapter 2 (Guiding principles for ethical research) that broad ethical principles form the foundation of norms: ‘This chapter sets out the broad principles underpinning research that inform the norms and standards.’ The specific, relevant broad or underlying principle to which the DoH refers is ‘respect of persons’ that is described as human dignity and autonomy (2.1). 2. In close relation to this principle, the DoH’s guidelines state in Chapter 2 that privacy and confidentiality are two key norms and basic rights that flow from the respect for people (human dignity and autonomy): ‘The key ethical norms and standards are ongoing respect for participants, including privacy and confidentiality’ (2.3; 2.3.7). SA has a long history of recognising the right to privacy and confidentiality in common law[17] and the Constitution.[17] These two principles also form part of the HPCSA’s rules and guidelines for healthcare professionals in SA.[18] 3. The DoH’s guidelines[10] provide the following definitions of these two key ethical norms:

• Simply stated, privacy is concerned with who has access to personal information and records about the participant, including clinical health care records (2.3.7; 3.1.8). • However, ‘confidentiality’ is about ensuring that appropriate measures will be implemented to prevent disclosure of information that might identify the participant (inadvertently or not), either during the course of the research or afterwards (2.3.7; 3.1.8). 4. It is stated clearly that the privacy and confidentiality of participants in research must be protected: • Thus researchers and research ethics committees (RECs) should pay careful attention to measures that will protect privacy and confidentiality interests (2.3.7; 3.1.8; 3.5.2.3). 5. The different possible ways in which privacy and confidentiality of the participants must be protected are indicated briefly: • In general terms, a person should know what information is being collected, why it is being collected, what will happen to it, how long it will be retained, whether it will identify the person, whether it will be shared with others and why, whether it will be sent outside SA and why. The person should agree to these terms.(3.1.8; 3.5.2.3). • Broad consent: the donor permits use of the specimen for current research, for storage and possible future research purposes, even though the precise nature of future research may be unclear at present. The nature of the further usage should be described as fully as possible and should stipulate that further prior ethics review of the new study is necessary. Permission may be sought to recontact the person if intended future use is outside the scope of the current consent (3.3.6). • The Protection of Personal Information Act No. 4 of 2013 (partially in effect) has increased the need to ensure computer safety, locked record storage facilities and careful gate keeping about access to raw data, including completed informed consent documents (3.1.8). It should be remembered that research records, including informed consent documentation, may be solicited by interested parties via application in terms of the Promotion of Access to Information Act No. 2 of 2000. • Researchers should take measures to ensure privacy and confidentiality interests throughout the research period, including when disseminating results or findings (2.3.7; 3.1.8). • Institutions and researchers that maintain repositories (biobanks or tissue banks) must have appropriate facilities, equipment, policies and procedures to store human biological materials and data safely and in compliance with accepted standards (3.5.2.2). • Appropriate safeguards, including physical, administrative and technical, must exist to protect against unauthorised handling (3.1.8; 3.5.2.2). • The location, context and timing of recruitment and enrolment should be appropriate for protection of privacy and confidentiality interests (3.1.4). • The proposal should explain why particular identifying information is required for the study that purports to collect data anonymously (3.1.8). • RECs should assess whether notifiable activities might occur amongst participants, for example abuse of minors or notifiable diseases and, consequently, whether appropriate measures are in place and are explained in the research proposal (3.1.8; 3.3.8). • If the information is to be sent outside the Republic, the recipient must assure that the level of protection afforded in that country is commensurate with that expected in SA (3.1.8). • Information about a person’s health or sex life, inherited characteristics and biometric information must be necessary for the research activity (3.1.8).

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• Usually, demographic and medical information about the donors is included in the repository, as are codes that link the material to the donors (3.3.3; 3.5.2.1). • Anonymised materials without any linkage to donors are unlikely to identify a donor (3.3.3). • Materials collected without identifiers of any kind are unlikely to identify an individual donor (3.3.3). • The consent documentation for donors should explain clearly … the conditions and requirements under which data or material will be shared with other researchers.(3.5.2.3). • The consent documentation for donors should explain clearly … information about the length of storage time … [and] when the current consent to use material or data will expire (3.5.2.3). • If a translator will be used in the consent process and be present for the discussions, the information materials should state that privacy will be compromised to that extent (4.5.1.9).

Conclusion

It is clear that the international community has respect for privacy and confidentiality as independent rights and that it regards respect for these rights as an obligation of all communities. In summary, the conclusion can be drawn that the ethical guidelines of the DoH, which also apply to biobanks and research, are broadly in line with the universal guidelines as spelled out in the UDBHR. Both documents take human dignity and autonomy as a point of departure, from which the norms of privacy and confidentiality flow, and they both state categorically that privacy and confidentiality must be protected. I am of the opinion that there is also a broad but definite agreement regarding the understanding of privacy, as both documents state that improper access to the person (implied space) is ethically unacceptable and that access to privacy is protected by informed consent. With regard to confidentiality, the documents state that information will be kept secret and may not be disclosed without consent. They also state that privacy and confidentiality are possibly not absolute and can be ignored in highly exceptional circumstances. It must also be mentioned that the SA Constitution recognises the rights of individuals as being paramount, except where it is ‘reasonable and justifiable’ to limit them.[17,18] The UDBHR, though, places greater emphasis on the right of the individual than on that of the community, whereas the DoH does not mention anything specific on the matter. In my view, the DoH meets objective 2(d) of the UDBHR as follows: ‘to recognize the importance of freedom of scientific research … while stressing the need for such research and developments to occur within the framework of ethical principles set out in this Declaration and to respect human dignity, human rights and fundamental freedoms.’[1] It is therefore incorrect to state that national policies in SA are not in concurrence with global guidelines regarding the regulation of research and biobanks. Nevertheless, the guidelines of the DoH must only be understood as a temporary document with specific shortcomings. For example, no attention is given to the issue of what the ethical implications will be if a biobank has to close prematurely or unexpectedly owing to financial problems, which will give creditors the right to sell assets and trustees to disregard previous

contracts, or if no attention is paid to material transfer agreements. [10] For the present, it also seems as if the UDBHR does not support the idea of broad ‘informed’ consent in Article 9, because privacy and confidentiality have to be directed very narrowly (this statement needs further study). In light of this, the appeal by leading SA bioethicists, jurists and physicians, such as a A Dhai, S Mahomed and I Sanne, can be supported, i.e. that an ‘ethico-regulatory framework’ that is exclusively focused on biobanks[16] and in concurrence with all the principles of the UDBHR and international guidelines for biobanks should be developed and implemented in SA in the near future.[7-9] Acknowledgements. None. Author contributions. Sole author. Funding. None. Conflicts of interest. None. 1. United Nations Educational, Scientific and Cultural Organization. Universal Declaration on Bioethics and Human Rights. Paris: UNESCO, 2006. http://unesdoc.unesco.org/images/0014/001461/146180e. pdf (accessed 27 March 2017). 2. International Bioethics Committee. Report of the International Bioethics Committee of UNESCO: On Consent. Paris: UNESCO, 2008. http://unesdoc.unesco.org/images/0017/001781/178124e.pdf (accessed 27 March 2017). 3. Solbakk J. Vulnerability: A futile or useful principle in healthcare ethics? In: Chadwick R, ten Have H, Meslin EM, eds. The Sage Handbook of Health Care Ethics. London: Sage, 2011:228-238. 4. United Nations Educational, Scientific and Cultural Organization. Explanatory Memorandum on the Elaboration of the Preliminary Draft Declaration on Universal Norms on Bioethics. Paris: UNESCO, 2005. http://unesdoc.unesco.org/images/0013/001390/139024e.pdf (accessed 27 March 2017). 5. Mathooko J, Kipkemboi J. African perspectives. In: Ten Have H, Gordijn B, eds. Handbook of Global Bioethics. Dordrecht: Springer Science and Business Media, 2014:253-268. 6. Langlois A. Negotiating Bioethics: The Governance of UNESCO’s Bioethics Programme. New York: Routledge, 2013:1-192. 7. Dhai A. Establishing national biobanks in South Africa: The urgent need for an ethico-regulatory framework. S Afr J Bioethics Law 2013;6(2):38-39. https://doi.org/10.7196/sajbl.296 8. Dhai A, Mahomed S, Sanne I. Biobanks and human health research: Balancing progress and protections. S Afr J Bioethics Law 2015;8(2)55. https://doi.org/10.7196/SAJBL.8060 9. Dhai A, Mahomed S. Biobank research: Time for discussion and debate. S Afr Med J 2013;103(4):225227. https://doi.org/10.7196/samj.6813 10. Department of Health. Ethics in Health Research: Principles, Processes and Structures. 2nd ed. Pretoria: DoH, 2015. http://sun.ac.za/research/assets/files/Integrity_and_Ethics/DoH%202015%20 Ethics%20in%20Health%20Research%20-%20Principles,%20Processes%20and%20Structures%20 2nd%20Ed.pdf (accessed 27 March 2017). 11. Shickle D. Biobanking. In: Ten Have AMJ, Gordijn B, eds. Handbook of Global Bioethics. Dordrecht: Springer Science and Business Media, 2014:485-503. 12. United Nations Educational, Scientific and Cultural Organization. Bioethics Core Curriculum, Section 1. Syllabus: Ethics Education Programme. Paris: UNESCO, 2008. http://unesdoc.unesco.org/ images/0016/001636/163613e.pdf (accessed 27 March 2017). 13. United Nations Educational, Scientific and Cultural Organization. Casebook on Human Dignity and Human Rights, Bioethics. Core Curriculum Casebook Series, No. 1. Paris: UNESCO, 2011. http:// unesdoc.unesco.org/images/0019/001923/192371e.pdf (accessed 27 March 2017). 14. Stiennon J-A. Article 9: Privacy and confidentiality. In: Ten Have AMJ, Jean MS, eds. The UNESCO Universal Declaration on Bioethics and Human Rights: Background, Principles and Application (Ethics Series). Paris: UNESCO, 2009:165-172. 15. Martin JF. Privacy and confidentiality. In: Ten Have AMJ, Gordijn B, eds. Handbook of Global Bioethics. Dordrecht: Springer Science and Business Media, 2014:119-137. 16. World Medical Association. WMA Declaration on Ethical Considerations Regarding Health Databases and Biobanks: A Draft from the Work Group Intended for Open Consultation After Acceptance of the Executive Committee of the WMA. Ferney-Voltaire: WMA, 2015. http://wma.net/en/20activities/10et hics/15hdpublicconsult/2015-Draft-policy-HDB_BB.pdf (accessed 27 March 2017). 17. Dhai A, McQuoid-Mason D. Confidentiality. In: Dhai A, McQuoid-Mason D, eds. Bioethics, Human Rights and Health Law: Principles and Practice. Claremont: Juta, 2011:88. 18. Health Professions Council of South Africa. Guidelines for Good Practice in the Health Care Professions. Confidentiality: Protecting and Providing Information, Booklet 10. Pretoria: HPCSA, 2008. http://hpcsa. co.za/Uploads/editor/UserFiles/downloads/conduct_ethics/rules/generic_ethical_rules/booklet_10_ confidentiality_protecting_and_providing_information.pdf (accessed 17 January 2017).

Accepted 25 January 2017.

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

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MEDICINE AND THE LAW

Legal liability for failure to prevent pregnancy (wrongful pregnancy) L C Coetzee, BLC, LLB, LLM Department of Criminal and Procedural Law, College of Law, University of South Africa, Pretoria, South Africa Corresponding author: L C Coetzee (coetzlc@unisa.ac.za)

Can the conception of a child ever constitute damage recoverable in law? This article considers the liability of healthcare practitioners for failing to prevent a pregnancy. Developments leading to the recognition of wrongful pregnancy as a cause of (legal) action in South Africa (SA), are briefly outlined. The salient points of the relevant judgments by our courts are set out to expose the rationale underlying the judgments and to highlight that recognition of liability for wrongful pregnancy resulted from an application of fair and equitable principles of general application. Conduct that could expose practitioners to liability is identified from reported cases and inferred from general principles laid down in case law. For current purposes, wrongful pregnancy may be defined as a situation in which a child is conceived to a parent or parents who had received negligent advice or treatment from an expert aimed at and expected to prevent a pregnancy or aimed at confirming the parent’s or parents’ inability to procreate.[1] The legal action is instituted against the expert – usually a medical practitioner – whose negligent treatment or advice causally contributed to the pregnancy.

Choice and responsibility

We live in a time of increased difficulty in conceiving, and one in which assisted reproduction has developed into a huge and profitable industry. Conversely, our age is also one of a world facing overpopulation, in which contraceptive measures play a role in avoiding the ills of overpopulation and the alleviation of poverty. Owing to huge scientific advances, we now have more options with regard to procreation than ever before. For example, the development of contraceptive measures brought the possibility of avoiding procreation, where procreation would be economically devastating to the parents. The question arose whether a person can be held liable for frustrating such a decision to prevent a pregnancy. At the time when humankind lacked the knowhow and ability to manipulate their procreative functions, the law was silent. The choices that were opened up through science brought with them responsibilities, and the law has assumed much greater significance in regulating reproduction. The right to make decisions regarding reproduction is now entrenched in the SA Constitution.[2] The medical profession plays an important role in ensuring the realisation of this right. Those using contraceptives expect these

products to be free from defects and safe for use, and they will use them under expert medical guidance in the hope of effectively avoiding pregnancy.[1] Most literate persons will know that contraceptive methods are not foolproof and the possibility of failure could be anticipated. In the event of a pregnancy, despite the use of contraceptives, it would be very difficult to prove a causal connection between any act or omission on the part of any one person and the resultant pregnancy.[1] The chances of successfully laying the blame for an unwanted pregnancy on a medical practitioner are much larger where the latter is approached for sterilisation. Here the intention is clearly to avoid pregnancy at all cost; the person who undertakes to render the sterilisation service is easily identifiable and clearly bears the responsibility of exercising reasonable care and applying reasonable skill to ensure success (see Definitions of concepts below).[1] However, it does not automatically follow that a medical practitioner who renders such services, necessarily and by implication, warrants the success of the procedure.[3] In the case of a vasectomy, for instance, the patient’s ejaculate may still contain sperm for a considerable time after the procedure. In roughly 1/80 000 cases, a man may even father a child despite the apparent absence of spermatozoa in his ejaculate.[4,5] Thus, for instance, a case occurred in the UK, where a woman fell pregnant while her husband produced persistently negative seminal specimens.[1,6,7] However, it remains the responsibility of the practitioner to ensure that the patient is properly informed of such risks, including the possibility of conception despite the operation ‘due purely to the vagaries of nature’,[7] as well as of the modus operandi for establishing or confirming sterility. Practitioners are often consulted for expert advice on reproductive health. A patient may want to know whether he or she would be able to have children, or whether there is any medical reason for not conceiving, despite sexual intercourse without contraceptives. Here, negligence in the performance of the indicated tests, handling specimens, failure to do such tests as are necessary to establish sterility, or even a misrepresentation that the patient is indeed incapable of procreating, may easily lead to a pregnancy that, if not unwanted, was at least beyond the parents’ contemplation. In this

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kind of situation – just as in the case of a failed sterilisation – the party responsible is readily identifiable and can easily be called to account.

Definitions of concepts

As it is possible to base a claim for wrongful pregnancy on either contract or delict, it is apposite to explain these concepts. In the normal course of events, health practitioner and patient would enter into a contract[1] for the provision of contraceptive services, whether it be the prescription, dispensing or placement of oral contraceptives, hormonal injections, implants, vaginal rings, intrauterine devices, or the performance of a vasectomy, tubal ligation or other sterilisation procedure. Most often, the terms of the contract include the provision of contraceptive advice, either in conjunction with the foregoing, or independently. Ordinarily, the contract for the provision of contraceptive services is not required to be in writing.[8] In the case of surgical sterilisation, however, written consent is required,[9] and a form is prescribed for the purpose of obtaining consent. The written consent form furnishes proof of the existence of a contract between medical practitioner and patient. It is an implied term of the contract between doctor and patient that the doctor will exercise such professional skill, competence and judgment as the reasonable practitioner of his/her branch of the profession possesses, and will treat the patient with the care that may reasonably be expected from such a practitioner.[10] A medical practitioner who fails to perform in accordance with an express or implied term of a contract commits breach of contract. Hence, failure to measure up to the standard of reasonable care would amount to a breach of contract.[10-12] It is, however, also a general principle of SA law that a contract that is contrary to public policy (contra bonos mores) is unenforceable.[12] A patient’s ability to institute legal action against a medical practitioner does not depend on the existence of a contract. It is a general principle of SA law that a legal obligation arises where a person, through his/her (i) conduct, (ii) wrongfully and (iii) culpably (i.e. negligently or intentionally), (iv) causes (v) harm to another.[12,13] Provided all five the abovementioned elements can be proved, the conduct constitutes a delict (civil wrong) in SA law. When interpreting negligence, our courts also have regard to the standard of skill and care possessed and exercised by the reasonable practitioner belonging to the defendant’s particular branch of the profession. Hence, it is evident that a medical practitioner can incur liability based either on breach of contract or delict if he/she fails to exercise reasonable care and/or apply reasonable skill in providing contraceptive services. The types of loss or damages that can result from the kind of conduct under consideration, can be categorised as either patrimonial or non-patrimonial in nature. Patrimonial loss is a calculable monetary loss or decrease in the plaintiff ’s patrimony (estate), i.e. a loss or reduction in value of a positive asset in the plaintiff ’s estate, or the creation or increase of a negative element of his/her estate (i.e. a debt).[13] Pure economic loss is damage of a patrimonial nature that is not the result of physical injury, personality impairment, or damage to property.[13] Non-patrimonial loss, on the other hand, is a harmful change in, or factual disturbance of, a person’s legally protected personality interests (e.g. physical-mental integrity, dignity, privacy, feelings), which change or disturbance does not affect the person’s economic position.[13]

Development in SA law

The courts have had the opportunity on a number of occasions to consider liability for wrongful pregnancy. Through their judgments they laid down the law and created precedents. The development of SA law on wrongful pregnancy is traced in the three subsections below.

Pregnancy after vasectomy: Behrmann v Klugman[14]

The plaintiffs were the parents of a normal child conceived and born after the defendant, a surgeon, had performed a vasectomy on the father. Their action was based upon alleged breach of contract, and alternatively, delict. They contended that the surgeon had failed to advise the child’s father to have a sperm count before resuming intercourse without contraception. They alleged that the surgeon had made certain statements that caused them to believe that the vasectomy would render the man sterile after 10 weeks. The doctor testified that it was his practice to warn patients not to engage in unprotected intercourse before he had declared the man sterile, and that it could take up to 9 months to obtain two negative sperm counts. On the facts before the court it found in favour of the surgeon. The court was not convinced that the plaintiffs had really believed that sterility would be achieved after 10 weeks, as they had waited much longer before resuming intercourse without contraception. The court held that the plaintiffs had failed to establish that the contract between them and the doctor contained an express or implied term or warranty regarding the permanent success of the operation. In view of the court’s finding on the facts, it was unnecessary to consider the more fundamental question, i.e. whether recognition of this type of claim would be contra bonos mores. Although the plaintiffs’ claim was rejected, the judgment did not exclude the possibility that a claim for wrongful pregnancy could succeed where the facts support such an action. Taking into account subsequent case law (as discussed below), in which it was held that this type of action is not contra bonos mores, it is conceivable that such claim will succeed if the plaintiff can prove that he was not properly informed of, for example, the necessity of first establishing sterility before resuming unprotected intercourse or the risks of recanalisation of the vas deferens. The case further illustrates the importance of keeping proper records, also of the information given to the patient.

Recognition of contractual liability for failure to perform a tubular ligation: The Edouard case[15]

The facts giving rise to the claim In this case, the court had to decide whether the action for wrongful conception/pregnancy was contra bonos mores, as it was beyond dispute that the agreed-upon procedure, a tubal ligation, was never performed. The defendant had contracted with the plaintiff and his wife to perform a tubal ligation on the woman at the time of giving birth by caesarean section to her third child. Believing that the sterilisation procedure had been performed, the couple took no precautions to prevent pregnancy, and the woman fell pregnant 4 months after the birth of her third child. The tubal ligation was eventually performed at the woman’s insistence when the fourth child was born. The damages claimed The child's father brought action for damage allegedly suffered in consequence of breach of contract. He claimed: (i) the cost of the tubal ligation eventually performed on his wife; (ii) the cost of maintaining the child from her birth until she attains the age of 18 years; and (iii) non-patrimonial damages for the discomfort, pain and suffering, and a loss of amenities of life suffered by his wife in consequence of the pregnancy and the birth of the child by caesarean section. The defendant conceded that it was liable for damages for breach of contract as a result of its failure to effect the tubular ligation that had been agreed upon, but contended that payment of the cost of the tubal ligation would discharge its liability. It is important to note that the parties were in agreement that, to their knowledge, the reason for seeking a tubal ligation was that the

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plaintiff and his wife could not afford to support more children.[15] It was also common cause that the plaintiff and his wife would not have agreed to give the child born as a result of the failure to perform the sterilisation out for adoption.[15] The defendant denied liability for the cost of raising the child on the grounds that although the contract for the woman’s sterilisation was valid and enforceable and in itself not contrary to public policy, it would nonetheless be contrary to public policy to allow the parents of a healthy and normal but unplanned child to recover such costs where the parents refuse to give the child out for adoption.[15] The argument was that in assessing such damages the court is called upon to decide whether a pecuniary value can be placed on a healthy life. It was argued that it would run counter to the sanctity of human life for a court to have to hold that the cost of maintaining a healthy child could constitute damage or injury to the parents. The judgment by the Durban and Coast Local Division of the Supreme Court The court was at pains to explain that contractual liability for this type of claim is in accordance with the general principles of our law. A court will only depart from the general principles regarding liability if there are public policy considerations that are so cogent as to justify a modification of or exception to the general principles: ‘Courts of law will be reluctant to discover new principles of morality or considerations of expediency and policy on which to invalidate contracts which on accepted legal principles would be valid, because it is a fundamental principle of our law as well (a principle which is itself based on public policy) that contracts which have been freely and seriously entered into should be enforced.’[15] Unable to find public policy considerations cogent enough to justify an exception to or modification of the general principles, the court rejected the defendant’s contentions. In its judgment the court said that it ‘is part of the parental instinct to accept and love, and care for, a child – even an unplanned one’, and there is ‘nothing inconsistent in the attitude of the parents if they were to say that they had not wanted another child but that now that the child has been born they love it and refuse to part with it’.[15] However, because of the breach of contract, the parents now face the dilemma that they had sought to avoid with the sterilisation operation, i.e. having a child whom they are unable to support.

Judgment was granted in favour of the plaintiff for the relief sought, with the exception of the claim for non-patrimonial loss ((iii) above). After a thorough examination of the common law, case law and legal opinion, the court concluded that non-patrimonial loss was not recoverable for breach of contract, and refused to follow the lead given by courts in the UK, where such damages can indeed be claimed on contract.[15] The court pointed out that in the case of a breach of contract resulting in bodily injuries, there would be a concurrent claim for damages in delict in every case where the breach was wrongful and accompanied by fault (intention or negligence) on the part of the defaulting party.[15] As a delictual claim can easily be conjoined with a contractual claim in the case of concurrent liability, the court refused to extend liability in contract to nonpatrimonial loss.[15] However, in the case at hand, a delictual claim was not conjoined and, therefore, non-patrimonial loss could not be recovered. Arguments raised on appeal to the Appellate Division, and the court’s answers to these Edouard’s case was taken on appeal to the Appellate Division, where it was heard by a five-judge bench (Table 1). The Appellate Division’s judgment The Appellate Division unanimously confirmed the judgment of the trial court and the judgment was reported as Administrator, Natal v Edouard.[16] The Appellate Division agreed with the trial court’s refusal to award non-patrimonial damages for the woman’s pain and suffering, as the claim was brought in contract, and non-pecuniary loss cannot be recovered in contract.[16] As a general rule, such damages can be claimed on the basis of negligence in delict. However, the Appellate Division was not convinced that the facts agreed upon in this case could find a claim for pain and suffering. The court remarked obiter that it may be questioned whether neglect leading to conception and a consequent birth could be equated with the inflicting of a bodily injury.[16] An obiter remark does not have binding force in law, as it represents an opinion uttered in a judgment on a matter that is not essential to reaching a decision. Note also that the Appellate Division did not reject the notion that conception and birth could be equated to the inflicting of a bodily injury, but merely indicated that it may be open to attack.

Table 1. Arguments raised on appeal in Edouard, and the Appellate Division’s answers to these Appellant’s argument

Court’s pronouncement in answer to appellant’s argument

The birth of a normal, healthy child cannot be regarded as a legal wrong against its parents[16]

The wrong is not the unwanted birth as such, but the prior breach of contract that led to financial loss[16]

The financial burden of having to maintain a child is outweighed by the benefits of parenthood (the birth of a child is a blessed event)[16]

Although tangible benefits accruing as a result of a breach of contract or the commission of a delict must be set off against the gross loss suffered by a plaintiff, there is no basis in SA law that the nonpecuniary benefits must be brought into account[16]

It would be highly undesirable for any child to learn that a court has publicly awarded damages to his parents because his birth was a mistake[16]

The possibility that a child will learn later in his life about such a judgment is rather remote. Once it is recognised in our law that this type of claim is well founded, relatively few cases of this nature will go to court. In any event, a child who is not given up for adoption ceases to be unwanted. Only the additional financial burden caused by its birth remains unwanted[16]

The award of damages will transfer the obligation to support and maintain the child from its parents to the defendant. This runs counter to public policy, which demands that there be no interference with the sanctity accorded by law to the relationship between parent and child[16]

This is a fallacious argument. The award of damages does not extinguish the parents’ obligation to maintain the child, but at best enables them to fulfil it. For example, should the award be made and the money be stolen, the parents will remain obliged to support the child[16]

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The court’s obiter remark does no more than raise some doubt as to the likelihood of a claim for non-patrimonial damages succeeding in delict. The court qualified the applicability of its judgment by stating that the finding that the claim of wrongful pregnancy was admissible was intended to pertain only to a case where, as here, a sterilisation procedure was requested and performed for socioeconomic reasons. The Appellate Division agreed[16] with the trial court’s caution that ‘[d]ifferent considerations might well apply where the consideration influencing the decision to have the operation was not an economic one’.[15]

Recognition of delictual liability for misrepresentation leading to pregnancy: Mukheiber v Raath[17]

In Mukheiber v Raath[17] the plaintiff instituted a delictual action against the doctor in circumstances where no agreement had ever been reached that the doctor would perform a sterilisation on the patient.[17] Liability founded on contract was, therefore, out of the question. The facts giving rise to the claim A married woman and her husband claimed damages from a gynaecologist following the birth of a normal child. The gynaecologist had attended to two previous pregnancies of the woman. During the latter of these pregnancies, the woman visited the gynaecologist a number of times for routine antenatal consultations.[17] In the course of one of these visits, they agreed that the gynaecologist would deliver the baby that the woman was carrying at the time by way of caesarean section some 11 days later. During the same consultation, the question of a sterilisation arose when the woman told the gynaecologist that she did not wish to fall pregnant again. The gynaecologist required the woman to discuss the matter with her husband and to convey their decision to him at their next consultation.[17] The woman did not discuss the matter with her husband that evening and went into spontaneous labour early the next morning. The baby was delivered by the gynaecologist by way of emergency caesarean section. It was common cause that the parties had never agreed on sterilisation and the gynaecologist never performed one.[17] Six days after the caesarean section, the woman accompanied by her husband visited the gynaecologist for the removal of the sutures. The parties’ versions of what was said in the course of that visit differed completely.[17] The plaintiffs averred that, having removed the sutures, the gynaecologist called the patient’s husband into the surgery and told them that ‘he had performed a sterilisation on [the patient], that she was now a “sports model”, and that they did not need to worry about contraception’.[17] The defendant disputed the plaintiffs’ version. The trial court could not decide which of the versions was more probable and therefore found that the plaintiffs had not acquitted themselves of the onus of establishing that the defendant made the alleged misrepresentation.[17] On appeal to a full court of the Cape High Court, the trial court’s judgment was reversed. The gynaecologist then appealed to the Supreme Court of Appeal. The damages claimed The plaintiffs’ claim was based on delict. They alleged that the gynaecologist’s negligent conduct (the negligent misrepresentation) had caused them damages in the form of pure economic loss when, relying on the misrepresentation, they failed to take contraceptive measures and a child was conceived and born. They claimed compensation for: (i) confinement costs; and (ii) maintenance of the child until he becomes self-supporting.[17] Non-patrimonial damages were not claimed. The judgment by the Supreme Court of Appeal The Supreme Court of Appeal agreed with the full court’s finding that the probabilities favoured the plaintiffs’ version, i.e. that the

gynaecologist had made the misrepresentation (i.e. that the patient had been sterilised).[17] Regarding the element of unlawfulness, the court stated that the test in the context of misrepresentation was whether, in the particular circumstances, the defendant had a legal duty to take reasonable steps to ensure that the representation was correct before making it.[17] In this particular case, the following circumstances were held to indicate the existence of such a duty: the doctor-patient relationship that existed between the parties required the defendant to be careful and accurate; the objectively material nature of the representation (carrying the real, objective risk of the conception of an unwanted child) and the subjectively material nature of the representation (the dangers of a false representation should have been obvious to a gynaecologist in the defendant’s position); the misrepresentation inducing the plaintiff and her husband not to take contraceptive care; that it must have been obvious to the defendant that the plaintiffs would rely on what he tells them; and the representation related to technical matters concerning a surgical procedure about which lay people would be ignorant and the defendant knowledgeable.[17] As far as the element of negligence was concerned, the court found that the defendant should reasonably have foreseen the possibility that his representation could cause damage to the plaintiffs and should have taken reasonable steps to guard against such occurrence. As he failed to take such steps, his conduct was negligent.[17] The court concluded that the defendant factually caused the damages claimed: had it not been for his misrepresentation, the plaintiffs would have taken contraceptive measures, and the child would probably not have been conceived and born.[17] However, the defendant contended that his liability should be limited by the mechanism of legal causation in terms of which damages that are too remote cannot be recovered.[17] The court found that the yardstick to be applied in determining the extent of the liability (i.e. the limitation of liability so as to exclude excessively remote damages) is that of public policy.[17] The public policy considerations that underlie the judgment in Administrator, Natal v Edouard[16] were found to be applicable in the case at hand. The court found that the limits of liability depend on the same considerations of public policy, whether a claim was founded in delict or contract.[17] The court saw no need for limiting claims, such as those under discussion, to cases where the request for sterilisation is made for socioeconomic reasons.[17] In this regard, the Mukheiber judgment extended the recognition afforded wrongful pregnancy claims beyond the circumstances contemplated by the trial court and the Appellate Division in Edouard’s case (see The Appellate Division’s judgment above). The court went even further and made it clear that such claims should not be limited to instances where the request for sterilisation was made by a married couple, or to instances where the husband had given his consent. In the case at hand, the plaintiffs’ wish not to have any more children was motivated by socioeconomic and family reasons, which were socially acceptable reasons that could not bar them from succeeding with their claim.[17] As regards the extent of damages claimable, the court held that both confinement and maintenance costs were reasonably foreseeable and therefore compensable. However, the court placed the following limitations on the doctor’s liability: (i) it cannot exceed the parents’ obligation to maintain their child ‘according to their means and station in life’; and (ii) it lapses when the child is reasonably able to support himself.[17] In light of the above, the court concluded that considerations of public policy did not preclude the granting of the relief claimed, and dismissed the appeal.

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Summary of principles espoused in case law

The judgment in Behrmann confirmed that: • in the absence of an express warrantee, a court should be slow to find that the contract between doctor and patient contained an implied warrantee as to the results of an intended operation – in this case a warrantee of infertility. The judgment in Edouard confirmed that: • contractual liability can be incurred on the general principles of contract law for failing to prevent a pregnancy and resulting birth • there are no policy considerations cogent enough to justify an exception to or modification of the general principles of contract in the case of a wrongful pregnancy • only patrimonial damages can be recovered for a wrongful pregnancy resulting if the claim is founded on a breach of contract • it is questionable whether neglect leading to conception and birth could be equated with the inflicting of a bodily injury for which compensation may be sought in delict • the defendant could be liable for the reasonable costs involved in raising a child to the age of 18 • there is no duty on the plaintiff to mitigate his/her loss by having an abortion or giving the child up for adoption • the court’s finding that the claim of wrongful pregnancy was admissible was intended to pertain only to a case where a sterilisation procedure was performed for socioeconomic reasons. The judgment in Mukheiber confirmed that: • even in the absence of a contract, a patient may recover damages for wrongful pregnancy • liability could be incurred even in the absence of clinical negligence • liability could be incurred on the basis of a misrepresentation • the yardstick to be applied in determining the extent of the liability (i.e. the limitation of liability so as to exclude excessively remote damages) is that of public policy • the same considerations of public policy apply, whether a claim was founded in delict or contract • there is no reason to limit wrongful pregnancy claims to instances where the request for sterilisation was made by a married couple, or to instances where the husband had given his consent, or, most importantly, to instances where the motive for requesting sterilisation was of a socioeconomic nature • reasonably foreseeable damages can be recovered, but liability is limited in the following respects: – it cannot exceed the parents’ obligation to maintain their child ‘according to their means and station in life’ – it lapses when the child is reasonably able to support himself. In view of the general principles enunciated in our case law, one may deduce that the following types of conduct could conceivably give rise to an actionable claim for wrongful pregnancy: • incorrect, inadequate, or lack of preoperative counselling, e.g. on the danger of recanalisation of the vas deferens after a vasectomy, or of female sterilisation not achieving sterility[3,18] • failure to perform an agreed sterilisation or other contraceptive measure • failure to perform a sterilisation properly so as to result in infertility, e.g. by ligating a ligament rather than a fallopian tube during a sterilisation on a woman[18,19] • misrepresentation that a sterilisation was performed, while it was in fact not done

• false assurance that a patient (either before or after sterilisation) is infertile, whether it be as a result of negligent testing or negligent interpretation of test results[3] • failure to carry out sperm tests correctly or properly after a vasectomy[19] • incorrect contraceptive advice leading to pregnancy • incorrect, inadequate, or lack of postoperative advice, e.g. on the need to use contraceptives until sperm tests have proved negative[3,18,19] • incorrect positioning of intrauterine contraceptive, resulting in pregnancy • the wrong advice on their chances of having a child with a disability deprives the couple of the choice to rather prevent the pregnancy than to take the risk of conceiving a child with a disability. Although there has not yet been a reported case where a claim was instituted for the birth of a normal but unwanted child born after, and as a result of, a failed abortion, it is conceivable that such a claim could also succeed in SA law, provided that the failed abortion was one that met the requirements in terms of the Choice on Termination of Pregnancy Act.[20] Liability might also follow where medical interventions aimed at addressing childlessness or infertility result in multiple pregnancies. Prospective parents might be prepared and capable of raising one child, but they may not necessarily be desirous or prepared and capable of raising more than one child of the same age at the same time. It is therefore very important to inform prospective parents of the risk of more than one live birth associated with such interventions. Acknowledgements. None. Author contributions. Sole author. Funding. None. Conflicts of interest. None. 1. Mason JK. The Troubled Pregnancy: Legal Wrongs and Rights in Reproduction. Cambridge: Cambridge University Press, 2007. 2. Constitution of the Republic of South Africa, 1996, section 12(2). 3. Jackson E. Medical Law: Text, Cases and Materials. Oxford: Oxford University Press, 2006. 4. Smith JC, Cranston D, O’Brien T, Guillebaud J, Hindmarsh J, Turner AG. Fatherhood without apparent spermatozoa after vasectomy. Lancet 1994;344(8914):30. https://doi.org/10.1016/s01406736(94)91052-9 5. O’Reilly PH, Gradwell M. Fatherhood with no apparent spermatozoa. BJU Int 2000;86(3):407. https:// doi.org/10.1046/j.1464-410x.2000.00842-9.x 6. Stobie v Central Birmingham Health Authority 1994 (22) BMLR 135. 7. Mason JK, Laurie GT. Mason and McCall-Smith’s Law and Medical Ethics. 9th ed. Oxford: Oxford University Press, 2013. 8. Slabbert MN. South Africa. In: Nys H, ed. International Encyclopaedia of Laws/Medical Law. Alphen aan den Rijn, the Netherlands: Kluwer Law International, 2014. 9. South Africa. Sterilisation Act No. 44 of 1998, section 4. 10. Coetzee LC, Carstens P. Medical malpractice and compensation in South Africa. In: Oliphant K, Wright RW, eds. Medical Malpractice and Compensation in Global Perspective. Berlin: De Gruyter, 2013:397-437. 11. Claassen NJB, Verschoor T. Medical Negligence in South Africa. Pretoria: Digma, 1992. 12. Carstens P, Pearmain D. Foundational Principles of South African Medical Law. Durban: LexisNexis, 2007. 13. Neethling J, Potgieter JM. Neethling-Potgieter-Visser Law of Delict. 7th ed. Durban: LexisNexis, 2015. 14. Strauss SA. Doctor, Patient and the Law: A Selection of Practical Issues. 3rd ed. Pretoria: JL van Schaik, 1991:41,176-177. 15. Edouard v Administrator Natal 1989 (4) SA 309 (D); 1989 (2) SA 368 (D). 16. Administrator, Natal v Edouard 1990 (2) SA 374 (A); 1990 (3) SA 581 (A). 17. Mukheiber v Raath 1999 (3) SA 490 (A); 1999 (3) SA 1065 (SCA). 18. Herring J. Medical Law and Ethics. 4th ed. Oxford: Oxford University Press, 2012. 19. Todd S. Actions arising from birth. In: Grubb A, Laing J, McHale J, eds. Principles of Medical Law. 3rd ed. Oxford: Oxford University Press, 2010. 20. South Africa. Choice on Termination of Pregnancy Act No. 92 of 1996.

Accepted 20 January 2017.

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

CASE REPORT

Paraquat poisoning: Acute lung injury – a missed diagnosis S D Ntshalintshali, MD (Cuba), MB ChB; T C Manzini, MB ChB, FCP (SA), Infect Dis Cert Department of Internal Medicine, Ngwelezana Hospital, Empangeni, KwaZulu-Natal, South Africa Corresponding author: S D Ntshalintshali (sipho.duncan@gmail.com)

Paraquat is a herbicide of great toxicological importance because it is associated with high mortality rates, mainly due to respiratory failure. We report the case of a 28-year-old man admitted to the casualty department at Ngwelezana Hospital, Empangeni, KwaZuluNatal, South Africa, with a history of vomiting and abdominal pain after ingestion of ~100 mL of an unknown substance, later identified as paraquat, together with an unknown amount of alcohol, in a suicide attempt. He developed respiratory distress associated with lung parenchymal infiltrates that required ventilatory support and later a spontaneous pneumothorax, and died in the intensive care unit. We discuss the importance of a high index of suspicion of paraquat poisoning in rural areas, where paraquat is readily available as a herbicide on farms, in patients with a similar presentation. We further stress the importance of identifying the classic radiological progression after paraquat poisoning, to help avoid a delay in diagnosis if the culprit substance is not known (as happened in our case). Lastly, we look at the importance of avoiding oxygen supplementation, and early administration of immunosuppressive therapy, to improve outcome. S Afr Med J 2017;107(5):399-401. DOI:10.7196/SAMJ.2017.v107i5.12306

Paraquat poisoning is frequent in rural and agricultural regions around the world owing to the agricultural use of this compound as a herbicide.[1] It is readily available in agricultural areas of South Africa (SA), as evident in the case described below. Making a timeous diagnosis and administering appropriate stepwise treatment is of paramount importance. In writing this article, we specifically hoped to raise awareness about the pulmonary manifestations and treatment of acute lung injury after paraquat ingestion.

Case report

In November 2016, a 28-year-old man presented to Ngwelezana Hospital, Empangeni, KwaZulu-Natal, SA, with a history of having attempted suicide ~2 hours earlier by ingesting ~100 mL (half a cup) of herbicide after drinking an unknown amount of alcohol. On the 7th day after admission the herbicide was positively identified as paraquat when relatives brought an empty can to the hospital. He had no comorbid illnesses, but had experienced an episode of abdominal discomfort and vomiting on his way to the emergency department. On examination, the patient appeared to have alcohol intoxication, with slurred speech, an ataxic gait and an ethanol smell. He was well hydrated and coherent to commands. He had no stigmata of any chronic illnesses. His vital signs, oxygen saturation, glucometer reading and urine dipstick test results were within normal limits. The rest of the examination was unremarkable. On day 5 after admission to hospital, the patient developed multiple ulcerating bleeding lesions in his mouth and pharynx, and type 1 respiratory failure. At this point he was commenced on intravenous antibiotics and oxygen supplementation on the assumption that he had developed a nosocomial pneumonia. The respiratory failure worsened, and he was transferred to the intensive care unit (ICU) for ventilatory support on day 6. Of note, the chest radiograph on admission (Fig. 1) was normal. A series of chest radiographs from days 5 to 9 (Figs 2 - 5) showed progression of the lung injury from confluent infiltrates to a

spontaneous right pneumothorax. After 5 days in the ICU, on the 11th day after the initial admission, the patient died of multiple organ failure including kidney, liver and respiratory failure (Table 1). During his stay in the ICU he was treated with antibiotics and furosemide.

Discussion

Paraquat (known in chemistry as 1,1ʹ-dimethyl-4,4ʹ-bipyridinium dichloride) is a herbicide that has been in the international market

Fig. 1. Chest radiograph on day 0 (admission). The lung fields are clear and no pathology is detectable.

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Fig. 2. Chest radiograph on day 5, showing homogeneous opacification of the right middle and lower zones (black arrow). The costophrenic angle is not visualised (yellow arrow). In the left lower zone, there is a fine reticulonodular appearance (blue arrow).

Fig. 4. Chest radiograph on day 7. Worsening of the nodular opacification of both lungs is evident, with visible air bronchograms (orange arrow), and a suggestion of an initial pneumothorax in the right lower zone (black arrow).

Fig. 3. Chest radiograph on day 6, showing worsening of the lung opacification bilaterally, with predominance of a nodular pattern sparing the upper zones (black arrows). At this stage, the patient was intubated and having cardiac monitoring.

Fig. 5. Chest radiograph on day 9. Pneumothorax occupying the right hemithorax (white arrow) is evident, and a slight mediastinal shift towards the left suggests a tension pneumothorax.

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Table 1. Blood results Parameter

Admission (day 0)

ICU transfer (day 6)

Death (day 11)

White cells (× 109/L)

10.19

14.36

16.89

Haemoglobin (g/dL)

12.6

12.1

11.9

Platelets (× 109/L)

237

102

INR

1.03

1.29

1.89

Urea (mmol/L)

26.2

42.5

Creatinine (mmol/L)

951

1 031

ALT (U/L)

262

687

Bilirubin (umol/L)

157

254

7.17

7.06

PO2 (KPa)

5.1

7.8

PCO2 (KPa)

5.7

6.1

HCO3 (mmol/L)

55% on 100% FiO2

45% on 100% FiO2

Oxygen saturation (%)

98% on 21% FiO2

INR = international normalised ratio; ALT = alanine aminotransferase; PO2 = partial pressure of oxygen; PCO2 = partial pressure of carbon dioxide; HCO3 = bicarbonate; FiO2 = fraction of inspired oxygen.

since 1958. It has been shown to have toxic effects on the lungs, liver and kidneys in humans and livestock when inhaled or orally ingested (accidentally or intentionally), and is associated with high mortality.[2-4] Since the 1970s, death of patients with paraquat poisoning has been identified as mainly associated with acute lung injury.[5] The pathophysiology of paraquat-induced acute lung injury resulting in spontaneous pneumothorax was first described by Daisley and Barton[6] in 1990, after a report by Nakaoka et al. in 1987 of a spontaneous pneumothorax that occurred 7 years after paraquat ingestion (cited by Daisley and Barton[6]). Daisley and Barton[6] discussed proposed mechanisms for the development of spontaneous pneumothorax in the setting of acute paraquat ingestion, including the deleterious effects of oxygen supplementation. Im et al.[7] described the findings on chest radiographs and computed tomography after paraquat poisoning, emphasising the sequential abnormalities that are visible on radiographs and their clinical implications. They identified a pattern of diffuse consolidation to be the most common early finding, which may appear in the first 7 days after ingestion. These changes evolved into a small cystic linear pattern up to about 15 days after ingestion, and a few weeks later patients who survived the acute event were found to have interstitial pulmonary fibrosis with decreased lung capacity. In the same study,[7] patients who developed pneumomediastinum within 7 days all died. Some of these patients had pneumothoraces. The mortality rate for patients who had used paraquat in a suicide attempt was 96% (26/27), while that after accidental ingestion was 40% (6/15). The overall mortality rate was 76% (32/42). Patients in the suicide group who died did so from 1 to 51 days after ingestion (mean 8.0), while those in the accidental ingestion group who died did so after 8 - 17 days (mean 11).[7] The combination of early identification of the culprit substance, avoidance of oxygen supplementation, and early administration of immunosuppressive therapy such as cyclophosphamide, methylprednisolone and dexamethasone has been described as associated with good outcomes.[8]

Learning points

• In rural areas such as northern KwaZulu-Natal, where our patient was from, paraquat ingestion should be included in the differential diagnosis when dealing with patients with a history of ingesting an unknown substance. A high index of suspicion is the key to making the early diagnosis of paraquat-induced acute lung injury in patients with respiratory failure who have ingested an unknown substance. • The classic radiological progression in paraquat poisoning is helpful, as diagnosis may be delayed without positive identification of the culprit substance (e.g. by obtaining the container), as happened in our case. • Avoiding oxygen supplementation, and early administration of immunosuppressive therapy, can improve outcome. Acknowledgements. We thank Dr L Padayachee, of the ICU at Ngwelezana Hospital. Author contributions. SDN: concept, literature review and writing of the article; TCM: identification of the case for publication, and revision of the manuscript. Funding. None. Conflicts of interest. None. 1. Daisley H, Hutchinson G. Paraquat poisoning. Lancet 1998;352(9137):1393-1394. http://dx.doi. org/10.1016/S0140-6736(05)60796-9 2. Campbell S. Paraquat poisoning. Clin Toxicol 1968;1(3):245-249. http://dx.doi.org/10. 3109/15563656808990576 3. Paraquat poisoning. Lancet 1971;2(7732):1018-1019. http://dx.doi.org/10.1016/S0140-6736(71)90332-1 4. Davies DS, Hawksworth GM, Bennett PN. Paraquat poisoning. In: European Society of Toxicology. Clinical Toxicology: Proceedings of the meeting held at Edinburgh, June 1976. Amsterdam: Excerpta Medica, 1977:21-26. 5. Bismuth C, Garnier A, Baud FJ, et al. Paraquat poisoning: An overview of the current status. Drug Saf 1990;5(4):243-251. http://dx.doi.org/10.2165/00002018-199005040-00002 6. Daisley H, Barton EN. Spontaneous pneumothorax in acute paraquat toxicity. West Indian Med J 1990;39(3):180-185. 7. Im JG, Lee KS, Han MC, Kim SJ, Kim IQ. Paraquat poisoning: Findings on chest radiography and CT of 42 patients. AJR Am J Roentgenol 1991;157(4):697-701. http://dx.doi.org/10.2214/ajr.157.4.1892020 8. Neves FF, Sousa RB, Pazin-Filho A, Cupo P, Elias J, Nogueira-Barbosa MH. Severe paraquat poisoning: Clinical and radiological findings in a survivor. J Bras Pneumol 2010;36(4):513-516. http://dx.doi. org/10.1590/S1806-37132010000400019

Accepted 25 January 2017.

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CASE REPORT

A rare case of massive hepatosplenomegaly due to acute lymphoblastic leukaemia in pregnancy R Gonçalves, MB ChB, MMed (Int Med), Cert Cardiol; R Meel, MB ChB, MMed (Int Med), Cert Cardiol, PhD Department of Internal Medicine, School of Medicine, Faculty of Health Sciences, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa Corresponding author: R Gonçalves (drrgoncalves@gmail.com)

Acute lymphoblastic leukaemia (ALL) is rarely seen in pregnancy. Massive hepatosplenomegaly as a presentation of ALL has not been described previously in any patient population. A 30-year-old pregnant woman presented at 16 weeks’ gestation with epistaxis, jaundice, diffuse abdominal pain and distension, massive hepatosplenomegaly and peripheral oedema. On the basis of blood tests, bone marrow biopsy and imaging, a diagnosis of ALL complicated by massive hepatosplenomegaly with splenic infarctions was made. The patient was referred to oncology for appropriate chemotherapy. S Afr Med J 2017;107(5):402-404. DOI:10.7196/SAMJ.2017.v107i5.12313

Cancer in pregnancy is rare, occurring in about one in 1 000 pregnancies.[1] The most common malignancies in pregnancy are breast cancer, cervical cancer, melanoma, leukaemia and lymphoma. Specifically, acute leukaemia is extremely uncommon in pregnancy, with an incidence of 1 in 75 000.[2] Acute lymphoblastic leukaemia (ALL) accounts for 28% of cases of leukaemia diagnosed during pregnancy, the remainder being acute myeloid and chronic myeloid leukaemias.[3] Massive hepatosplenomegaly as a presentation of ALL has not been reported previously in any patient population. We describe the first case of massive hepatosplenomegaly in a pregnant patient with ALL.

Case report

A 30-year-old pregnant woman, previously healthy, presented with a 3-week history of nosebleeds, yellow discolouration of the eyes and skin, diffuse abdominal pain and distension, and swelling of the legs. The pain was worst in the left hypochondrium and was dull and constant. The epistaxis had worsened, prompting her to seek help at the referring hospital. She reported dyspnoea at rest and paroxysmal nocturnal dyspnoea. The urine was dark and the stools were pale. Fever, night sweats and weight loss of ~5 kg were also reported. Clinical examination revealed marked pallor, without significant lymphadenopathy. Peripheral oedema and overt jaundice were noted. The urine was dark, with bilirubin present on dipstick examination. Her vital signs revealed a tachycardia (126 bpm), a blood pressure of 114/64 mmHg and a respiratory rate of 36 breaths per minute. Cardiovascular examination was remarkable only for an ejection systolic murmur over the base of the heart. The findings on respiratory examination were normal. The abdomen was distended, with significant tenderness on light palpation. Rebound tenderness but no rigidity was present. There was clinical hepatosplenomegaly, with a liver span of 26 cm in the mid-clavicular line and the spleen measuring 14.5 cm inferior to the lower rib margin. The uterus was palpable (about 16 - 18 weeks’ gestation). Signs of ascites could not be elicited owing to the tenderness. Examination of the head and neck revealed no epistaxis at the time of examination, and no obvious nasal pathology. The findings on skin and musculoskeletal examination were normal.

A full blood count revealed anaemia (red blood cell count 4.62 × 1012/L, haemoglobin 10.6 g/dL, haematocrit 0.324, mean corpuscular volume 70 fL, mean corpuscular haemoglobin 23 pg, mean corpuscular haemoglobin concentration 32.8 g/dL), with a platelet count of 525 × 109/L and a white cell count of 10.5 × 109/L. Leukaemic blasts were noted in the blood. Serum biochemical investigations showed normal renal function and features consistent with cholestasis on liver enzyme tests. The erythrocyte sedimentation rate and C-reactive protein level were elevated at 78 mm/h and 86.1 mg/L, respectively. A chest radiograph and abdominal ultrasound scan were requested. An elevated diaphragm was noted on the chest radiograph (Fig. 1). An abdominal ultrasound scan revealed no thrombi in the inferior vena cava or the portal or iliac veins. The liver was enlarged (25 cm in the mid-clavicular line) with normal portal vein and hepatic vein flow. The gallbladder wall was thickened. The kidneys were normal in size. The spleen was enlarged at 19 × 9 cm. Ascites was present. A fetus was noted, about 16 weeks’ gestational age, with a heart rate of 145 bpm. Despite the pregnancy, we elected to perform a computed tomography (CT) scan of the chest to exclude a pulmonary embolism. No pulmonary embolism was evident, and no lymphadenopathy was noted in the chest. The scan was extended to the abdomen to identify the cause of the abdominal pain and delineate the pathology better. It showed massive hepatosplenomegaly with multiple splenic infarctions (Fig. 2). There was compression of the inferior vena cava (IVC) and features of portal hypertension. No abdominal lymphadenopathy was present. A bone marrow aspirate was consistent with acute leukaemia, with 23% blast cells. In conjunction with the flow cytometry, the overall picture was suggestive of precursor T-cell ALL with aberrant expression of CD16. A final diagnosis of precursor T-cell ALL in a pregnant patient, complicated by massive hepatosplenomegaly with multiple splenic infarctions, cholestasis and probable portal hypertension, was made. The patient was referred to oncology, where she was treated with steroids and combination chemotherapy including anthracyclines.

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Fig. 1. Chest radiograph (anteroposterior (left) and lateral (right) views) demonstrating an elevated diaphragm (arrows) caused by massive hepatosplenomegaly.

Discussion

This case represents a rare presentation of an uncommon malignancy in pregnancy. Massive hepatosplenomegaly, although common in chronic myeloid leukaemias, has not been described as a presentation of ALL at all. The most common listed causes of massive hepatosplenomegaly include chronic lymphoproliferative malignancies, infections (malaria, leishmaniasis) and glycogen storage diseases (Gaucherâ&#x20AC;&#x2122;s disease).[4] In our case the probable causes of the massive hepatosplenomegaly were a combination of late presentation after symptom onset, leukaemic infiltration and secondary compression of the IVC with resultant portal hypertension. The case highlights the importance of maintaining a high index of suspicion for uncommon causes of massive hepatosplenomegaly as well as rare malignancies in pregnancy. ALL is diagnosed occasionally in pregnancy.[5] Early diagnosis and treatment are advisable. Pregnancy itself does not alter the course of acute leukaemia, but urgent chemotherapy is essential to improve the outcome. Treatment in the first trimester carries a high risk of fetal anomalies and miscarriage. Leukapheresis may be considered in the first trimester to delay chemotherapy. In recent years, numerous reports have addressed issues pertaining to chemotherapy in later stages of pregnancy.[5-14] Chemotherapy was well tolerated by the majority of patients, with a low incidence of spontaneous abortion. Germann et al.[5] reported normal deliveries in 73% of 160 pregnant patients treated with anthracycline chemotherapy. Intensive chemotherapy in the second and third trimesters does not pose an inordinate risk to fetal or neonatal development, although increased rates of premature delivery and perinatal mortality, and lower birth weight for gestational age, have been noted.[5-14] A multidisciplinary approach involving the patient, obstetrician, physician, haematologist and oncologist is mandatory for optimal clinical outcome.

Fig. 2. CT scan of the abdomen (coronal (top) and sagittal (bottom) views) demonstrating massive hepatosplenomegaly (black arrows), splenic infarcts (white arrows) and a 16-week fetus (white block arrow).

Acknowledgements. Consent was obtained from the patient for publication of this case report. Author contributions. The authors contributed in equal part to the preparation of this manuscript.

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Funding. None. Conflicts of interest. None.

1. Donegan WL. Cancer and pregnancy. CA Cancer J Clin 1983;33(4):194-214. 2. Lichtman MA, Liesveld JL. Acute myelogenous leukemia. In: Beutle RE, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams Hematology. 6th ed. New York: McGraw-Hill, 2001:10471084. 3. Terek M, Ozkinay E, Zekioglu O, et al. Acute leukemia in pregnancy with ovarian metastasis: A case report and review of the literature. Int J Gynecol Cancer 2003;13(6):904-908. 4. Houghton AR, Gray D. The gastrointestinal system. In: Houghton AR, Gray D, eds. Chamberlain’s Symptoms and Signs in Clinical Medicine: An Introduction to Medical Diagnosis. 13th ed. London: Hodder Arnold, 2010:108-136. 5. Germann N, Goffinet F, Goldwasser F. Anthracyclines during pregnancy: Embryo-fetal outcome in 160 patients. Ann Oncol 2004;15(1):146. http://dx.doi.org/10.1093/annonc/mdh009 6. Saleh AJ, Alhejazi A, Ahmed SO, et al. Leukemia during pregnancy: Long term follow up of 32 cases from a single institution. Hematol Oncol Stem Cell Ther 2014;7(2):63-68. http://dx.doi.org/10.1016/j. hemonc.2014.03.001 7. Chelghoum Y, Vey N, Raffoux E, et al. Acute leukemia during pregnancy: A report on 37 patients and a review of the literature. Cancer 2005;104(1):110-117. http://dx.doi.org/10.1002/cncr.21137

8. Molkenboer JF, Vos AH, Schouten HC, et al. Acute lymphoblastic leukaemia in pregnancy. Neth J Med 2005;63(9):361-363. 9. Pizzuto J, Aviles A, Noriega L, et al. Treatment of acute leukemia during pregnancy: Presentation of nine cases. Cancer Treat Rep 1980;64(4-5):679-683. 10. Ticku J, Oberoi S, Friend S, et al. Acute lymphoblastic leukemia in pregnancy: A case report with literature review. Ther Adv Hematol 2013;4(5):313-319. http://dx.doi.org/10.1177/2040620713492933 11. Reynoso EE, Shepherd FA, Messner HA, et al. Acute leukemia during pregnancy: The Toronto Leukemia Study Group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J Clin Oncol 1987;5(7):1098-1106. 12. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004;5(5):283291. http://dx.doi.org/10.1016/S1470-2045(04)01466-4 13. Khandaker S, Munshi S. A rare case of acute lymphoblastic leukaemia in pregnancy – unique maternal-fetal challenges. J Clin Diagn Res 2014;8(10):OD10-OD12. http://dx.doi.org/10.7860/ JCDR/2014/9720.5069 14. Milojkovic D, Apperley JF. How I treat leukemia during pregnancy. Blood 2014;123(7):974-984. http:// dx.doi.org/10.1182/blood-2013-08-283580

Accepted 18 January 2017.

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RESEARCH

South African medical students’ perceptions and knowledge about antibiotic resistance and appropriate prescribing: Are we providing adequate training to future prescribers? S Wasserman,1 MB ChB, MMed; S Potgieter,2 MB ChB; E Shoul,3 MB ChB; D Constant,4 PhD, MPH; A Stewart,5 MPH; M Mendelson,1 MD, PhD; T H Boyles,1 MD Division of Infectious Diseases and HIV Medicine, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Division of Infectious Diseases, Department of Internal Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 3 Division of Infectious Diseases and HIV Medicine, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 4 Women’s Health Research Unit, School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 5 Clinical Research Centre, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: S Wasserman (sean.wasserman@gmail.com) Background. Education of medical students has been identified by the World Health Organization as an important aspect of antibiotic resistance (ABR) containment. Surveys from high-income countries consistently reveal that medical students recognise the importance of antibiotic prescribing knowledge, but feel inadequately prepared and require more education on how to make antibiotic choices. The attitudes and knowledge of South African (SA) medical students regarding ABR and antibiotic prescribing have never been evaluated. Objective. To evaluate SA medical students’ perceptions, attitudes and knowledge about antibiotic use and resistance, and the perceived quality of education relating to antibiotics and infection. Methods. This was a cross-sectional survey of final-year students at three medical schools, using a 26-item self-administered questionnaire. The questionnaires recorded basic demographic information, perceptions about antibiotic use and ABR, sources, quality, and usefulness of current education about antibiotic use, and questions to evaluate knowledge. Hard-copy surveys were administered during whole-class lectures. Results. A total of 289 of 567 (51%) students completed the survey. Ninety-two percent agreed that antibiotics are overused and 87% agreed that resistance is a significant problem in SA – higher proportions than those who thought that antibiotic overuse (63%) and resistance (61%) are problems in the hospitals where they had worked (p<0.001). Most reported that they would appreciate more education on appropriate use of antibiotics (95%). Only 33% felt confident to prescribe antibiotics, with similar proportions across institutions. Overall, prescribing confidence was associated with the use of antibiotic prescribing guidelines (p=0.003), familiarity with antibiotic stewardship (p=0.012), and more frequent contact with infectious diseases specialists (p<0.001). There was an overall mean correct score of 50% on the knowledge questionnaire, with significant differences between institutions. Students who used antibiotic prescribing guidelines and found their education more useful scored higher on knowledge questionnaires. Conclusion. There are low levels of confidence with regard to antibiotic prescribing among final-year medical students in SA, and most students would like more education in this area. Perceptions that ABR is less of a problem in their local setting may contribute to inappropriate prescribing behaviours. Differences exist between medical schools in knowledge about antibiotic use, with suboptimal scores across institutions. The introduction and use of antibiotic prescribing guidelines and greater contact with specialists in antibiotic prescribing may improve prescribing behaviours. S Afr Med J 2017;107(5):405-410. DOI:10.7196/SAMJ.2017.v107i5.12370

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12370

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RESEARCH

Critical care admission of South African (SA) surgical patients: Results of the SA Surgical Outcomes Study D L Skinner,1 FCS (SA), MMed (Surg), Cert Crit Care (SA); K de Vasconcellos,1 FCA (SA), Cert Crit Care (SA); R Wise,1 FCA (SA), MMed (Anaes), Cert Crit Care (SA); T M Esterhuizen,2 MSc (Epidemiology); C Fourie,3 MMed (Anaes); A Goolam Mahomed,4 FCP (SA); P D Gopalan,1 FCA (SA); I Joubert,5 FCA (SA); H Kluyts,6 MMed (Anaes); L R Mathivha,7 FCPaed (SA), Cert Crit Care; DBS (BM); B Mrara,8 FCA (SA); J P Pretorius,9 FCS (SA); G Richards,7 PhD; O Smith,10 FCA (SA), Cert Crit Care (SA); M G L Spruyt,11 MMed (Chir); R M Pearse,12 MD (Res); T E Madiba,13 PhD; B M Biccard,14 PhD; on behalf of the South African Surgical Outcomes Study (SASOS) investigators Discipline of Anaesthesiology and Critical Care, School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa Centre for Evidence-Based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 3 Department of Critical Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 4 Department of Critical Care, Sefako Makgatho Health Sciences University, Pretoria, South Africa 5 Division of Critical Care, Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 6 Department of Anaesthesiology, Sefako Makgatho Health Sciences University, South Africa 7 Department of Critical Care, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 8 Department of Anaesthesiology, Faculty of Health Sciences, Walter Sisulu University, Mthatha, South Africa 9 Department of Critical Care, Faculty of Health Sciences, University of Pretoria, South Africa 10 Department of Anaesthesia, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 11 Department of Critical Care, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 12 Department of Intensive Care Medicine, Queen Mary University of London, UK 13 Department of Surgery and Gastrointestinal Cancer Research Centre, School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa 14 Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: B M Biccard (bruce.biccard@uct.ac.za) Background. Appropriate critical care admissions are an important component of surgical care. However, there are few data describing postoperative critical care admission in resource-limited low- and middle-income countries. Objective. To describe the demographics, organ failures, organ support and outcomes of non-cardiac surgical patients admitted to critical care units in South Africa (SA). Methods. The SA Surgical Outcomes Study (SASOS) was a 7-day national, multicentre, prospective, observational cohort study of all patients ≥16 years of age undergoing inpatient non-cardiac surgery between 19 and 26 May 2014 at 50 government-funded hospitals. All patients admitted to critical care units during this study were included for analysis. Results. Of the 3 927 SASOS patients, 255 (6.5%) were admitted to critical care units; of these admissions, 144 (56.5%) were planned, and 111 (43.5%) unplanned. The incidence of confirmed or strongly suspected infection at the time of admission was 35.4%, with a significantly higher incidence in unplanned admissions (49.1 v. 24.8%, p<0.001). Unplanned admission cases were more frequently hypovolaemic, had septic shock, and required significantly more inotropic, ventilatory and renal support in the first 48 hours after admission. Overall mortality was 22.4%, with unplanned admissions having a significantly longer critical care length of stay and overall mortality (33.3 v. 13.9%, p<0.001). Conclusion. The outcome of patients admitted to public sector critical care units in SA is strongly associated with unplanned admissions. Adequate ‘high care-dependency units’ for postoperative care of elective surgical patients could potentially decrease the burden on critical care resources in SA by 23%. This study was registered on ClinicalTrials.gov (NCT02141867). S Afr Med J 2017;107(5):411-419. DOI:10.7196/SAMJ.2017.v107i5.11455

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.11455

May 2017, Print edition

RESEARCH

Factors associated with contracting malaria in Ward 29 of Shamva District, Zimbabwe, 2014 G Muchena,1 MB ChB, MPH; N Gombe,1 BTech, MPH; L Takundwa,1 MB ChB, MPH; M Tshimanga,1 MD, MPH; D Bangure,1 BSc, MPH; N Masuka,2 MB ChB, MPH; T Juru,1 BSc, MPH 1 2

Department of Community Medicine, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe Provincial Medical Directorate, Matabeleland North Province, Ministry of Health and Child Care, Bulawayo, Zimbabwe

Corresponding author: T Juru (tsitsijuru@gmail.com) Background. Malaria cases at Wadzanayi Clinic in Shamva District, Zimbabwe, increased drastically, surpassing the epidemic threshold, in week four of December 2013. This rise was sustained, which necessitated an investigation of the outbreak. Objectives. To identify risk factors and system weaknesses to improve epidemic preparedness and response. Methods. An unmatched 1:1 case-control study was conducted in Ward 29 of Shamva District in Zimbabwe. Epidemic preparedness and response were assessed using the Zimbabwean epidemic preparedness and response guidelines. Results. The sociodemographic characteristics of all participants were similar, except for gender. The risk factors for contracting malaria were performing early morning chores (odds ratio (OR) 2.75; 95% confidence interval (CI) 1.20 - 6.32), having a body of water near the home (OR 3.41; 95% CI 1.62 - 7.20) and having long grass near the home (OR 2.61; 95% CI 1.10 - 6.37). Protective factors were staying indoors at night (OR 0.13; 95% CI 0.06 - 0.28) and staying in a sprayed home (OR 0.36; 95% CI 0.21 - 0.92). All cases were diagnosed with a malaria rapid diagnostic test. All complicated cases were treated with quinine. Four out of 58 uncomplicated cases were treated with quinine. The rest were treated with co-artemether. There was no documentation of the outbreak response by the district health executive. Respraying (indoor residual spraying) was carried out, with a coverage of 78% of rooms sprayed. One nurse out of seven at Wadzanayi Clinic was trained in integrated disease surveillance and response, and malaria case management. District malaria thresholds were outdated. Malaria commodities such as drugs and sprays did not have reorder limits. Conclusion. This study re-emphasises the importance of environmental- and personal-level factors as determinants of malaria. Poor outbreak preparedness and response may have propagated the malaria outbreak in this setting. Health education and the use of mosquito repellants should be emphasised. Larvicide may reduce the malaria burden. Epidemic preparedness and response need to be strengthened. Outbreak investigation remains important. This study emphasises the need for malaria interventions to be tailored to locally prevailing determinants to avert outbreaks. S Afr Med J 2017;107(5):420-423. DOI:10.7196/SAMJ.2017.v107i5.12204

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12204

Predicting postoperative haemoglobin changes after burn surgery P Slabber,1 MB ChB, DA (SA), FCA (SA); Z Farina,2 MB ChB, FCA (SA); N Allorto,2 MB ChB, FCS (SA), MMed; R N Rodseth,2,3 MB ChB, DA (SA), FCA (SA), MMed, MSc, Cert Crit Care, PhD Department of Anaesthetics, Grey’s Hospital, Pietermaritzburg, South Africa Peri-operative Research Group, Metropolitan Department of Anaesthetics, Critical Care and Pain Management, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Pietermaritzburg, South Africa 3 Department of Outcomes Research, Cleveland Clinic, Cleveland, OH, USA 1 2

Corresponding author: P Slabber (sknoetze@yahoo.com) Background. Burn surgery is associated with significant blood loss and fluid shifts that cause rapid haemoglobin (Hb) changes during and after surgery. Understanding the relationship between intraoperative and postoperative (day 1) Hb changes may assist in avoiding postoperative anaemia and unnecessary peri-operative blood transfusion.

May 2017, Print edition

RESEARCH

Objective. To describe the Hb changes into the first day after burn surgery and to identify factors predictive of Hb changes that would guide blood transfusion decisions. Methods. This was a single-institution, retrospective cohort study that included 158 patients who had undergone burn surgery. Hb was measured at the start and end of surgery, and on the first day (16 - 32 hours) after surgery, and the results were analysed. Peri-operative factors (Hb at the end of surgery, total body surface area operated on (TBSA-op), fluid administration and intraoperative blood administration) were evaluated to determine their association with Hb changes on the first day after surgery. Results. The mean (standard deviation) preoperative Hb was 10.6 (2.29) g/dL, the mean postoperative Hb was 9.4 (2.01) g/dL, and the mean Hb on the first day after surgery was 9.2 (2.19) g/dL. Median total burn surface area was 7% (interquartile range 9%, min. 1%, max. 45%), with a mean body surface area operated on (debridement area plus donor area) of 9.7%. Of the 158 patients, 26 (16%) had an Hb <7 g/dL (transfusion trigger) on the first day after surgery. For patients with a high (≥9 g/dL), intermediate (≥7 - <9 g/dL), or low (<7 g/dL) Hb measurement at the end of burn surgery, those with an Hb below the transfusion trigger on the first day after burn surgery were 0%, 27%, and 75%, respectively. End-of-surgery Hb and TBSA-op strongly predicted the first day Hb level. In the intermediate group, 55% of patients with a TBSA-op ≥11% had an Hb below the transfusion trigger on the first day after surgery. Conclusion. Hb at the end of burn surgery was the best predictor of Hb on the first day after surgery. Patients with an Hb <7 g/dL remained as such on the first postoperative day. Half of the patients with an end-of-surgery Hb ≥7 - <9 g/dL and who had ≥11% TBSA-op had an Hb <7 g/dL on the first postoperative day. S Afr Med J 2017;107(5):424-427. DOI:10.7196/SAMJ.2017.v107i5.12192

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12192

Influence of HIV and other risk factors on tuberculosis S Mahtab,1 MBBS, MPH; D Coetzee,2 FCPHM 1 2

Department of Paediatrics, Faculty of Health Sciences, University of Cape Town, South Africa Centre for Infectious Disease and Epidemiology and Research, Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: S Mahtab (sanamahtab@hotmail.com) Background. Tuberculosis (TB) notification in South Africa has increased six-fold over the past two decades, mainly because of the HIV epidemic. Objectives. To describe the sociodemographic and outcome characteristics of TB patients, and to identify risk factors associated with TB treatment outcomes stratified by HIV status. Methods. A cross-sectional study was used to analyse data from the Cape Town Metro East geographical service area (GSA) electronic TB register (ETR.Net), including adult patients aged ≥15 years who initiated TB treatment between 1 July 2011 and 30 June 2012. Results. TB case notification in the GSA was 922 per 100 000 population. Of the 12 672 TB patients registered, 50.5% were co-infected with HIV. The death rate in co-infected patients was 5.4% v. 2.8% in HIV-negative patients, the rate of treatment success 66.6% v. 73.5%, and the rate of unfavourable treatment outcome 28.1% v. 23.7%. The Khayelitsha subdistrict had the highest proportion of TB burden (37.0%) and co-infection (47.6%). Fourteen percent of patients had extrapulmonary TB, 65.9% of whom were co-infected with HIV. In the multivariate analysis, HIV infection (relative risk (RR) 1.2), retreatment (RR 1.4) and sputum smear microscopy not done (RR 1.4) were significantly associated with unfavourable treatment outcome. The Eastern (RR 0.9) and Northern (RR 0.7) subdistricts were less likely to have unfavourable outcomes compared with Khayelitsha. In the stratified analysis, retreatment and smear not done were significant risk factors for an unfavourable treatment outcome in both co-infected and HIV-negative patients. Conclusions. The burdens of both TB and co-infection were high in this community, although HIV prevalence varied. Mortality was higher and treatment completion lower in co-infected patients than in those who were HIV-negative. Co-infection, previous TB treatment and smear not done were significant risk factors for an unfavourable outcome in all patients. S Afr Med J 2017;107(5):428-434. DOI:10.7196/SAMJ.2017.v107i5.11271

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.11271

May 2017, Print edition

RESEARCH

Bacteria isolated from the airways of paediatric patients with bronchiectasis according to HIV status C Verwey, FCPaed (SA); S Velaphi, FCPaed (SA); R Khan, FCPaed (SA) Department of Paediatrics, Chris Hani Baragwanath Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: C Verwey (charl.verwey@wits.ac.za) Background. Knowledge of which bacteria are found in the airways of paediatric patients with bronchiectasis unrelated to cystic fibrosis (CF) is important in defining empirical antibiotic guidelines for the treatment of acute infective exacerbations. Objective. To describe the bacteria isolated from the airways of children with non-CF bronchiectasis according to their HIV status. Methods. Records of children with non-CF bronchiectasis who attended the paediatric pulmonology clinic at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa, from April 2011 to March 2013, or were admitted to the hospital during that period, were reviewed. Data collected included patient demographics, HIV status, and characteristics of the airway samples and types of bacteria isolated. Results. There were 66 patients with non-CF bronchiectasis over the 2-year study period. The median age was 9.1 years (interquartile range 7.2 - 12.1). The majority of patients (78.8%) were HIV-infected. A total of 134 samples was collected (median 1.5 per patient, range 1 7), of which 81.3% were expectorated or induced sputum samples. Most bacteria were Gram negatives (72.1%). Haemophilus influenzae was the most common bacterium identified (36.0%), followed by Streptococcus pneumoniae (12.6%), Moraxella catarrhalis (11.1%) and Staphylococcus aureus (10.6%). There were no differences between HIV-infected and uninfected patients in prevalence or type of pathogens isolated. Conclusion. Bacterial isolates from the airways of children with non-CF bronchiectasis were similar to those in other paediatric populations and were not affected by HIV status. S Afr Med J 2017;107(5):435-439. DOI:10.7196/SAMJ.2017.v107i5.10692

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.10692

Obstructive pulmonary disease in patients with previous tuberculosis: Pathophysiology of a community-based cohort B W Allwood,1,2 PhD; R Gillespie,1 MSc (Nursing); M Galperin-Aizenberg,3 PhD; M Bateman,1 MD; H Olckers,1 BTech Hons; L Taborda-Barata,4 PhD; G L Calligaro,1 MD; Q Said-Hartley,5 MD; R van Zyl-Smit,1 PhD; C B Cooper,6 PhD; E van Rikxoort,7 PhD; J Goldin,6 PhD; N Beyers,8 PhD; E D Bateman,1 PhD University of Cape Town Lung Institute, Cape Town, South Africa Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 3 Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, USA 4 CICS – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal 5 Department of Radiology, Faculty of Health Sciences, University of Cape Town, South Africa 6 David Geffen School of Medicine, University of California, Los Angeles, USA 7 Radboud University Medical Center, Nijmegen, Netherlands 8 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 1 2

Corresponding author: B W Allwood (brianallwood@gmail.com) Background. An association between chronic airflow limitation (CAL) and a history of pulmonary tuberculosis (PTB) has been confirmed in epidemiological studies, but the mechanisms responsible for this association are unclear. It is debated whether CAL in this context should be viewed as chronic obstructive pulmonary disease (COPD) or a separate phenotype.

May 2017, Print edition

RESEARCH

Objective. To compare lung physiology and high-resolution computed tomography (HRCT) findings in subjects with CAL and evidence of previous (healed) PTB with those in subjects with smoking-related COPD without evidence of previous PTB. Methods. Subjects with CAL identified during a Burden of Obstructive Lung Disease (BOLD) study performed in South Africa were studied. Investigations included questionnaires, lung physiology (spirometry, body plethysmography and diffusing capacity) and quantitative HRCT scans to assess bronchial anatomy and the presence of emphysema (<–950 HU), gas trapping (<–860 HU) and fibrosis (>–200 HU). Findings in subjects with a past history and/or HRCT evidence of PTB were compared with those in subjects without these features. Results. One hundred and seven of 196 eligible subjects (54.6%) were enrolled, 104 performed physiology tests and 94 had an HRCT scan. Based on history and HRCT findings, subjects were categorised as no previous PTB (NPTB, n=31), probable previous PTB (n=33) or definite previous PTB (DPTB, n=39). Subjects with DPTB had a lower diffusing capacity (Δ=–17.7%; p=0.001) and inspiratory capacity (Δ=–21.5%; p=0.001) than NPTB subjects, and higher gas-trapping and fibrosis but not emphysema scores (Δ=+6.2% (p=0.021), +0.36% (p=0.017) and +3.5% (p=0.098), respectively). Conclusions. The mechanisms of CAL associated with previous PTB appear to differ from those in the more common smoking-related COPD and warrant further study. S Afr Med J 2017;107(5):440-445. DOI:10.7196/SAMJ.2017.v107i5.12118

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12118

Validating the utilisation of venous bicarbonate as a predictor of acute kidney injury in crush syndrome from sjambok injuries D L Skinner,1 MB ChB, MMed, FCS (SA), Cert Crit Care (SA); G L Laing,2,3 MB ChB, PhD, FCS (SA), Cert Trauma Surgery (SA); J Bruce,2,3 MB ChB, FCS (SA); B Biccard,4 MB ChB, MMedSci, PhD, FCA (SA), FFARCSI; D J J Muckart,3 MB ChB, MMedSci, FRCS, Cert Crit Care (SA) Department of Anaesthesiology and Critical Care, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 2 Pietermaritzburg Metropolitan Trauma Service, KwaZulu-Natal, South Africa 3 Department of General Surgery, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 4 Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: D L Skinner (drdavidskinner@gmail.com) Background. Crush injury secondary to sjambok beatings is a well-described phenomenon in southern Africa. Owing to a number of factors, it can result in acute kidney injury (AKI). In 1992, Muckart et al. described a risk stratification system using venous bicarbonate (VB) that can be used in the management of these patients. Objective. To validate this score in the modern era of AKI risk stratification. Methods. A retrospective study was performed on a local trauma database from June 2010 to December 2012. All patients with crush injury from sjambok/blunt instrument beatings were included in the analysis. VB was compared with the Kidney Disease Improving Global Outcomes scoring system for AKI. Serum base excess (BE) and creatine kinase were also examined as biomarkers. The endpoints were the need for renal replacement therapy (RRT) and mortality. Results. Three hundred and ten patients were included. The overall mortality rate was 1.9%, 14.8% of patients had AKI, and 3.9% required RRT. Both VB and BE performed well in RRT prediction, with areas under the receiver operating characteristic curve of 0.847 (95% confidence interval (CI) 0.756 - 0.938; p<0.001) and 0.871 (95% CI 0.795 - 0.947; p<0.001), respectively. The sensitivity and specificity of BE were 83.3% and 80.2% at an optimal cut-point of –7.25 mmol/L, while those of VB were 83.3% and 79.5% at an optimal cut-point of 18.85 mmol/L. VB was significantly different across the AKI risk groups (p<0.001), in keeping with the original Muckart risk stratification system.

May 2017, Print edition

RESEARCH

Conclusion. The risk stratification score using VB is valid and should continue to be used as a tool in the management of patients with sjambok injuries. BE performs well in predicting the need for RRT, with a value of <â&#x20AC;&#x201C;7.25 mmol/L indicating severe injury. S Afr Med J 2017;107(5):446-450. DOI:10.7196/SAMJ.2017.v107i5.12213

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12213

Codeine misuse and dependence in South Africa: Perspectives of addiction treatment providers C D H Parry,1.2 PhD; E Rich,3 MA; M C van Hout,4 PhD; P Deluca,5 PhD Alcohol, Tobacco and Other Drug Research Unit, South African Medical Research Council, Cape Town, South Africa Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 3 Alcohol, Tobacco and Other Drug Research Unit, South African Medical Research Council, Pretoria, South Africa 4 School of Health Sciences, Waterford Institute of Technology, Ireland 5 Institute of Psychiatry, Psychology & Neuroscience, Kingâ&#x20AC;&#x2122;s College London, UK 1 2

Corresponding author: C D H Parry (cparry@mrc.ac.za) Background. General practitioners are referring patients with codeine-related problems to specialist treatment facilities, but little is known about the addiction treatment providers, the kinds of treatment they provide, and whether training or other interventions are needed to strengthen this sector. Objectives. To investigate the perspectives of addiction treatment providers regarding treatment for codeine misuse or dependence. Method. Twenty addiction treatment providers linked to the South African Community Epidemiology Network on Drug Use and the South African Addiction Medicine Society were contacted telephonically and asked 20 questions. Results. While many participants had received training in pharmacological management of individuals with opioid dependence, only two had received specific training on codeine management. Between half and two-thirds of the treatment settings they worked in provided detoxification, pharmacotherapy, psychosocial treatment and aftercare. Very few treatment settings offered long-term treatment for codeine misuse and dependence. Participants indicated that over half of their codeine patients entered treatment for intentional misuse for intoxication, and dependence resulting from excessive or long-term use. The main barriers to patients entering treatment were seen as denial of having a problem, not being ready for change, mental health problems, stigma, and affordability of treatment. Participants identified a need for further training in how to manage withdrawal and detoxification, treatment modalities including motivational interviewing, and relapse prevention. Conclusions. Gaps in training among treatment providers need to centre on how to manage withdrawal from codeine use and detoxification, motivational interviewing and relapse prevention. Interventions are needed to address barriers to entering treatment, including user denial. S Afr Med J 2017;107(5):451-456. DOI:10.7196/SAMJ.2017.v107i5.12242

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.12242

May 2017, Print edition

RESEARCH

Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10 A Vorster,1 MSc; P Beighton,1 MD, PhD, FRCP, FRSSA; M Chetty,2 BChD, MChD, PhD; Y Ganie,3,4 MB ChB, FCP (Paeds); B Henderson,5 MB ChB, DCH, MMed; E Honey,6 MB ChB, MMed (Paed); P MarĂŠ,7 MB ChB, FCOrth (SA); D Thompson,7 MB ChB, FRCS (Glasg); K Fieggen,8 MB ChB, FCPaed, Cert Med Genet; D Viljoen,9 MB ChB, FCP; R Ramesar,1 MSc, PhD, Exec MBA MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa 2 Department of Oral and Molecular Biology, Faculty of Dentistry, University of the Western Cape, Cape Town, South Africa 3 Department of Paediatrics and Child Health, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 4 Division of Paediatric Endocrinology, Inkosi Albert Luthuli Central Hospital, Durban, South Africa 5 Division of Clinical Genetics, Department of Neurology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa 6 Department of Genetics, Faculty of Health Sciences, University of Pretoria, South Africa 7 Paediatric Orthopaedic Unit, Department of Orthopaedic Surgery, Greyâ&#x20AC;&#x2122;s Hospital, Pietermaritzburg, and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 8 Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 9 Foundation for Alcohol Related Research (FARR), Rondebosch, Cape Town, South Africa 1

Corresponding author: A Vorster (vorster@sun.ac.za) Background. A relatively high frequency of autosomal recessively inherited osteogenesis imperfecta (OI) type 3 (OI-3) is present in the indigenous black southern African population. Affected persons may be severely handicapped as a result of frequent fractures, progressive deformity of the tubular bones and spinal malalignment. Objective. To delineate the molecular basis for the condition. Methods. Molecular investigations were performed on 91 affected persons from seven diverse ethnolinguistic groups in this population. Results. Following polymerase chain reaction amplification and direct cycle sequencing, FKBP10 mutations were identified in 45.1% (41/91) OI-3-affected persons. The homozygous FKBP10 c.831dupC frameshift mutation was confirmed in 35 affected individuals in the study cohort. Haplotype analysis suggests that this mutation is identical among these OI-3-affected persons by descent, thereby confirming that they had a common ancestor. Compound heterozygosity of this founder mutation was observed, in combination with three different deleterious FKBP10 mutations, in six additional persons in the cohort. Four of these individuals had the c.831delC mutation. Conclusion. The burden of the disorder, both in frequency and severity, warrants the establishment of a dedicated service for molecular diagnostic confirmation and genetic management of persons and families with OI in southern Africa. S Afr Med J 2017;107(5):457-452. DOI:10.7196/SAMJ.2017.v107i5.9461

Full article available online at http://dx.doi.org/10.7196/SAMJ.2017.v107i5.9461

May 2017, Print edition

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The CPD programme for SAMJ is administered by Medical Practice Consulting. CPD questionnaires must be completed online at www.mpconsulting.co.za. True (A) or false (B): SAMJ Ethical and legal perspectives on use of social media by health professionals in South Africa (SA) 1. Facebook users must be careful about what they post on Facebook, but there are no legal consequences associated with ‘liking’ or being ‘tagged’ in a Facebook post. Paraquat poisoning: Acute lung injury – a missed diagnosis 2. Death in patients with paraquat poisoning is usually associated with acute lung injury. South African medical students’ perceptions and knowledge about antibiotic resistance and appropriate prescribing: Are we providing adequate training to future prescribers? 3. Most antibiotics are prescribed in outpatient and community settings. 4. One of three major findings in the study was that undergraduate students have inadequate knowledge of basic antibiotic prescribing guidance. Factors associated with contracting malaria in Ward 29 of Shamva District, Zimbabwe, 2014 5. Zimbabwe has unstable malaria transmission with seasonal epidemics. 6. Performing early morning chores was a risk factor for contracting malaria in this study. Influence of HIV and other risk factors on tuberculosis 7. In the Cape Town Metro East area, the Khayelitsha subdistrict had the lowest proportion of TB burden and HIV co-infection. 8. Significant risk factors for an unfavourable treatment outcome in both co-infected and HIV-negative patients were retreatment and smear not done.

CME Diagnosis, monitoring and treatment of tuberous sclerosis complex (TSC): An SA consensus response to international guidelines 11. TSC can affect almost any organ system in the body, including the brain, heart, skin, kidneys and lungs. 12. The greatest morbidity and mortality in TSC is associated with neurological, neuropsychiatric and renal manifestations. 13. Individuals with TSC are always intellectually impaired. 14. The term variable expression in TSC describes the variable ways in which different organ systems can be involved. 15. Skin and renal manifestations are typically not present at birth, but gradually appear over the first 5 - 15 years of life. 16. In the first few years of life, the most typical presentation of TSC is likely to be with seizures, in particular focal seizures and infantile (epileptic) spasms, often with an onset in the first 12 months of life. 17. Autism spectrum disorder is seen in 40 - 50% of individuals with TSC, and TSC is seen in as many as 4% of children with autism spectrum disorder. 18. Adolescent boys or young men with TSC are sometimes diagnosed when they have a skin rash (often misdiagnosed as acne) that causes profuse bleeding during shaving. 19. A proportion of mildly affected individuals with TSC are only diagnosed when they have a child diagnosed with TSC. 20. Some young people and adults with TSC present with ungual growths on their hands or feet that cause embarrassment or discomfort.

Obstructive pulmonary disease in patients with previous tuberculosis: Pathophysiology of a community-based cohort 9. In low- and middle-income countries, factors other than cigarette smoking contribute to the pathogenesis of chronic obstructive pulmonary disease. Validating the utilisation of venous bicarbonate as a predictor of acute kidney injury in crush syndrome from sjambok injuries 10. Crush injury secondary to sjambok beatings can result in acute kidney injury.

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