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MODERN MEDICINE T h e
I r i s h
J o u r n a l
o f
C l i n i c a l
M e d i c i n e
Now incorporating Osteowise, PainWise and RespiratoryWise
Editor: Kennas Fitzsimons
Managing Director: Carol Manweiler
Advertising Manager: Amanda O’Keeffe
Publisher: Chris Goodey
Art Editor/Illustrator: Lisa Melvin
Chairman: Dr Eamon de Valera
Operations Director: Caoimhe Tierney
Financial Controller: David Scott
EDITORIAL BOARD
Dr Liam Lacey General Practitioner Dublin (Medical Editor) Dr Éamann Breatnach Consultant Radiologist Mater Hospital, Dublin
Dr Garrett Fitzgerald Consultant Physician Waterford Regional Hospital
Professor C F McCarthy Consultant Gastroenterologist University College Hospital, Galway
Dr Dermot Canavan Eglinton Road, Donnybrook, Dublin 4
Professor Pierce Grace Vascular Surgeon Regional Hospital and University Hospital Limerick
Dr Peter McParland Consultant Obstetrician Holles Street Hospital, Dublin
Professor Kevin O’Malley Consultant Pharmacologist, RCSI
Dr Brian Maurer Consultant Cardiologist Blackrock Clinic Dublin
Mr Gerry O’Sullivan Consulant Surgeon Mercy Hospital, Cork
Dr Simon Mills Barrister-at-Law General Practitioner Dublin
Dr Mary Short General Practitioner Blackrock, Co Dublin
Dr Stephen Murphy General Practitioner, Dublin
Dr Sarah Rogers Consultant Dermatologist St Vincent’s Hospital, Dublin
Dr Geoffrey Chadwick Dun’s Tutor Royal College of Physicians of Ireland Dr Gary Courtney Consultant Gastroenterologist St Luke’s General Hospital, Kilkenny Mr Tom Creagh Consultant Urologist Beaumont Hospital, Dublin Dr Maeve Doyle Consultant Microbiologist Waterford Regional Hospital Dr James Finucane Consultant Endocrinologist Beaumont Hospital, Dublin
Dr Orla Hardiman Consultant Neurologist Beaumont Hospital, Dublin Dr Brendan Kelly Consultant Psychiatrist Mater Hospital, Dublin Dr Peter Keogh General Practitioner, Dublin Dr Conor McCarthy Consultant in Rheumatology Mater Misericordiae University Hospital
Modern Medicine is a professional journal, written and edited by doctors for general practitioners, specialists and hospital residents. Editorial content is devoted to the diagnosis and treatment of medical problems and diseases, with the objective of providing a regular source of postgraduate clinical information which will be of maximum value to the reader in his/her profession. Abstracts, which constitute an important part of the journal, are scientifically condensed from articles selected continuously from nearly 400 of the world’s recognised leading medical publications. In addition, each issue carries features and original articles which examine and report on significant medical cases and up-to-the-minute developments in medical science. The content of this issue has been selected by the Editor, with advice from the Editorial Board, in an attempt to provide readers with a broad spectrum of opinion on a wide range of subjects. Opinions expressed are those of the original authors and do not necessarily reflect those of the Editor, the Editorial Board or the Publisher.
Dr Alf Nicholson Consultant Paediatrician Our Lady of Lourdres Hospital Drogheda, Co Louth
Dr David O’Flaherty Consultant in Anaesthesia & Chronic Pain, Portiuncula Hospital, Co Galway
Dr J Bernard Walsh Consultant Geriatrician St James’s Hospital, Dublin
Modern Medicine is published bimonthly by M&C Group Ltd, 7 Lower Fitzwilliam Street, Dublin 2. Tel: (01) 799 5800 Fax: (01) 678 0068 kfitzsimons@eireannpublications.ie www.modernmedicine.ie © COPYRIGHT 2008 M&C GROUP LTD No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means – electronic, mechanical or photocopy recording or otherwise – whole or in part, in any form whatsoever for advertising or promotional purposes without the prior written permission of the Publisher.
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editorial MODERN MEDICINE The Irish Journal of Clinical Medicine Now incorporating Osteowise, PainWise and RespiratoryWise
XXX Dr Liam Lacey
xxxxxxx
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MODERN MEDICINE The Irish Journal of Clinical Medicine
The Irish Journal of Clinical Medicine Volume 38 Number 6 December/January 2009
Now incorporating Osteowise, PainWise and RespiratoryWise
Diagnosis and management of fibromyalgia Dr Craig Dunlop, Dr Therese O’Connor
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REVIEW
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Inflammatory bowel disease Dr Faisal Zeb, Dr Abdur Rahman Aftab FORENSIC MEDICINE FOR THE BUSY DOCTOR
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Common injuries part 3 – lacerations and incisions Dr Simon Mills REVIEW
59
Disorders of the inner ear – the role of the neurotologist Part 2 Mr Brendan G Fennessy, Mr Usman Noma, Mr Peter O’Sullivan REVIEW
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Malaria and the traveller Dr Dom Colbert REVIEW
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Overview of postpartum depression Dr Muhammad Arshad , Professor Michael Fitzgerald FOCUS ON
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Sleep disturbances after anaesthesia Dr Simon Mills CASE REPORT
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Management of acute recurrent pulmonary embolism in pregnancy Dr Sabitabrata Sarkar, Mr OA Adeyemi CASE REPORT
Gallstone ileus Mr Ehab Mansour, Dr Aoife Laffan, Mr Walter Conway, Dr Nagabathula Ramesh CROSSWORD ABSTRACTS
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DX RX
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ABSTRACTS
Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn’s disease
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Olmesartan medoxomil in elderly patients with essential or isolated systolic hypertension
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Safety of metformin in the treatment of elderly type 2 diabetes mellitus
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Agomelatine treatment of major depressive disorder
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DIAGNOSIS AND MANAGEMENT OF FIBROMYALGIA SUMMARY Fibromyalgia is a common chronic pain disorder which presents diagnostic and therapeutic challenges. In this article we review issues related to diagnosis, and the current evidence regarding management. KEY POINTS • Fibromyalgia presents a diagnostic challenge, with history and examination paramount. • Fibromyalgia is increasingly recognised as a disorder of central pain processing. • Published criteria including specified trigger points have been useful for guiding research, but need to be interpreted with caution in a clinical setting. • Antidepressants remain the first line pharmacological management, with the efficacy of calcium channel α2−δ ligands also increasingly recognised. • There is little evidence to support nonpharmacological therapies, but they may remain of benefit in the context of an overall treatment plan. Fibromyalgia is a common chronic pain disorder. Approximately 10% of the Western population are estimated to have chronic widespread pain, while 1 to 2% have fibromyalgia. It is more common in females, in those over 60 years-of-age, and shows familial tendencies.1-3 The disease is heterogenous in nature and may be looked at as part of a spectrum which also includes disorders such as irritable bowel syndrome and temporomandibular joint dysfunction. Diagnosis is difficult, and despite increased research, management options remain limited. Surveys suggest an enormous range of treatments in use, suggesting that no one strategy is effective in treating the group as a whole.4
EVALUATION A careful history and examination is, of course, paramount in establishing the diagnosis. Illnesses that may mimic fibromyalgia or occur concurrently include hypothyroidism, ankylosing spondylitis, tendonitis, systemic lupus erythematosus, rheumatoid arthritis and osteoarthritis. Guidelines published by the American Pain Society5 recommend a full blood count, erythrocyte sedimentation rate, muscle enzymes, electrolytes, liver function and thyroid function tests. The disorder is characterised by widespread musculoskeletal pain, fatigue, stiffness, and poor sleep. It is often associated with psychological disturbances such as anxiety and depression, with the latter associated with a worse prognosis.6 One multicentre study following patients over a sevenyear period demonstrated no improvement in symptoms despite treatment,7 while other reviews have been more optimistic and suggested a modest improvement is possible with a comprehensive pharmacological and nonpharmacological approach.8 Those seen in a primary care setting tend to have a better prognosis than those in tertiary referral centres.9 Patients can be said to experience pain differently compared to the general population, and may report a long standing history of pain disorders. The underlying mechanism of the disease itself is increasingly thought to relate to abnormal central pain processing with central sensitisation, suppression of descending inhibitory pain pathways and abnormal neurotransmitter release.10 Many of the pharmacological treatments available are targeted at modification of these areas. A hallmark of examination is tenderness to palpation. The specific diagnostic criteria for fibromyalgia were established in 1990 by the American College of Rheumatology and include
Dr Craig Dunlop SpR in Anaesthesia and Pain Management Dr Therese O’Connor Consultant in Anaesthesia and Pain Management Sligo General Hospital, The Mall, Sligo, Ireland
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the presence of widepread pain of at least three months’ duration, present in at least two contralateral quadrants of the body, with objective tenderness to palpation in at least 11 of 18 specific trigger points.11 The amount of pressure applied to these points has classically been described as enough to blanch the thumbnail bed. The trigger point criteria have been useful in research, but are increasingly controversial when applied to clinical practice. No gold standard for assessing tenderness exists, and significant variability may be seen even between experienced assessors.12 Variability also exists within patients when assessed at different times, and the trigger point criteria may also be fulfilled by patients who do not have fibromyalgia.13 Finally, some argue that in this setting specific trigger points are as much a measure of anxiety and depression as local tenderness, and that it distracts from the concept of the underlying pathophysiology being more related to abnormal central pain processing than peripheral muscle pathology.14 PHARMACOLOGICAL TREATMENTS
Tricyclic antidepressants Tricyclic antidepressants (TCAs) such as amitriptyline are among the most commonly researched treatments in fibromyalgia. As with all therapies in this disorder, large randomised controlled trials are lacking, though systematic reviews have been supportive of beneficial effects on pain, sleep patterns and fatigue.15-17 TCAs increase activity of the descending inhibitory pain pathway by inhibiting uptake of serotonin and norepinephrine in the central nervous system. Side effects include somnolence, dry mouth, constipation, confusion and occasionally cardiac arrythmias. Amitriptyline 25 to 50mg at night seems an optimal dose, increased from initial doses of 5 to 10mg to improve tolerability. In common with many antidepressants, at least three to four weeks at adequate dosage are required to properly assess therapeutic benefit.
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tend to be increased.16,17 Highly selective drugs such as citalopram seem to be less effective, and it is thought that balanced inhibition of both sertraline and noradrenaline uptake may provide the most effective analgesia. Newer selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) are similar to TCAs in their central mode of action but have less activity at other receptor systems, thus improving the side effect profile. A recent systematic review concluded that duloxetine in doses of 60 to 120mg daily was effective in providing a 50% improvement in pain, with a number needed to treat of six.18 Treatment is normally begun at a dose of 30mg daily and increased at weekly intervals. Improvement in pain control and functional symptoms seems to occur independently of improvement in mood, which suggests that overall efficacy is not a simple function of antidepressant effects.
Calcium channel a2-δ The calcium channel α2−δ ligands gabapentin and pregabalin are increasingly being used in the management of many chronic pain disorders. Pregabalin and duloxetine remain the only treatments approved by the United States Food and Drug Administration in the management of fibromyalgia. Initial trials have been encouraging, showing a sustained benefit in pain symptoms, sleep patterns and fatigue.19,20 These agents bind to the α2−δ subunit of voltagegated calcium channels, causing a decrease in release of glutamate, norepinephrine and substance P. They are generally well tolerated, with the most common adverse effects including somnolence, dizziness, weight gain and peripheral oedema. Pregabalin is titrated over a number of weeks to a dose of 300 to 450mg daily, and again requires a period of three to four weeks to assess therapeutic benefit. Dose reduction may be required in the elderly and those with renal impairment. They may be used alone or in combination with antidepressant agents.
Opioids Selective serotonin and noradrenaline reuptake inhibitors These antidepressant agents tend to have a better side effect profile, and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are frequently used. Benefit is seen but relative dosage requirements 10 MODER N MEDICINE
Opioids have not been shown to be effective in the management of fibromyalgia and should only be considered when all other treatment options have been exhausted. Tramadol, a weak µ-opioid receptor agonist which also inhibits reuptake of serotonin and norepinephrine, is an exception with some evidence
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of benefit.21,22 The side effect profile is similar to that of other opioids, although there is less potential for abuse. Care should be taken in those with epilepsy, and patients receiving SSRIs or SSNRIs may be at risk of serotonin syndrome. Dosing commencing at 50mg twice daily can be titrated to a maximum divided dose of 400mg daily.
Other agents Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are among the most commonly prescribed agents for fibromyalgia. Unfortunately trials have failed to show any benefit in symptom control23,24, although they may be of benefit as adjuncts to other therapies described above and in the management of concurrent pain conditions. Paracetamol combined with tramadol in particular has been studied with some modest improvement seen.25,26 Corticosteroids offer no benefit. Benzodiazepines may be useful in the management of associated sleep disorders but have no role in the syndrome itself. NON-PHARMACOLOGICAL TREATMENTS AND ALTERNATIVE MEDICINE Aerobic exercise and muscle strengthening has been widely advocated in the management of fibromyalgia. While results of studies have been generally positive,27,28 there is little high quality evidence available thus limiting the ability to draw meaningful conclusions.29 It has been suggested that exercise may initially increase symptoms, and that benefit may not be obtained without first bringing patients to a baseline level of exercise without exacerbation of pain.30 Compliance has also been an issue. Hydrotherapy seems to be better tolerated, and while evidence is again limited a recent systematic review reached promising conclusions.31 Cognitive behavioural therapy has similarly been studied with mixed results. Some suggest in a certain population sustained improvement in symptoms may be seen, with greatest effect on sleep pattern and fatigue rather than pain itself.32,33
Complementary medicine Fibromyalgia presents a diagnostic challenge, and the nature of the disorder is such that a single approach to all patients is unlikely to be broadly successful. Careful explanation and patient education regarding the
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condition is likely to aid overall management. Most pharmacological therapies require a period of several weeks at adequate dosage to accurately gauge efficacy. TCAs remain first line, while SSRIs and SSNRIs may be of particular benefit in those with concurrent depression. Pregabalin can be added where patients fail to respond to initial therapy. Sustained improvement may not be seen, and rotation of therapies may be required. Commencement of an exercise programme combined with cognitive behavioural therapy may be useful. Complementary and non-pharmacological approaches are lacking in evidence but may provide benefit in the context of an overall treatment plan. REFERENCES 1. Neumann L, Buskila D. Epidemiology of fibromyalgia. Curr Pain Headache Report 2003; 7: 362-8. 2. Wolfe F, Ross K, Anderson J, et al. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995; 38: 19-28. 3. Yunus MB, Inanici F, Aldag JC, et al. Fibromyalgia in men: comparison of clinical features with women. J Rheumatol 2000; 27:485-90. 4. Galea C, Lim A, Reisine S, et al. Self reported medication and perceived efficacy of treatment among a sample of fibromylagia patients. Arthritis Rheum 2003; 48(Suppl): S711. 5. Fibromyalgia Syndrome Pain Management Guideline Panel 2002-2005. Guideline for the Management of Fibromyalgia Syndrome Pain in Adults and Children. APS Clinical Practice Guidelines Series 2005, No. 4. 6. Finset A, Wigers SH, Gotestam KG. Depressed mood impedes pain treatment response in patients with fibromyalgia. J Rheumatol 2004; 31: 976-80. 7. Wolfe F, Anderson J, Harkness D, et al. Health Status and disease severity in fibromyalgia: results of a six-center longitudinal study. Arthritis Rheum 1997; 40: 1571-9. 8. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004; 292: 2388-95. 9. MacFarlane GJ, Thomas E, Papgeorgiou AC, et al. The natural history of chronic pain in the community: a better prognosis than in the clinic? J Rheumatol 1996; 23: 1617-20. 10. Abeles AM, Pillinger MH, Solitar BM, et al. The Pathophysiology of Fibromyalgia. Ann Intern Med 2007; 146: 726-734. 11. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter MODER N MEDICINE
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Criteria Committee. Arthritis Rheum 1990; 33: 160-72. 12. Tunks E, McCain GA, Hart LE, et al. The reliability of examination for tenderness in patients with myofascial pain, chronic fibromyalgia and controls. J Rheumatol 1995; 22: 944-52. 13. Wolfe F, Simons DG, Fricton J, et al. The fibromyalgia and myofascial pain syndromes: a preliminary study of tender points and trigger points in persons with fibromyalgia. J Rheumatol 1992; 19: 944-51. 14. Clauw DJ. Fibromyalgia: Update on Mechanisms and Management. J Clin Rheum 2007; 13: 102-9. 15. Nishishinya B, Urrutia G, Walitt B, et al. Amitriptyline in the treatment of fibromyalgia: a systematic review of its efficacy. Rheumatology 2008; 47: 1741-6. 16. Üçeyler N, Häuser W, Sommer C. A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome. Arthritis Rheum 2008; 59: 1279-98. 17. Perrot S, Javier RM, Marty M, et al. Is there any evidence to support the use of antidepressants in painful rheumatological conditions? Systematic review of pharmacological and clinical studies. Rheumatology 2008; 47: 1117-23. 18. Sultan A, Gaskell H, Derry S, et al. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurology 2008; 8: 29. 19. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arhritis Rheum 2005; 52: 1264-73. 20. Crofford LJ, Simpson S, Young JP, et al. A six month, double-blind, placebo-controlled, durability of effect study of pregabalin for pain associated with fibromyalgia. Arthritis Rheum 2006; 54: 4118. 21. Biasi G, Manca S, Manganelli S, et al. Tramadol in fibromyalgia syndrome: a controlled clinical trial versus placebo. Int J Clin Pharmacol Res 1998; 18: 13-9. 22. Russell J, Kamin M, Bennett RM, et al. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatol 2000; 6: 250-7. 23. Yunus MB, Masi AT, Aldag JC. Short term effects of ibuprofen in primary fibromyalgia syndrome: a double blind, placebo controlled trial. J Rheumatol 1989; 16: 527532. 24. Goldenberg DL, Felson DT, Dinerman HA. Randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum 1986; 29: 1371-7. 25. Bennett RM, Kamin M, Karim R, et al. Tramadol and 12 MODER N MEDICINE
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acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebocontrolled study. Am J Med 2003; 114: 537-45. Bennett RM, Schein J, Kosinski MR, et al. Impact of fibromyalgia pain on health-related quality of life before and after treatment with tramadol/acetaminophen. Arthritis Rheum 2005; 53: 519-27. Busch AJ, Barber KAR, Overend TJ, et al. Exercise for treating fibromyalgia syndrome. Cochrane Database Systematic Rev 2007; 4: CD003786. Karjalainen K, Malmivaara A, van Tulder M, et al. Multidisciplinary rehabilitation for fibromyalgia and musculoskeletal pain in working age adults. Cochrane Database Syst Rev 1999; 3: CD001984. Sim J, Adams N. Systematic review of non-pharmacological interventions for fibromyalgia. Clin J Pain 2002; 18: 32436. Abeles M, Solitar BM, Pillinger MH, et al. Update on Fibromyalgia Therapy. Am J Med 2008; 121: 555-61. McVeigh JG, McGaughey H, Hall M, et al. The effectiveness of hydrotherapy in the management of fibromyalgia syndrome: a systematic review. Rheumatol Int 2008; 29: 119-30. Edinger JD, Wohlgemuth WK, Krystal AD, et al. Behavioral insomnia therapy for fibromyalgia patients: a randomized clinical trial. Arch Intern Med 2005; 165: 2527-35. Williams DA, Cary MA, Gronerr KH, et al. Improving physical functional status in patients with fibromyalgia: a brief cognitive behavioral intervention. J Rheumatol 2002; 29: 1280-6. Harris RE, Tian X, Williams DA, et al. The treatment of fibromyalgia with acupuncture: effects of needle placement, needle stimulation, and dose. Arthritis Rheum 2003; 48(Suppl 9): 1811. Assefi NP, Sherman KJ, Jacobsen C, et al. A randomized clinical trial of acupuncture compared with sham acupuncture in fibromyalgia. Ann Intern Med 2005; 143: 10-9.
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INFLAMMATORY BOWEL DISEASE Inflammatory bowel disease (IBD) consists of two major disorders: ulcerative colitis and Crohn’s disease. Inflammation in ulcerative colitis usually involves the colon and rarely involves any other part of the gut. It is limited to the superficial mucosal layer. In contrast, Crohn’s disease is characterised by patchy, transmural inflammation and can affect any part of the gastrointestinal tract. EPIDEMIOLOGY, PATHOGENESIS AND RISK FACTORS IBD is more common in northern climates and developed countries, and lowest in equatorial climates, suggesting an environmental contribution to its aetiology. The pathogenesis of IBD remains unclear and a number of risk factors have been identified. It is more common in people of Jewish origin. It tends to run in families; 10% to 25% of patients with IBD have first-degree relatives affected with either ulcerative colitis or Crohn’s disease. Smoking increases the risk of Crohn’s disease and decreases the risk of ulcerative colitis through unknown mechanisms. Appendectomy may protect against IBD. The onset of IBD is most commonly between the ages of 15 and 40 years, with a second peak between 50 and 80 years. Both males and females have a similar risk of developing IBD. CLINICAL FEATURES Ulcerative colitis can have a variable presentation. Distal disease refers to colitis confined to the rectum (proctitis) or rectum and sigmoid colon (proctosigmoiditis). More extensive disease includes left-sided colitis (up to splenic flexure), extensive colitis (up to hepatic flexure), and pancolitis (affecting the whole colon). Bloody diarrhoea is the cardinal presentation. Other symptoms are colicky, lower abdominal pain, tenesmus, fever and weight loss. On physical examination pallor, anaemia, abdominal tenderness, evidence of weight loss and red blood on rectal
examination can be found. In most cases the disease runs a course of remission and exacerbation. Crohn’s disease is more heterogeneous than ulcerative colitis. Symptoms include abdominal pain, prolonged diarrhoea with or without gross bleeding, fever, weight loss and fatigue. It can also result in strictures, fistulae or abscesses due to transmural involvement and can present with intestinal obstruction or perforation. About onethird of patients can present with perianal disease. Symptoms and signs include perianal pain, large skin tags, anal fissure, perirectal abscesses, and anorectal fistulae.
Dr Faisal Zeb Registrar in Gastroenterology Dr Abdur Rahman Aftab Consultant Gastroenterologist Department of Gastroenterology, St Luke’s Hospital, Kilkenny
DIAGNOSIS AND INVESTIGATIONS The diagnosis of IBD is established by characteristic history, clinical evaluation and a combination of biochemical, endoscopic, radiological and histological investigations. Detailed history should include duration of symptoms, number of bowel motions per day, rectal bleeding, nature of abdominal pain, malaise, weight loss and fever. Extra-intestinal manifestations of IBD include joint, skin, liver, renal and eye involvement. Laboratory investigations can aid diagnosis. Patients with both ulcerative colitis and Crohn’s disease may show iron-deficiency anaemia, hypoalbuminaemia, raised platelets, white cell count (WCC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Stool samples are helpful to exclude an infective aetiology to the presenting symptoms. Small bowel meal X-rays can delineate small bowel involvement. Ultrasound and computed tomography (CT) scanning are helpful in detecting intra-abdominal complications such as abscess formation.
Colonoscopy Colonoscopy with biopsies remains the gold standard for diagnosis, and to delineate the extent of disease in ulcerative colitis. For clinically mild-tomoderate cases, colonoscopy is preferable to flexible sigmoidoscopy. In moderate-to-severe cases MODER N MEDICINE
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review there is a higher risk of bowel perforation so flexible sigmoidoscopy is safer. It may be appropriate to defer investigations until symptoms improve after empirical treatment. Endoscopic features of ulcerative colitis include loss of vascular markings, erythematous mucosa and contact haemorrhage. More severe cases can be associated with macroulcerations, profuse bleeding and copious exudates. In Crohn’s disease, colonoscopy with intubation of the ileum is the major tool used to establish the diagnosis of ileocaecal Crohn’s disease. Endoscopic findings include focal ulcerations adjacent to areas of normal mucosa (skip lesions) with polypoid mucosal changes which suggest a cobblestone appearance. In advanced cases strictures and fistulae can occur. Serial colonic and terminal ileal biopsies should be taken even where the mucosa appears macroscopically normal, as the presence of noncaseating granulomata/giant cell can aid the diagnosis of Crohn’s disease. MANAGEMENT Symptoms in patients with IBD can have a huge impact on the patient’s lifestyle. They can result in loss of education, difficulty in obtaining a job or in a change of profession. Patients can be diagnosed at a young age with a lifelong illness, which can result in stress and psychological problems. The patient’s preferences should be taken into consideration for joint decisions made between patient and health professionals. The following views have been expressed by national associations for colitis and Crohn’s disease: • Someone with IBD should be seen as an individual and should not be defined by their illness; • Individuals differ in the way they choose to live with IBD; • Individuals often develop expertise about their own condition and needs which should be respected; • Patients place a high value on sympathy, compassion and interest; • There should be equitable access to treatments and services and early referral of complex cases to specialist centres where local expertise is exceeded. Patients with a suspected diagnosis of IBD should be referred to a gastroenterology team experienced in the care of IBD and which adopts a 14 MODER N MEDICINE
multidisciplinary approach together with experienced surgeons, radiologists, pathologists and IBD nurses. Once the diagnosis is established it should be discussed in detail with the patient, who should be offered written information and audiovisual material along with contact details for support groups and allow time (where possible) to consider his/her best options. MEDICAL MANAGEMENT Drug therapy depends upon both the extent and severity of disease at the time of presentation.
Aminosalicylates Sulphasalazine consists of 5-ASA and sulphapyridine. Sulphasalazine possesses both antiinflammatory (5-ASA) and anti-bacterial (sulphapyridine) properties. Suphasalazine is less used now because of side effects which the newer 5-ASA agents do not have. Mesalazine (Asacolon or Pentasa) is formed by coating 5-ASA with pH-sensitive acrylic resins which results in delivery of the drug to the distal small intestine and colon. The exact mechanism of action responsible for clinical efficacy is not known. Aminosalicylates are used for IBD, both in active disease and for maintenance of remission. Remission rates as high as 93% have been reported and remission is maintained in 75% of these patients. They are available in oral tablets, sachets, enemas or suppositories. Topical therapy (enemas, suppositories) with aminosalicylates is beneficial in patients with distal colitis. Mesalazine compounds are generally better tolerated than sulphasalazine. The starting dose is 1.2 to 1.6g per day and can be gradually increased up to 4.8g per day in three divided doses. The maintenance dose for sulphasalazine is usually 2g per day and for mesalazine 2.4 to 4g per day. Although still widely used in Crohn’s disease, 5-ASA has been shown to have little benefit for this form of IBD. Conflicting views exist on whether the 5ASA has a chemoprotective effect on bowel cancer. Both sulphasalazine and mesalazine can be used safely in pregnancy. Mesalazine has fewer side effects than sulphasalazine. Common side effects are fever, rash and hypersensitivity reactions. Rarely, they can cause interstitial nephritis and nephrotic syndrome.
Corticosteroids Corticosteroids are potent anti-inflammatory agents
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review for moderate-to-severe relapses of both ulcerative colitis and Crohn’s disease. They have no role in maintenance therapy for either disease. They act through inhibition of several inflammatory pathways (i.e. suppressing interleukin formation, suppression of arachidonic acid metabolism and stimulation of apoptosis of lymphocytes). They are available in oral tablets, liquid and foam enemas, suppositories and intravenous form. In severe disease treatment is usually commenced with hydrocortisone 100mg every six hours intravenously and switched to the oral route after benefit is seen in a few days. Oral prednisolone is usually started at 40mg per day with the aim of reducing the dose to zero by stepwise reduction over eight weeks. Up to 80% of patients respond to this dose within 10 to 14 days of treatment. Side effects of steroids include dyspepsia, sleep or mood disturbances, acne, glucose intolerance and hypertension. Effects associated with prolonged use are osteoporosis, osteonecrosis of femoral head, myopathy, cataract and susceptibility to infections. Calcium supplements are advisable during steroid therapy. IMMUNOMODULATOR THERAPY Patients with ulcerative colitis and Crohn’s disease who remain refractory to therapy with 5-ASA, steroids or those who frequently depend upon steroids to control the disease are relatively common and present a challenging problem requiring immunomodulation.
Azathioprine and 6-mercaptopurine Azathioprine and 6-mercaptopurine (6-MP) are purine anti-metabolites which inhibit ribonucleotide synthesis inducing T-cell apoptosis. Generally azathioprine is tried first and 6-MP only introduced if azathioprine is unsuccessful or causes adverse effects. They can be used as steroid-sparing agents in fistulising disease and as maintenance therapy. The usual starting dose of azathioprine and 6-MP is 50mg and 25mg per day respectively. If the drugs are well tolerated after one month, and if clinically indicated by a partial response, then the dose of azathioprine can be increased up to 100 to 200mg per day and 6-MP up to 75 to 100mg/day. Depending upon symptoms the maximum daily dose for azathioprine is 2.5mg/kg and 6-MP is 1.25mg/kg. Remission is maintained in approximately 40% to 70% of patients. Patients should have weekly full blood count (FBC) and liver blood tests for the first month or until the maintenance dose is reached as leucopenia, anaemia,
thrombocytopenia and acute hepatitis may occur. Other side effects are flu-like illness, nausea, vomiting, rash and pancreatitis. It is preferable to avoid these drugs in pregnancy.
Methotrexate Methotrexate is an alternative for Crohn’s disease patients who do not tolerate or become unresponsive to azathioprine/6-MP. It inhibits the binding of dihydrofolic acid to the enzyme dihydrofolate reductase, which in turn inhibits cytokine and eicosanoid synthesis leading to the anti-inflammatory effects. For maximum bioavailability, it should be initiated intramuscularly at a dose of 25mg once-weekly and a response is anticipated in three months. Once a response is achieved, or after 16 weeks, the route can be switched to oral methotrexate once-weekly. Monitoring of full blood count and liver function tests is advisable weekly, then four-weekly. Up to 50% remission rates have been reported. Side effects include hepatotoxicity, pulmonary fibrosis, myelosuppression and nephrotoxicity. Nausea, vomiting, diarrhoea and stomatitis can also occur. Methotrexate interferes with cellular utilisation of folic acid and folate depletion is considered to be the major cause of side effects. It is therefore advisable to administer oral folic acid 5mg weekly. Methotrexate is contraindicated in pregnancy as it can cause congenital anomalies. The drug should be continued as long as it is tolerated and demonstrates a clinical response – possibly for three to four years.
Cyclosporine Cyclosporine may be suitable in steroid-resistant patients with refractory severe or fulminant ulcerative colitis. It is not used for Crohn’s disease. It is an inhibitor of calcineurin, preventing clonal expansion of T-cell subsets. It can be given as a continuous infusion with a dose of 4mg/kg/day for seven to 10 days. For responding patients who have not previously been on azathioprine or 6-MP, oral cyclosporine 8mg/day should be continued for three to four months while azathioprine or 6-MP is introduced. For patients who are on azathioprine or 6-MP, cyclosporine can be discontinued at an early stage depending upon the patient’s clinical status. Blood levels of cyclosporine (100-200ng/ml) must be monitored carefully during its administration. Measurement of blood pressure, full blood count and renal function is advisable at zero, one and two MODER N MEDICINE
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weeks then monthly. The cholesterol level should be checked before starting therapy as administration with low cholesterol level (<3mmol/l) can cause seizures. Its use is controversial because of toxicity and long-term failure rate. Surgery is recommended if a response is not seen in seven to 10 days. Recently cyclosporine has tended to be replaced by earlier use of biological agents as a “rescue therapy” in severe/fulminating disease. BIOLOGICAL AGENTS Tumour necrosis factor-alpha (TNF-α) plays a central role in the pathogenesis of mucosal inflammation in IBD. Biological agents are mouse/human monoclonal antibodies against TNF-α. Two commonly used antiTNFs are infliximab (Remicade) and adalimumab (Humira). Clinical trials and experience have demonstrated significant utility of these agents for induction of remission and maintenance of IBD. They are helpful both in ulcerative colitis and in Crohn’s disease, especially with fistulising Crohn’s disease.
Infliximab Infliximab is given as an intravenous infusion with the usual dose of 5mg per kg starting at zero, two and six weeks followed by maintenance dosing every eight weeks if required. Responses up to 81% at four weeks of treatment with 5mg/kg have been reported. A chest radiograph should always be performed before starting treatment as reactivation of tuberculosis is a risk. Other side effects include joint pain, myalgia, fever and, rarely, anaphylactic reaction.
Adalimumab Adalimumab is administered subcutaneously, making it convenient to use. It may also be an option for patients who have lost response to or had an adverse reaction to infliximab. The recommended dose regimen is 160mg at week zero followed by 80mg at week two and then the maintenance dose of 40mg fortnightly. For induction treatment it should be given in combination with corticosteroids. During maintenance treatment, corticosteroids can be tapered and stopped. Up to 60% of patients achieved clinical response at week four of treatment. Biological agents can be used alongside other immunomodulators, for example azathioprine/616 MODER N MEDICINE
MP, to maintain remission, especially after the biological agent is withdrawn. There are rare reports of hepatosplenic T-cell lymphomas in children given these drugs. For acute severe Crohn’s disease or ulcerative colitis there is debate as to what the best initial treatment is. One method is to start the 5-ASA and progress to immunomodulators or biological therapies depending on the response (so-called “step-up” therapy). The other method is to start with biological therapy (so-called “step-down” therapy). The jury is still out on which method is more effective. It should be noted that biological agents are very expensive.
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COMMON INJURIES PART 3 – LACERATIONS AND INCISIONS INTRODUCTION Among lay people (and even among doctors) there is a great degree of confusion about the meaning of the word “laceration” and the distinction between it and “incision” or “stabbing” and such terms. While it is true that, in common parlance, the distinction has almost vanished, for doctors it is important to remember that a laceration is quite different from an incision. LACERATIONS Lacerations are wounds penetrating the full thickness of the skin which are caused by a relatively blunt injury. It is the causative injury that is the distinguishing feature: lacerations are not caused by sharp objects, but rather are tears in tissue caused by a comparatively blunt impact. Lacerations are common after both assaults and accidental injuries, especially traffic accidents. When trauma is massive, there may be laceration to internal organs such as the liver (see Figure 1). Examination of a laceration may disclose the presence of a foreign body (such as a fragment of an implement that caused a laceration) that may be of evidential value.
Figure 1. Lacerations to the liver following abdominal trauma in a road traffic accident.
FLAYING INJURIES Skin on a limb may also sometimes be “flayed”, i.e. stripped of a large area of skin and muscle by the rolling action of a rotating wheel. This may happen when the wheel of a car goes over a pedestrian or in
some industrial accidents.
Dr Simon Mills Barrister at Law
INCISED WOUNDS An incised wound is caused by a sharp cutting edge penetrating the full thickness of the skin. There are two categories of incised wound with simple distinguishing characteristics: 1. The slashed wound (also sometimes called an “incised wound”) is longer than it is deep; 2. The stab wound is deeper than it is long. A wound can sometimes exhibit mixed stabbing and slashing features, for example injuries caused by an assailant wielding a broken glass or bottle, but any sharp implement can be used to both slash and stab, and so it is not uncommon for the two types of incision to co-exist on the same victim. SLASHED WOUNDS The severity of any slashed wound depends upon the site and the depth. Injuries to the neck and other body parts where large blood vessels are near the surface (groin, front of the elbow and wrist) can be especially dangerous, although any incision may well be superficial (see Figure 2). The wound will gape according to the depth of the wound and its relation to skin creases, muscle planes and other features. When reporting on a slashed wound, the important details of the wound to record are length, angle of the incision and direction. This information can assist in reconstructing events leading to the wound. The direction of travel of the knife is not always easy to discern, but usually the deeper part of the wound is near the end where the wound was first inflicted; the knife or other weapon tends to move superficially as it leaves the body. The depth of the wound may be irregular, especially where the cutting implement has passed over an irregular surface (for example, the back of the hand). Very little can be deduced about the nature of the weapon causing a slash would, apart from its probable sharpness or bluntness – divined from the raggedness or otherwise of the wound edges. MODER N MEDICINE
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forensic medicine for the busy doctor A slashing wound inflicted by a heavy implement, such as a cleaver or sword, may also do significant damage to underlying tissues, including bones.
Figure 2. A superficial incised wound to the hand, caused by a rose thorn.
STAB WOUNDS A stab wound can reveal much more about the weapon causing it than does a slash wound, although much of this information can only come from the deep inspection of the wound during autopsy or surgery. Surface inspection of the wound is a poor guide to the width of the knife blade for two reasons: 1. Skin tends to retract and gape after withdrawal of a blade, so that the length of the wound shortens and the lateral width slightly increases; 2. A knife is rarely plunged in and removed in a perfectly perpendicular way – rocking of the blade tends to make the wound wider than the weapon. The shape of the blade may sometimes be deduced from the extremities of the wound. A blade with a single cutting edge and a blunt back may show corresponding appearances in the wound, whereas a two-edged dagger may cause very sharply-cut edges at either end. A knife with serrations may leave a wide ragged margin at one end. However, even a one-edged blade (or even a square-edged object such as a chisel) may leave a wound with sharp extremities at either end, due to skin splitting at the blunt end. DISTINGUISHING LACERATIONS AND INCISIONS Following certain assaults, some lacerations may closely resemble the clean-cut wound produced by a knife, in spite of being caused by blunt injury. This tends to happen where skin is stretched over a bony surface, especially the scalp, orbital margin/cheekbone and shin (similarly, where the skin is stretched tight over bone, it will take comparatively less force to produce a laceration; see Figure 3). Failing to distinguish properly 20 MODER N MEDICINE
between lacerations (wounds caused by blunt objects) and incisions (wounds caused by sharp objects) is a relatively common error. Close examination will always distinguish lacerations from incised wounds: • There is invariably crushing of the wound margins in a laceration, although the crushed margin may be very narrow and difficult to see macroscopically; • On the scalp, the usual site of such lacerations, hairs will be forced into the wound; • Magnified examination with a lens will reveal inversion of the wound edges with bruising in the immediate vicinity, a phenomenon not occurring with incisions; • Lacerations may bleed profusely, but haemorrhage is often noticeably less than with an incised wound, because blunt trauma tends to retract and occlude the ends of torn vessels rather than slicing through them cleanly; • Lacerations may have residual skin bridging across the wound, particularly near or at either end of the wound.
Figure 3. Laceration to the forehead.
READING LIST Knight JB. Legal Aspects of Forensic Medicine, 5th edition (Ch 15). Shepherd R. Simpson’s Forensic Medicine, 12th edition (Ch 9). Saukko P, Knight JB. Knight’s Forensic Pathology, 3rd edition (Ch 4). Payne-James J, Bussutil A, Smock W. Forensic Medicine – Clinical and Pathological Aspects (Chs 22 and 30).
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DISORDERS OF THE INNER EAR â&#x20AC;&#x201C; THE ROLE OF THE NEUROTOLOGIST PART 2 Mr Brendan G Fennessy BSc MRCSI ENT Specialist Registrar Mr Usman Noma MD ENT Specialist Registrar Mr Peter Oâ&#x20AC;&#x2122;Sullivan BSc MPhil FRCSI (ORL-HNS) ENT Consultant Department of ENT, South Infirmary and Victoria University Hospital, Old Blackrock Road, Cork
SUDDEN-ONSET SENSORINEURAL HEARING LOSS Sudden onset sensorineural hearing loss (SNHL) is an otological emergency that warrants urgent referral to an ENT specialist. The widely accepted definition is a loss of 30dB or more, over at least three contiguous frequencies, which develops over three days or fewer. Approximately 5 to 10% of cases are related to an infectious, traumatic, neoplastic, toxic, auto-immune, neurologic and metabolic pathology; the majority are idiopathic, with postulated causes including a viral labyrinthine infection, vascular insult, intra-cochlear membrane rupture and autoimmune inner ear disease. The earlier the patient is treated, the higher the chance of recovery. Poor prognosis is associated with a profound hearing loss in a patient older than 60 years with associated vertigo. Management includes audiological assessment, screening blood tests and an MRI. While the optimal dose and length of treatment has not been determined, prednisolone at 1mg/kg per day, reducing for 10 days, is often prescribed. Acyclovir does not appear to improve hearing outcome whether given alone or in combination with steroids. Treatment with diuretics, vasodilators and carbogen (5% carbon dioxide/95% oxygen) inhalation is no better than spontaneous recovery. Overall 50% have spontaneous recovery from unilateral SNHL (37% in bilateral cases); patients with a severe-to-profound SNHL are unlikely to recover, while those with a mild-to-moderate SNHL have a better prognosis. Patients should be warned to avoid ototoxic medications where possible and
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should the SNHL occur in their other ear, urgent treatment should be sought REHABILITATION OF HEARING Hearing loss affects 40% of the adult population over the age of 65 years and represents the fourth most common chronic disability. Hearing loss, even in the mildest form, impairs the ability of the individual to communicate adequately with the outside world. Sudden sensorineural hearing loss should be urgently referred to an ENT specialist for further evaluation and management. The neurotologist has a vital role in facilitating the hearing-impaired to minimise their difficulties by thorough and proper evaluation and selection of the most appropriate rehabilitation.
Conductive hearing loss Conductive hearing loss is usually amenable to surgical correction, either in the form of middle ear surgery, (i.e. tympanoplasty, ossicular reconstruction or stapedectomy, or implantable hearing devices (IHDs)). IHDs that are currently available include bone conduction implantable hearing aids, middle ear implants for ossicular stimulation and inner ear stimulators. Bone-anchored hearing aid (BAHA) is one of the implantable hearing devices (see Figure 3). BAHA offers a low-risk, highly acceptable method of aural rehabilitation for those with conductive hearing loss or in patients with one-ear sensorineural hearing loss. The basic principle is to use a transducer that will act directly upon the temporal bone to transmit vibration to the cochlea, or to the opposite cochlea in patients with SNHL.
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Figure 3. Bone-anchored hearing aid in situ.
Sensorineural hearing loss When amplification of sound with the aid of conventional hearing aids fails to improve hearing in patients with severe-to-profound SNHL, a cochlear implant is able to bypass impairment or dysfunction in the auditory system to send sound signal directly to the hearing nerve. The cochlear implant consists of a microphone, which is placed above the ear, a sound processor, receiver-stimulator and an implantable electrode, which is placed into the cochlea (see Figure 4). Cochlear implants were implanted initially for postlingually deaf adults, however they can now be used in children under one year old. All patients must have full audiological and radiological evaluation before the procedure. Some centres use brain stem implantable hearing devices. The patient and their family must be highly motivated and yet have realistic expectations. There must be commitment to an educational programme emphasising auditory skills. Despite the widespread availability of neonatal hearing screening in the Western world, and intense Government lobbying by medical groups, it still has not been introduced nationally in Ireland to date. Prior to its introduction in the UK in 2001/2002, almost a quarter of children born deaf were not identified until they were over 3.5 years-of-age. A landmark study has demonstrated that children whose hearing loss was identified by six months-of-age demonstrated significantly better receptive and expressive language skills than those identified after six months.4 TUMOURS OF THE TEMPORAL BONE AND LATERAL SKULL BASE Temporal bone tumours are rare. The temporal bone and its contents are derived from all three embryonic primordial layers. Consequently, tumours may be ectodermal (e.g. squamous cell carcinoma), 24 MODER N MEDICINE
Figure 4. Cochlear implant.
mesodermal (e.g. glomus tumours) and endodermal (e.g. vestibular schwannoma) in origin. The presentation of the tumour can mimic that of other relatively more benign pathologies of the ear, such as otitis externa or chronic suppurative otitis media. The patient, therefore, may present with any common ear symptoms such as otalgia, otorrhoea that may be bloody, hearing loss and vertigo. Early biopsy of any suspicious lesion within the external ear canal and middle ear may facilitate early diagnosis. Highresolution CT and MRI are required to determine the extent of bone, soft tissue and vascular involvement. These rare temporal bone tumours are treated by a multidisciplinary approach incorporating neurosurgery, maxillofacial and plastic surgery, radiotherapy and medical oncology.
Cerebellopontine angle tumours Approximately 8 to 10% of intracranial tumours occur in the cerebellopontine angle; 80% are vestibular schwannomas (see Figure 5), the remaining 20% incorporate meningiomas, epidermoid cysts, facial nerve schwannomas, glomus tumours and metastatic disease. All these tumours have similar clinical signs: tinnitus, hearing loss, and/or vertigo. However the unusual tumours are more likely to produce atypical symptoms such as diplopia, headache, facial paralysis, and dysphagia. Vestibular schwannomas (also known as acoustic neuromas) are benign tumours that originate from the Schwann cells surrounding the vestibular nerve. They are relatively uncommon, with incidence of approximately one new case per 100,000. The mean age at presentation is 47 years and there is a slight preponderance of females. Between 2% and 4% of all patients with vestibular schwannoma have neurofibromatosis type 2, which is characterised by the
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review development of bilateral lesions. Presentation is with gradual sensorineural hearing loss and poor speech discrimination that is out of proportion to the degree of hearing loss. Often there is associated tinnitus, vertigo and aural fullness. MRI with gadolinium enhancement is the gold standard diagnostically. In treating these benign tumours, one must consider tumour size, functional hearing and facial nerve involvement, in addition to the patientâ&#x20AC;&#x2122;s general health and age.5 Treatment options include conservative management (with six-monthly MRI), radiotherapy and surgery. Radiotherapy is ill-advised in tumours more than 3cm. Stereotactic radiosurgery and radiotherapy which delivers a single fraction of radiotherapy to the tumour has been used to good effect.6 For large tumours surgical resection remains the treatment of choice via a translabyrinthine, retro-sigmoid or posterior cranial fossa approach. In modern medicine, many conditions are increasingly becoming amenable to medical rather than surgical intervention. The place of the neurotologist remains assured in the role of diagnosing and managing conditions within the labyrinth that is the lateral temporal bone and skull base.
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Figure 5. MRI with gadolinium illustrating a left acoustic neuroma.
REFERENCES 4. Yoshinaga-Itano C, Sedey AL, Coulter DK, Mehl AL. Language of early and later identified children with hearing loss. Pediatrics 1998; 102: 1161-71. 5. Mendenhall WM, Friedman WA, Amdur RJ, Antonelli PJ. Management of acoustic schwannoma: Am J Otolaryngol Jan-Feb 2004; 25(1): 38-47. 6. Wackym PA, Runge-Samuelson CL, Poetker DM et al. Gamma knife radiosurgery for acoustic neuromas performed by a neurotologist: early experiences and outcomes. Otol Neurotol 2004; 25: 752-761.
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MALARIA AND THE TRAVELLER Dr Dom Colbert SUMMARY MD FRCSI MFTM Malaria is the most common cause of death in the (GLASG) BSC CTH, returned traveller and a missed diagnosis can have Travel Medicine, Galway catastrophic effects. Understanding the mode of
transmission and subsequent cycle in humans is domcolbert@eircom.net essential in order to provide rational prophylaxis and
treatment. Those most at risk are visitors to or from sub-Saharan Africa, especially those visiting friends and relatives (VFRs), pregnant women, children, the immunocompromised and the elderly. Plasmodium falciparum is the most lethal type. However a fifth type of malaria, so-called “monkey malaria”, has recently been recognised in southeast Asia and represents an ominous progression of an infectious disease from other primates to man. Malaria did occur in Ireland in the past, especially in the 17th century. INTRODUCTION Malaria is one of the most common and feared diseases of the tropics, accounting for an estimated 3,000 deaths per day.1 Each year around 2,000 new cases are reported in the UK with around 20 deaths, while in Ireland the corresponding figures are 100 to 200 cases with zero to three deaths annually.2 The majority of these cases occur in those who have returned from visiting friends and relatives (VFRs), particularly in sub-Saharan Africa, and the majority are due to the parasite Plasmodium falciparum which causes the deadliest form of the disease. The most recent available statistics from the Central Statistics Office are for 2006. Examination of these by the Health Protection Surveillance Centre showed 96 cases, an increase of 118% on the 2005 figures.3 There is absolutely no doubt that malaria is under-reported in Ireland because many patients are treated abroad and many who return only develop mild symptoms or develop malaria a long time afterwards.
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TRANSMISSION OF THE PARASITE A single bite from an infected female anopheles mosquito can transmit Plasmodium spp. Only female mosquitoes require a blood meal (to nourish their young) whereas male mosquitoes live on plant sap and nectar. The bite takes place from dusk to dawn with pre-dawn being a common time in some countries. It should be pointed out that the mosquito normally bites up to 20 times before locating a small blood vessel and starting its blood feed. To do this, without our noticing, it injects a local anaesthetic first so the bite can hardly be felt and so we are unaware of what is happening. This contrasts with bites from other mosquitoes, notably Culex and Aedes, where the bite is often painful. Indeed Culex mosquitoes (e.g. those that transmit West Nile virus) are painful and persistent biters, preferring domestic animals and birds to humans despite the fact that they often enter houses for a blood meal. HUMANS ATTRACT ANOPHELES The Anopheles mosquito that carries malaria is attracted to us by body heat, sweat, CO2 and body odour. Our hormonal state is also an important attractant; thus the well-known propensity of some people, like women (especially pregnant women), to be bitten more often than others. For this reason one should take seriously the sometimes tonguein-cheek claim by some patients that “mosquitoes love them”. Anopheles is also attracted more to children than to adults. The reason for this is not known. Remember that Anopheles prefers dark colours so it is always wise to wear brightly coloured clothes when travelling to an endemic area. The locals know this and, like many another custom handed down through the generations, there is much wisdom to be gleaned from observing local habits and listening to local lore.
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During the daytime the mosquito lurks in dark places, behind wardrobes, behind beds and under chairs. A favourite hideout is under the kneeling surface of pews in churches, so beware of what you may catch when kneeling at prayer, even during the daytime. RANGE OF FLIGHT Anopheles readily travel up to three miles and much further if there is a favourable wind. They have also adapted to fly at three to five miles per hour. This is just enough to keep pace with us when we take that evening stroll before dinner, enjoying star-laden skies and balmy breezes which refresh us at the end of a hot tropical day. Culex, on the other hand, seldom travel more than a kilometre from their breeding sites. Finally one should note that malaria-carrying mosquitoes seldom live higher than 1500m. Apart from altitude, a mean ambient temperature >20oC, a high humidity and an adequate rainfall are necessary for a thriving Anopheles population. ONCE BITTEN Despite the actual biting process being painless, once the bite has occurred it may become “red, itchy, bumpy and uncomfortable”. This is due to an allergic response to proteins in the mosquito saliva which remain in the skin after the mosquito has withdrawn her proboscis. The injured area swells and may become intensely itchy. First bites may cause no problem but succeeding ones may cause progressively more swelling and itch as the allergic reaction becomes more intense. For longer-stay people with repeated bites the skin reaction lessens much as if the subject had received a course of allergy shots. A similar pattern occurs after bites from bed bugs, chiggers, fleas and mites. Infected arthropod bites from pruritus-induced scratching is probably the commonest skin lesion which we see in the returned traveller. FIVE PLASMODIA SPECIES CAUSE MALARIA IN MAN Of the many hundreds of documented species of Plasmodium only four have been known to cause human disease up to now. These are P falciparum, P vivax, P ovale and P malariae. Recently, a fifth species, P knowlesi, endemic to macaque monkeys in southeast Asia, has been shown to cause much of
the human malaria in Malaysia. This transfer of “monkey malaria” to man is an exciting and challenging happening, since it may presage the transfer of other simian malarias and other simian infectious diseases to man. However, to date, it is still P falciparum that is by far the deadliest, despite recent reports of serious illness and even death from the so-called benign malaria cause by P vivax.
Figure 1. Macaque monkey carries fifth form of human malaria.
MALARIA LIFE CYCLE It is necessary for us to have a rough outline of what happens to the malaria parasite after it is introduced by the bite of an Anopheles mosquito. The reason is that all current anti-malarial drugs, both curative and prophylactic, target some aspect of the human segment of the parasite’s life cycle. A single bite introduces thousands of Plasmodium sporozoites into the circulation. Most of these settle in the liver within 20 minutes, although the blood is not completely cleared for about eight hours.4 Here they develop in the hepatocytes into liver or preerythrocytic schizonts. Intense asexual multiplication occurs now (20 times more with P falciparum than with other species). In seven to 10 days they pour out from the liver as merozoites and invade red blood cells. Some of the schizonts of P vivax and P ovale lie dormant in the liver for months or years and are called hypnozoites. Rupture of these after months or years is the cause of recurrent or relapsing malaria. P falciparum is notable in that it does not have a dormant phase and only exceptionally causes recurrent disease. Within the red blood cell the merozoites adopt ring forms, trophozoites, which undergo further MODER N MEDICINE
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multiplication before the red cells rupture in two to three days releasing millions of fresh merozoites into the circulation. This signals the onset of the clinical disease (fever, anaemia). Merozoites invade other red blood cells to repeat the cycle while some turn into gametocytes (both male and female) which can be picked up by another mosquito during another blood feed (see Figure 2).
Figure 3. Little egret, newcomer to our shores.
Figure 2. Life cycle of the malaria parasite in humans.
MALARIA IN IRELAND Currently none of the 18 different species of mosquitoes found in Ireland carry malaria, so the only malaria reported is among immigrants and returned travellers (especially among VFRs and children). Nonetheless endemic and autochthonous malaria may be a possibility in the future as we have seen in other countries (e.g. Corsican).5 Rapid modern travel is a major factor in this but global warming may also be a factor by attracting more and more exotic species of bird and arthropods to our shores. For example the little egret, unknown here until 1997, now resides and breeds in almost every coastal region and in some inland sites also.6
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We should remember too that, before modern travel and before rapid global warming, malaria existed in Ireland as well as in many parts of Europe. Thus it seems fairly certain that in the 17th century “country sickness” – a recurrent feverbased illness – was in fact recurrent malaria. The most notable victim is alleged to have been the 59year-old Oliver Cromwell, who died from it in 1658. REFERENCES 1. www.cso.ie (accessed August 2008). 2. Overbosch D. A step forward in family travel: Malaria prophylaxis for all ages. J Travel Med 2003; 10 Suppl 1: S1-S2. 3. www.hpsc.ie (accessed August 2008). 4. Gill GV and Beeching NJ eds. Tropical Medicine. Blackwell, 5th edition, 2004, pp 55-71. 5. Armengaus A, Legros F, D'Ortenzio E at al. A case of autochthonous Plasmodium vivax malaria. Corsica, August 2006. Travel Med Infect Dis 2008 6(1-2): 3640. Epub 20076. 6. www.birdwatchireland.ie (accessed August 2008).
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OVERVIEW OF POSTPARTUM DEPRESSION Dr Muhammad Arshad Consultant Child and Adolescent Psychiatrist, Hawkes Bay Hospital, New Zealand Professor Michael Fitzgerald Henry Marsh Professor, Trinity College Dublin
Postpartum depression (PPD) is a leading worldwide psychiatric disorder in mothers after childbirth (Goodman et al 2002, Wisner et al 2002, Murray et al 1996). An incidence of 23% affective disorder during pregnancy and the postpartum year has been noted (Wisner et al 1997, Watson et al 1984). As many as 85% of mothers exhibit some sort of mood disturbance, but 10% to 15% experience more disabling and persistent mood disturbances, such as PPD and psychosis. Antenatal and postnatal psychiatric disorders are not only associated with maternal morbidity and mortality, but increase morbidity in children as well (Stuart et al 1998). The World Health Organization (WHO) predicts that depression will be the second greatest cause of premature death and disability worldwide by the year 2020 (Murray et al 1996). PREVALENCE PPD usually occurs shortly after childbirth, with 10% to 15% of mothers experiencing a marked depressive illness within months of childbirth (Cox et al 1987, Paykel et al 1980, Cox et al 1982, O’Hare et al 1984, Watson et al 1984, Pop et al 1993, Yoshida et al 1997, Glasser et al 1998, Evans et al 2001, Peindl et al 2004). It is the most common complication, and occurs in 13% of mothers after pregnancy (O’Hare et al 1996). Half-a-million mothers in the US suffer from PPD (Katherine et al 2002). Paediatricians have recognised depressive symptoms in one-quarter of mothers (Heneghan et al 2000). Less than 5% of men, and 25% of mothers at risk, were found to have become depressed within three months of delivery. In the next nine months men were more prone to becoming depressed than previously, and their conditions tended to follow an earlier onset of depression in their spouses. There is an association between a mother’s depression and the subsequent report of the partner’s depression and general health problems (Ballard et al 1994, Lane et al 1997, Areias et al 1996). DURATION PPD episode duration without treatment is seven
months (Wisner et al 1998) and 15% to 85% of patients with a single episode will have at least one more episode after discontinuation of medication, but the risk increases with the number of previous episodes (APA 2000). So, long-term treatment for the prevention of recurrence should be considered for mothers who had three or more episodes of severe depression. RECURRENCE One-quarter of mothers experience a first episode of PPD, and the risk of recurrence is 25% after first episode of PPD (Wisner et al 2001). EPIDEMIOLOGY The exact cause is unknown but a number of factors have been identified (see Table 1). Table 1. Risk factors. Antenatal
Natal
History of depression
Caesarean delivery
Cigarette-smoking
Ill or brain-damaged baby
Low self-esteem Antenatal depression
Postnatal
Antenatal anxiety
Maternity blues
Life stress
Sleep problems
Low social support
Formula feeding
Poor marital relationship
Childcare stress
Single young mother
Infant temperament
Low socioeconomic status
problems/colic
Longer time to conception
(Collins et al 1996)
Unplanned/unwanted pregnancy Previous postpartum depression Family history of psychiatric illness Severe premenstrual symptoms (Sarah et al 2006, Beck 2001, Warner et al
Antenatal
Regier et al 1988, Hall et al 1998, Orr et al
More than one child
1984, Brown et al 1978, Beck 2001, Hagen
Lesbian and bisexual
1999, Lennon et al 2001, Spinelli et al
mothers
2003, Ross et al 2005, Howell et al 2006,
Anxiety about the foetus 32 MODER N MEDICINE
1996, Pedersen 1999, Areias et al 1996,
Segre et al 2006, O’Hara 1985, Field et al 1985; Gotlib et al 1991)
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review Mothers who have had several previous children without suffering PPD can nonetheless suffer it with their latest child. In addition, most mothers experience profound lifestyle changes with their first pregnancy, yet most do not suffer PPD (Forman et al 2000). Premenstrual dysphoric disorder, mood symptoms during the first two to four days postpartum, a past history of depression and mood symptoms during past oral contraceptive use were found to be significant risk factors for postpartum mood disorders (Block et al 2005). Levels of oestrogen, progesterone, and cortisol fall dramatically within 48 hours of delivery. Affected individuals may be abnormally sensitive to changes in the hormonal milieu and may develop depressive symptoms when treated with exogenous oestrogen or progesterone. CHARACTERISTICS PPD can present differently from mother to mother and can change over time for each individual. Some mothers experience panic attacks, and may develop phobias for going out, or being confined in a space, which they have never experienced before. The mother can adopt one of the following four coping strategies: 1. Avoidance coping: denial, behavioural disengagement. 2. Problem-focused coping: active coping, planning, positive reframing. 3. Support-seeking coping: emotional support, instrumental support. 4. Venting coping: venting, self-blame.
Table 2. Features of postpartum depression. Mood • Changes in mood (sadness) • Social withdrawal • Loss of interest • Irritability, easily frustrated • Anhedonia Physical • Change in appetite (increased or decreased) • Extreme tiredness or exhaustion • Poor sleep patterns • Agitation or psychomotor retardation Cognitive • Tearfulness • Hopelessness • Lack of libido • Lack of joie de vivre • Low self-esteem, guilt • Worthlessness • Inability to cope • Inability to concentrate • Undue anxiety • Phobias • “Not wanting to go on” • Feeling “unbonded” with baby Others • Alcohol or drug abuse • Suicide risk • Violent behaviour
Table 3. DSM-IV – PPD. Major depression is defined by the presence of five of the following symptoms, one of which must be either depressed mood or decreased interest or pleasure.
IMPACT ON THE CHILD Children of depressed mothers may show behavioural disturbance at three years (Wrate et al 1985) or cognitive defects at four years (Cogill et al 1986), which suggests that PPD may have a long-term negative impact on children’s social, emotional, cognitive and behavioural development (Cummings et al 1994, Tatano et al 1999, Weitzman et al 1992), as shown in Table 4. Depressed parents exhibit poor parenting skills, which can lead to depression in children (Raskin et al 1971; Weissman et al 1972; Parker 1979a,1979b,1981,1982; Ainsworth & Witting 1992). Maternal depression was associated with increased risk for depression in children (Welner & Rice 1988) and 40% of children of depressive
•
Depressed mood, often accompanied or overshadowed by severe anxiety
•
Markedly diminished interest or pleasure in activity
•
Appetite disturbance – usually loss of appetite with weight loss
•
Sleep disturbance/insomnia, even when the baby sleeps
•
Physical agitation or psychomotor slowing
•
Fatigue, decreased energy
•
Feelings of worthlessness or excessive guilt
•
Decreased concentration or ability to make decisions
•
Recurrent thoughts of death or suicidal ideation
PPD begins within four weeks of delivery.
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review parents had a psychiatric disorder of some sort (Beardslee et al 1983). Numerous Irish studies have linked maternal depression with childhood social and behavioural problems (FitzGerald 1993, Houlihan B, Fitzgerald M et al 1992). In one Irish study of 50 consecutive children attending a child psychiatric outpatient department, 70% of the mothers were found to have significant social problems (McNestry FB, Fitzgerald M, Kinsella A 1988).
Table 5. Symptoms of insecure attachment. Emotional
Low self-esteem, needy, clingy or pseudo-independent behaviour, inability to deal with stress and adversity, depression, and lack of empathy
Physical
Susceptibility to chronic illness; eating problems, such as refusal to eat
Social
Lack of self-control, inability to develop and maintain friendships, alienation from parents, caregivers, and other authority figures, aggression and
Table 4. Impact on the child.
violence, difficulty with genuine trust, Behavioural problems Sleep problems, temper tantrums, aggression, and
intimacy, and affection, hopelessness Learning
Behavioural
hyperactivity.
speech
problems
and
language
at
school,
problems,
incessant talk, difficulty learning. Cognitive development Often delayed in babies and children who have
Table 6. Reactive attachment disorder.
depressed mothers. They may learn to walk and talk later than other children and they may also have other
DSM-IV
learning difficulties, including problems with school.
•
Markedly
disturbed
and
developmentally
inappropriate social relatedness in most contexts. Social problems
•
Hard to make friends, socially withdrawn, or act out in
The disturbance is not accounted for solely by developmental delay and does not meet the
destructive ways.
criteria for PDD. •
Onset before five years-of-age.
Emotional problems
•
A history of significant neglect.
Lower self-esteem, anxious, fearful, passive, and less
•
An
independent.
implicit
lack
of
identifiable,
preferred
attachment figure. ICD-10: F94.1
Depression in early life
•
Particularly high for these children.
•
Onset is before the age of five years. The child exhibits strongly contradictory or ambivalent social responses that extend across social situations (but which may show variability
BONDING Mother-baby bonding is disturbed, and there are ambivalent or negative feelings toward the infant, including intrusive or unpleasant thoughts of harming their infant. Anxiety is prominent, including worries or obsessions about the infant’s health and well-being (Field et al 1985, Scholle et al 1998, Beck et al 2002, Cadzow et al 1999).
from relationship to relationship). •
Emotional disturbance is shown by lack of emotional responsiveness, withdrawal reactions, aggressive responses to the child’s own or others’ distress, and/or fearful hypervigilance.
•
Some
capacity
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social
reciprocity
and
normal adults. •
The criteria for PDDs are not met: Asperger’s syndrome,
ATTACHMENT Bowlby (1907-1990) described four characteristics of secure attachment: proximity maintenance, safe haven, secure base, and separation distress. Children of depressed mothers show insecure and reactive attachment disorders (see Tables 5 and 6).
for
responsiveness is evident in interactions with
autism,
childhood
disintegrative
disorder, mental retardation, Rett’s disorder.
DIFFERENTIAL DIAGNOSIS
Major depression Postpartum blues (PPB) Starts on the third or fourth day and remits within
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review two weeks, and affects 75% to 80% mothers. Rapidly fluctuating mood, sadness, tearfulness, irritability, insomnia, and anxiety are common symptoms that do not interfere with a motherâ&#x20AC;&#x2122;s ability to function and to care for her child. Postpartum depression (PPD) Occurs within six months of childbirth. The mother may have a number of symptoms such as sadness, lack of energy, trouble concentrating, anxiety, and feelings of guilt and worthlessness. Postpartum psychosis (PPP) Rare, occuring in one or two out of every 1,000 births, usually beginning in the first six weeks postpartum. Mothers who have bipolar disorder or schizoaffective disorder have a higher risk for developing PPP. Common symptoms include: hallucinations, delusions, illogical thoughts, insomnia, refusal to eat, extreme feelings of anxiety and agitation, periods of delirium or mania, suicidal or homicidal thoughts, obsessive thoughts about the baby, loss of interest and loss of touch with reality. Medical conditions: such as hypothyroidism, anaemia. Comorbidity: learning disability, bipolar illness, alcohol/drug abuse, post-traumatic stress disorder (PTSD). DIAGNOSIS PPD diagnosis is usually made by the family doctor, midwife, paediatrician or public health nurse based on symptoms which are reported by the mother or her family, and which have lasted several weeks. The Edinburgh Postnatal Depression Scale (EPDS) has been developed to detect depression in postnatal mothers, which has a 10-item questionnaire (Cox et al) and is a useful scale (Peindl et al 2004). MANAGEMENT PPD is a highly treatable disorder which demands early detection, as treatment is important for good long-term outcome of physical and psychological health of the infant and the mother. It should depend upon a multidisciplinary stepped approach, outlined in Table 7. APPROACHES 1. Comprehensive history and physical examination. 2. Routine blood tests: to rule out physical 36 MODER N MEDICINE
3. 4. 5. 6.
causes of depression such as hypothyroisism, anaemia and treat appropriately. Rule out drug and alcohol abuse. Psychosocial intervention: relationship counselling. Psychoeducation. Psychopharmacology. Antidepressants: SSRI (sertaline, paroxetine, citalopram, fluoxetine); SNRI (venlafaxine, duloxetine), tricyclics (nortryptyline, desipramine); other (bupropion, nefazodone, mirtazapine) (Appleby et al 1997, Stowe et al 1995, Cohen et al 2001). SSRIs taken after 20 weeksâ&#x20AC;&#x2122; gestation may be associated with an increased risk of persistent pulmonary hypertension in the neonate. Paroxetine taken in the first trimester may be associated with foetal heart
Table 7. Stepped care approach (NICE 2007). Step 1: GP, practice nurse, Assessment paediatrician, midwife Step 2: Primary care team, primary care mental health worker
Step 3: Primary care team, primary care mental health worker Step 4: Mental health specialists including crisis teams
Step 5: Inpatient care, crisis teams
Recognition
Mild depression
Watchful waiting, guided self-help, computerised CBT, exercise, brief psychological interventions
Moderate /severe depression
Medication, psychological interventions, social support
Treatmentresistant, recurrent, atypical and psychotic depression, and those at significant risk
Medication, complex psychological interventions, combined treatments
Risk to life, severe self-neglect
Medication, combined treatments, ECT
defects and venlafaxine may be associated with increased risk of high blood pressure at high doses. Antidepressants carry the risk of withdrawal or toxicity in neonates but generally the effects are mild and selflimiting. Six to 12 months of treatment is recommended in the first episode of depression and a long-term maintenance
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review treatment is indicated in recurrent depression with an antidepressant. Anxiolytic agents such as lorazepam and clonazepam may be useful as adjunctive treatment in patients with anxiety and sleep disturbance. Hormonal therapy: transdermal oestradiol had significantly reduced depression during the first month as compared with placebo (Larie et al 1998), but its effect is noted as modest by Gregoire et al (1996). Its usefulness for PPD is compromised by problems including potential endometrial hyperplasia, thromboembolism, and a diminished supply of breast milk. 7. Breastfeeding and drugs. Generally breast feeding is vigorously promoted, with 50% of mothers breastfeeding, so questions arise around the secretion of medications in breast milk (Misri et al 1991, Filer 1992). Studies suggested the use of amitriptyline, nortriptyline, desipramine, clomipramine, dothiepin or sertaline, as no reported adverse effects were reported in infants (Wisner et al 1985, Kemp et al 1985). Fluoxetine has been linked with irritability, sleep disturbance, poor feeding and colic in some infants exposed to it in breast milk, although other reports have not noted adverse incidents (Burt et al 2001). Imipramine, nortriptyline and sertraline are present in breast milk at low levels but citalopram and fluoxetine at relatively high levels. 8. Electroconvulsive therapy: rapid, safe, and effective for mothers with severe PPD, especially those with active suicidal ideation. 9. Psychotherapy: involves talking to a therapist, psychologist, or social worker to learn to change how depression makes you think, feel, and act. Interpersonal psychotherapy should be the first line of treatment for antepartum depression (Spinelli et al 2003). Interpersonal psychotherapy during pregnancy prevented PPD in 35 mothers with poor backgrounds (Zlotnick et al 2001) but psychotherapy, in addition to fluoxetine, did not improve outcomes more than fluoxetine alone (2001, Medical Economics). Mothers receiving interpersonal therapy were more likely to recover from their
depressive episode than mothers in the control group (Oâ&#x20AC;&#x2122;Hare et al 2000, Chabrol et al 2002). 10. Counselling: led to full recovery in 69% of the treatment group compared with 38% of the control group within three months of delivery (Holden et al 1989, Ray et al 2001) and in the intervention group (80%) compared with the control group (25%) (Wickberg et al 1996). But Cooper et al (2003) found that psychodynamic therapy produced a clinically significant reduction in depression compared with the control group at 4.5 months, and by nine months none of the treatments seemed superior to the control group. 11. Child-mother attachment: is very important and should be addressed appropriately. There should be parenting classes. 12.Physical exercise: has good evidence in reducing depression in the general population but little in PPD (Morgan et al 1987, Walker et al 2000). 13. Alternative therapies: bright light therapy, massage, acupuncture, aromatherapy, and relaxation techniques produce some improvements in PPD. St Johnâ&#x20AC;&#x2122;s wort (Hypericum perforatum) is also used without any clinical evidence of a potential for interactions with other prescription medicines (Briggs 1998). 14. Nutrition: a balanced diet may be a factor in preventing PPD, which should include omega3 fatty acids, protein, hydration, and vitamins. PREVENTION Early identification and intervention improves longterm prognoses for most mothers with PPD. Proper exercise and nutrition appears to play a role in preventing PPD, which should be considered after delivery for mothers who have experienced a previous episode of depression (Wisner et al 2001). Sufficient pain relief during delivery decreases the risk of PPD and the mode of pain relief during vaginal delivery seems to be associated with the incidence of PPD, especially immediately after delivery (Pauliina et al 2004). PROGNOSIS PPD may last more than six months in 30% to 50% of cases, and one in four affected mothers are still depressed on the childâ&#x20AC;&#x2122;s first birthday. Half of depressed mothers had not recovered by the end of MODER N MEDICINE
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review Table 8. Recommendations for mothers with PPD. •
Try to get as much rest as you can and get sleep when the baby is sleeping.
•
Be proud of your motherhood and enjoy it.
•
Stop putting pressure on yourself to do everything.
•
Ask for help with household chores and night-time feedings.
•
Talk to your partner, family, and friends about how you are feeling.
•
Do not spend a lot of time alone; try to spend time with your partner.
•
Talk with other mothers, so you can learn from their experiences.
•
Join a support group for mothers with PPD.
•
Don’t make any major life changes during pregnancy.
•
Talk to your health professional and seek help.
the first postpartum year (Cox et al 1984). Thirteen out of 101 mothers interviewed had marked PPD, but the majority of them did not receive any treatment for PPD (Cox et al 1982). Mental illness is also a significant factor in maternal mortality, and the UK Confidential Enquiry into Maternal Deaths (CEMD 2001) reported that psychiatric disorders contributed to 12% of all maternal deaths. Suicide is the second leading cause of maternal death in the UK, after cardiovascular disease, and is the main cause of maternal deaths in the first year postpartum, in the developed world (Howard 2006). CONCLUSION Postpartum mood disorder is highly prevalent during the childbearing years, with PPB being typically benign self-limited, while PPD and PPP cause significant distress and dysfunction. Despite the fact that it occurs in patients who have numerous contacts with medical professionals, PPD is frequently missed, and many mothers go without treatment. Untreated mood disorders place the mother at risk for recurrent disease, and PPD is associated with long-term cognitive, emotional, and behavioural problems in the child. National and international campaigns about PPD should be initiated on a yearly basis to increase public awareness, as well as awareness among health professionals in order to identify and manage it appropriately. Effective pharmacological 38 MODER N MEDICINE
and non-pharmacological therapies should be readily available to all family members.
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SLEEP DISTURBANCES AFTER ANAESTHESIA Dr Nadeem A Zaidi INTRODUCTION FCPS, FCARCSI Sleep, or a cycle of periodic activity/inactivity, is a Registrar, Anaesthesia normal physiological process. Department Dr Ellen Eileen Marnell FCARCSI Consultant Anaesthetist St Lukeâ&#x20AC;&#x2122;s Hospital, Kilkenny
General anaesthesia and surgery have a variable effect on normal sleep in the post-operative period. Both sleep architecture and total sleep time are affected. The clinical significance of all this is uncertain, and remains a debatable topic. This study highlights sleep disturbances after general anaesthesia and surgery in two groups of patients having surgery under general anaesthesia, either in the early hours or a later part of the day. METHODS Sleep disturbances in the post-operative period were assessed in two groups of adult patients (50 patients each) who underwent various elective general surgical or gynaecological procedures under general anaesthesia. Group A had surgery in the early hours of the day (before 1pm) while group B had surgery performed after 1pm. Patients were asked to answer various questions regarding sleep, for example: total sleep duration, quality of sleep (fragmented or disturbed sleep associated with frequent periods of awakening), daytime hangover and change in the pattern of sleep (daytime sleep with no sleep in the night) on the first, second, third, fourth and fifth postoperative day. Factors like pain, hospital atmosphere and disturbances were also examined. RESULTS In group A (surgery before 1pm) the first postoperative night was uneventful in 95% of patients. On the second post-operative night 75% of patients had a fragmented or disturbed sleep associated with frequent periods of awakening and daytime somnolence. On the third postoperative night about 54% of patients had a disturbed night associated with daytime sleep. Total sleep time increased on the fourth postoperative night (average 14 hours) in 84% of
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patients. Subsequently 98% of patients enjoyed their normal sleep routine. In group B (surgery after 1pm) the first postoperative night was uneventful in 98% of patients. On the second post-operative night 35% of patients had a fragmented or disturbed sleep associated with frequent periods of awakening and daytime somnolence. On the third postoperative night about 82% of patients had a disturbed night associated with daytime sleep. On the fourth post-operative night 48% had a fragmented sleep. Total sleep time increased on the fifth postoperative night (average 13 hours) in 82% of patients. Eighty per cent of patients enjoyed their normal sleep routine subsequently, while those remaining took one more night to return to routine. Pain and hospital atmosphere were the factors pointed out by the majority of patients resulting in sleep disturbance in the post-operative period in both groups. DISCUSSION General anaesthesia and surgery can have a profound effect on normal sleep in the postoperative period. Sleep architecture may be severely disrupted with frequent periods of disruption and awakenings. The mechanism of all this is unclear but may be related to a combination of factors including surgical stress and use of opioids in the perioperative period. Sleep is a normal physiological process associated with a state of reversible unconsciousness, decreased threshold of response to auditory stimuli and no response to visual stimuli; in other terms it is a state of functional blindness. Sleep, or a cycle of activity and inactivity, is present in all species although its exact function is still poorly understood. Apart from the fact that it is essential for well-being, other functions are attributed to sleep. Conservation of energy as body temperature and basal metabolic
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study rate (BMR) are reduced, compared with the awakestate. Another function sleep is associated with is the storage of long-term memory. Normal state of sleep is divided into two distinct states. These are non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM sleep is further divided into four stages. Stage 1 is the lightest while stage 4 is the deepest level of sleep. REM sleep is further subdivided into phasic and tonic phases. NREM and REM sleep follow a distinct pattern called the sleep cycle. In an adult the sleep cycle lasts for about 80 to 90 minutes, comprising NREM followed by REM sleep. These sleep cycles are separated by a period of awakening.1 Sleep is an actively initiated process, the periodicity of which is genetically determined and influenced by external factors like daylight, darkness, clock time, working hours and mealtime. Age has a major influence on the ratio of NREM to REM sleep, as well as on the total duration of sleep. Neonates generally sleep for 12 to 18 hours in 24 hours, with REM sleep accounting for 50% of sleep duration. Adults normally sleep for six to eight hours with REM sleep accounting for 15% to 20% of total sleep time. With increasing age, total sleep duration decreases, and sleep is more fragmented with longer awakening intervals.2 Both NREM and REM sleep are associated with typical patterns of electroencephalogram (EEG), electromyogram (EMG) and electrooculogram (EOG) activity. Moreover awakening from NREM sleep is associated with disorientation and slow response to stimuli. Return to sleep is easy and short arousal periods are rarely remembered while REM sleep is associated with normal wakening. Dreams associated with REM sleep are more structured and easy to recall compared with NREM sleep dreams.3 Although naturally occurring sleep and general anaesthesia both depress consciousness, distinct differences exist between the two states, as naturally occurring sleep is associated with characteristic physiological changes, regular pattern of sleep cycles and specific EEG changes.4 Numerous studies have been done to evaluate the effect of anaesthesia on subsequent sleep in the post-operative period. Following surgery sleep architecture is disturbed with a disproportionate reduction of REM and stage 3 to 4 of NREM sleep. Total duration of sleep is also reduced. At some stage in the first post-operative week there is
rebound firstly of total sleep time with mainly stage 2 of NREM sleep usually followed by rebound of REM sleep.5,6 Bromley demonstrated that patients coming to hospital for elective surgery sleep less than at home with more awakening periods but maintain the quality of sleep close to that they enjoy at home.7 Sleep disturbances have also been demonstrated in children in the post-operative period who underwent elective surgical procedures.8 Surgical stimuli is the main determinant of these changes. Other factors which contribute to this are: neuroendocrinal and psychological responses related to surgery and anaesthesia, and use of opioids and environmental factors such as light, noise and nursing activities. There may be considerable inter-individual variation in this regard, moreover timing of surgery (early or later parts of day) also has a variable effect on sleep in the postoperative period. The extent to which these changes influence morbidity and mortality in the post-operative period is unclear but there have been numerous speculations in this regard, for example postoperative increase in nocturnal hypoxaemia could be contributing to mental confusion, wound breakdown, myocardial infarction and stroke.5,9 Assessment of sleep in the post-operative period is difficult. Generally the patient is asked to complete a sleep questionnaire in the post-operative period, and an actigraph, a simple wristwatch-sized device, is used for the study of sleep.10 Some studies have used EEG recording for assessment of postoperative sleep.11 For sleep disorders like sleep apnoea, overnight polysomnography is used. We studied two groups of patients who underwent various elective general and gynaecological surgical procedures under general anaesthesia either in the early or later parts of day. On the first, second, third, fourth and fifth postoperative day patients were questioned regarding changes in sleep like total sleep duration, quality of sleep (fragmented or disturbed sleep associated with frequent periods of awakening), daytime hangover, and change in the pattern of sleep (daytime sleep with no sleep in the night). Associated factors like pain, hospital atmosphere and disturbances were also examined. In group A (surgery before 1pm) the second postoperative night was the most disturbed, with a return to normal pattern of sleep on the postMODER N MEDICINE
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operative night. In group B (surgery after 1 pm) the third post-operative night was the most disturbed. They took a longer period of time to return to their sleep routine. Hospital atmosphere and pain were the causative factors in majority of patients. The clinical significance of all this is uncertain, but a change in practice, like continuation of analgesic practice similar to the first post-operative night with subsequent night sedation, may be needed. This study highlights the problem of sleep disturbance in the post-operative period. It is difficult to reach a conclusion as many variables are involved, and more elaborate trials are needed. REFERENCES 1. Loadsman JA, Hillman DR. Anaesthesia and sleep apnoea. British Journal of Anaesthesia 2001; 86: 254-66. 2. Schupp M, Hanning CD. Physiology of sleep. Continuing education in anaesthesia, critical care and pain (CEACCP) June 2003; 3: 75-8. 3. Brandner B, Blagrove M. Dreams, images and emotions associated with propofol anaesthesia. Anaesthesia 1997; Aug 52 (8): 750-5. 4. Tung A, Mendelson WB. Anaesthesia and sleep. Sleep Med Rev 2004 Jun; 8 (3): 213-25. 5. Rosenberg J, Wilschiodtz G, Pedersen MH. Late post operative nocturnal episodic hypoxaemia and associated sleep pattern. British Journal of Anaesthesia 1994; 72: 145-50. 6. Rosenberg-Adamen S, Skarbye M. Sleep after laparoscopic cholecystectomy. British Journal of Anaesthesia 1996; 77: 572-75. 7. Bromley LM. Sleep quality following general anaesthesia. Anaesthesia 2003; 58: 1123-4. 8. Kein ZN, Maves LC, Caldwell-Anderson AA. Sleeping characteristics of children under going out patient elective surgery. Anesthesiology 2002; 97(5): 1093-101. 9. Rosenberg J, Ullstad T. Time course of post operative hypoxemia. European Journal of Surgery 1994; 160: 137-43. 10. Chambers MJ. Actigraphy and insomnia, a closer look. Part 1. Sleep 1994; 17: 405-8. 11. Edell-Gustafsson U, Hetta JE. Sleep and quality of life assessment in patients under going coronary bypass surgery. Journal of Advanced Nursing 1999; 29: 1213-20.
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MANAGEMENT OF ACUTE RECURRENT PULMONARY EMBOLISM IN PREGNANCY A 27-year-old woman was referred from the Emergency Department at 34 weeks and three daysâ&#x20AC;&#x2122; gestation with a history of severe shortness of breath gradually worsening over the preceding five days. She complained of chest pain two days prior to presentation, which eventually subsided. Her antenatal period was uneventful. There was no significant medical history except for a previous lower-segment Caesarian section (LSCS) for obstetric reasons. On examination, she appeared anxious, was sweaty, had severe shortness of breath and was tachycardic. Blood pressure was 100/62mmHg, oxygen saturation (SO 2) was low (84%), electrocardiogram (ECG) changes were consistent with acute pulmonary embolism (PE), arterial blood gasses revealed low PO2 and PCO2, and chest Xrays were normal. The patient was jointly reviewed by obstetric and medical teams and a diagnosis of PE was made clinically. She was treated with a therapeutic dose of low molecular weight heparin (LMWH). Saturation was maintained around 95% with 4l of humidified oxygen. She was stable with a good CTG. Leg Doppler was normal. A V/Q scan reported the
possibility of bilateral massive PE. Liver enzymes were elevated (Alt 528) on the third day of admission, still requiring 2 to 4l of oxygen. Echo showed signs of right heart strain and pulmonary hypertension. Her clinical condition stabilised over the next few days and the woman was discharged home on the 10th day of admission with LMWH. A plan was made for the induction of labour or for elective LSCS at around 38 to 39 weeks. The patient was induced with prostaglandin at 39 weeks and had elective forceps at full dilation after 12 hours of labour augmented with oxytocin under epidural analgesia. Oxygen saturation started to drop suddenly from the third postnatal day onwards, which necessitated high-flow oxygen to maintain saturation. The patient was transferred to the intensive care unit for persistent low saturation and was treated with intravenous heparin for recurrent PE. Repeat Doppler failed to show any thrombus on the pelvic vein and femoral veins. She was discharged home after 10 days in a stable clinical condition on a therapeutic dose of Clexane, although the possibility of vena-caval filter was discussed.
Dr Sabitabrata Sarkar Specialist Registrar Mr OA Adeyemi Consultant in Obstetrics Department of Obstetrics, Pilgrim Hospital, Boston, Lincolnshire, UK
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case report
GALLSTONE ILEUS INTRODUCTION Mechanical small bowel obstruction can be classified by cause into three main groups: 1. Intrinsic (e.g. adenocarcinoma, Crohn’s disease); 2. Extrinsic (adhesions, hernias, external masses); and 3. Intraluminal (foreign bodies, bezoars and, most importantly in terms of our discussion, gallstones).1 Cholelithiasis itself has a number of complications. The most common cases seen within clinical practice include acute cholecystitis, acute pancreatitis and cholangitis. Gallstone obstruction, or “gallstone ileus”, is one of a group of rare sequelae to cholecystitis, the others being Mirizzi syndrome and cholecystocholedochal fistula.2,3 Gallstone ileus is thought to account for 1% to 4% of all mechanical small bowel obstructions and can have a mortality rate of up to 18%.4 The high mortality rate is thought to be due to misdiagnosis and delays in diagnosis,5 perhaps because this form of ileus is seldom seen and is therefore not at the fore on the list of differentials. We here present a case of gallstone ileus followed by a discussion on the literature related to this uncommon condition. CASE REPORT A 56-year-old man presented to the Emergency Department with a four-day history of vomiting which included one episode of coffee ground vomitus. The patient also had generalised abdominal mild pain and constipation for two days. He had poorly controlled type 2 diabetes mellitus. On physical examination, the patient was dehydrated, his abdomen was soft and nontender, and there were infrequent weak bowel sounds with no palpable masses or organomegaly with no evidence of abdominal wall hernias or scars of previous abdominal operations. Digital rectal exam revealed hard stool in the rectum with a negative faecal occult blood test. His temperature was normal, blood urea was 20.6, creatinine 82.6 and his random blood glucose was
20.1. Plain film abdomen (PFA) revealed scattered non-significant small bowel fluid level with leftsided colon faecal impaction. The patient continued to vomit and a nasogastric tube was passed. Over the following admission day, the patient developed abdominal distension with absolute constipation. His abdominal girth began to increase and bowel sounds became tympanic. A computerised tomography (CT) scan of the abdomen showed dilated loops of small bowel with a zone of transition at the distal ileal loop. There was heterogeneous intraluminal mass surrounded by bowel oedema, interpreted as inspissated matter or foreign body ingested (see Figures 1 and 2).
Mr Ehab Mansour Surgery Department Dr Aoife Laffan Surgery Department Mr Walter Conway Surgery Department Dr Nagabathula Ramesh Radiology Department Midland Regional Hospital, Portlaoise, Co Laois
Figure 1.
Figure 2.
A midline exploration laparotomy was thus carried out and bowel loops were dilated with distal ileal loop collapse. At 1.2m from the ileocaecal valve a large (3.6 x 2.7cm; see Figure 3) impacted gallstone was discovered within the inflammatory mass of bowel loops surrounding the gallbladder. The area of impaction had a blackish, non-viable look, so it was safer to MODER N MEDICINE
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perform limited V-shaped small intestinal resection anastmosis of 15cm.
Figure 3.
No operative finding of fistula in the gut or gallstones by palpation could be detected. The pathology report documented small bowel jugenal loop intense inflammatory patches with focal necrosis going through the wall. This patient made an uneventful post-operative recovery. Seen three weeks later in the Outpatient Department, he had no complaint whatsoever and booked for ultrasonography (U/S) evaluation for biliary system and gastrograffin study for the gut to rule out fistulae. All investigations came back as normal. DISCUSSION Gallstones are a relatively common occurrence, with a reported prevalence of 10% to 12% in European populations.6,7,8 Only one-third of these are felt to be symptomatic, with the highest risk factors being the four we learnt in medical school: “fat, forty, fertile and female.”9 Recent studies have added a fifth “F” – “family history”, analysis indicating that having a first-degree relative with gallstone disease is a significant risk factor for developing cholelithiasis yourself.10 Gallstone disease can lead to one of a number of complications, which include acute cholecystitis, acute pancreatitis and acute cholangitis. Gallstone ileus is much less commonly encountered, but is nonetheless an important and significant complication to gallstones.2 It was in the mid-17th century when Bartolin first used the term “gallstone ileus”, which many today consider a misnomer for impaction by a gallstone leading to a true mechanical obstruction.11 The offending gallstone originates in the gallbladder and recurrent episodes of cholecystitis lead to chronic inflammation with adhesion of the gut to the gallbladder. The 48 MODER N MEDICINE
inflamed mucosa undergoes ischaemia with subsequent necrosis, and this allows the stone to slowly erode the tissue until a fistula forms between the gastrointestinal tract and the gallbladder.2,12 Once the fistula has formed, this allows the stone to pass freely into the gut. Most commonly, the fistulous communication is found in the region of the duodenum, but theoretically a fistula can form anywhere from the stomach to the colon.13 Our case here ended up having distal jejunal (proximal ileal) impaction that supports this theory. Although Ayantunde and Agrawal found that 86% of fistulae were cholecystoduodenal, the duodenum itself is a rare area for impaction of the stone.14 The size of the stone and the diameter of the lumen are the two main factors which determine whether or not a stone will cause obstruction. Rodriquez and Codina et al reported that a stone less than 2cm is unlikely to impact itself in the gut, but anything bigger than that (as in our case) can lead to obstruction.15 The terminal ileum is anatomically the narrowest part of the gastrointestinal system and it is therefore not surprising that it is here where the majority of impaction occurs. The ileocaecal valve is another common site with rarer obstruction occurring in the jejunum (like in our case), stomach and colon. Bouveret’s syndrome occurs when impaction of the duodenum leads to gastric outlet obstruction, again a rare entity.2,16,17 The clinical presentation of gallstone ileus can be vague. Most patients present with the symptoms of small bowel obstruction: abdominal pain, distension, nausea and vomiting. Our patient presented with vomiting and denied any history of abdominal pain. In hindsight, he reported one episode of severe upper abdominal pain months earlier for which he did not seek medical attention. Diagnosing gallstone ileus can be difficult and it is only with a high index of suspicion and concomitant radiological findings that one can be sure gallstone ileus is the cause of obstruction. Having said that, half of all cases are diagnosed at laparotomy.17 Plain abdominal radiographs show the classic Rigler’s sign, mechanical bowel obstruction, pneumobilia and an ectopic gallstone within the bowel in less than 50% of cases.18 Plain abdominal radiographs have a limited role
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because, unlike renal calculi, only 10% of all gallstones are sufficiently calcified to show themselves on film. In fact, a recent case report misdiagnosed a gallstone as faecal material on the initial X-ray.19 CT is increasingly the investigation of choice for bowel obstruction as it can readily determine the level and cause of obstruction. In gallstone ileus, CT allows direct visualisation of the fistula, the site and size of the stone.16,18 Management of gallstone ileus, as with any mechanical bowel obstruction, is surgical. There is no role for conservative management; once a stone becomes impacted, spontaneous passage is rare.20 The appropriate surgical procedure for gallstone ileus is still a matter of controversy. The main choices are a one-stage procedure, a twostage procedure or enterolithotomy alone. The one-stage procedure involves enterolithotomy, cholecystectomy and fistula repair. The two-stage procedure is identical, but with the cholecystectomy and fistula repair occurring four to six weeks after the initial enterolithotomy.21 Removal of the stone alone can predispose patients to complications related to not only the remaining gallbladder but also the persistent fistula, namely recurrent gallstone ileus; cholecystitis and cholangitis.20,22 However, Reisner and Cohen claim that cholecystectomy and fistula repair can be a technically difficult operation due to adhesions from chronic cholecystitis, with longer time spent in theatre and a higher mortality rate.17 They also report that recurrent gallstone ileus occurs in roughly 5% after simple enterolithotomy, but only 10% of these go on to require further surgery. Extracorporeal shock wave lithotripsy and endoscopic electrohyrdraulic lithotripsy have been suggested, but their use depends on the site of obstruction and should only be undertaken by experienced surgeons in highly selected patients.23 If a stone passes into the large bowel, an enema or colonoscopic removal can be attempted.24 Delays in the diagnosis of gallstone ileus, together with patient co-morbidities and the increasing age of Western populations, lead to a usually poor prognosis. A mortality rate of up to 18% has been reported.4 In conclusion, gallstone ileus is a rare cause of mechanical bowel obstruction. In patients with a
history of gallstones, gallstone ileus must be on the list of differentials. Plain abdominal radiographs do not always aid the diagnosis and a CT scan is the imaging technique of choice. The management of patients must be taken on an individual basis, taking into account physiological age and co-morbidities. Further randomised, controlled studies are needed to reach a decision on which surgical strategy is best when treating gallstone ileus. REFERENCES 1. Radiographic 2001; 21(3): 613-24. 2. Abou-Saif A, Al-Kawas FH. Complications of gallstone disease: Mirizzi syndrome, cholecystocholedochal fistula, and gallstone ileus. Am J Gastroenterol 2002; 97: 249-254. 3. Csendes A, Diaz JC, Burdiles P et al. Mirizzi syndrome and cholecystobiliary fistula: a unifying classification. Br J Surg 1989; 76: 1139-1143. 4. Doko M, Zovak M et al. Comparison of surgical treatments of gallstone ileus: preliminary report. World J Surg 2003; 27: 400-404. 5. Lobo DN, Jobling JC, Balfour TW. Gallstone ileus: diagnostic pitfalls and therapeutic successes. J Clin Gastroenterol 2000; 30: 72-76. 6. Barbara L, Sama C, Labate AMM et al. A population study on the prevalence of gallstone disease: the Sirmione study. Hepatology 1987; 7: 913. 7. Heaton KW, Braddon FE, Mountford RA et al. Symptomatic and silent gallstones in the community. Gut 1991; 32: 316. 8. Glambek I, Kvaale G, Arnesjø B et al. Prevalence of gallstones in a Norwegian population. Scand J Gastroenterol 1987; 22: 1089. 9. Egbert AM. Gallstone symptoms. Myth and reality. Postgrad Med 1991; 90(5): 119-126. 10. Nakeeb A, Comuzzie AG et al. Gallstones: genetics versus environment. Ann Surg 2002; 235(6): 842-849. 11. Zakir KM, Shlok B, Leslie HB. Colonic gallstones: a case report. Hepatobiliary Pancreat Dis Int 2007; 6: 324-325. 12. Lassandro F, Romano S, Ragozzino A et al. Role of helical CT in diagnosis of gallstone ileus and related conditions. AJR; 185: 1159-1165. 13. Pavlidis TE, Atmatzidis KS, Papaziogas BT et al. Management of gallstone ileus. J Hepatobiliary Pancreat Surg; 10: 299-302. 14. Ayantunde AA, Agrawal A. Gallstone ileus: diagnosis and management. World J Surg 2007; 31: 1292-1297. MODER N MEDICINE
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case report 15. Rodriguez Hermosa JI, Codina Cazador A et al. Gallstone ileus: results of analysis of a series of 40 patients. Gastroenterol Hepatol 2001; 24: 489-494. 16. Lassandro F, Gagliardi N, Scuderi M et al. Gallstone ileus analysis of radiological findings in 27 patients. Eur J Radiol 2004; 50: 23-29. 17. Reisner RM, Cohen JR. Gallstone ileus: a review of 1,001 reported cases. Am Surg 1994;60: 441-446. 18. Yu CY, Lin CC, Shyu RY et al. Value of CT in the diagnosis and management of gallstone ileus. World J Gastroenterol 2005; 11: 2142-2147. 19. Jen-Wei Chou, Chang-Hu Hsu et al. Gallstone ileus: Report of two cases and review of the literature. World Journal of Gastroenterology 2007; 28; 13(8): 821-825. 20. Clavien PA, Richon J, Burgan S et al. Gallstone ileus. Br J Surg 1990; 77: 737-742. 21. Zuegel N, Hehl A, Lindemann F, Witte J. Advantages of one-stage repair in cases of gallstone ileus. Hepatogastroenterology 1997; 44: 59-62. 22. Doogue MP, Choong CK, Frizelle FA. Recurrent gallstone ileus: underestimated. Aust NZ J Surg 1998; 68: 755-756. 23. Bourke MJ, Scheider DM, Herber GB. Electrohydraulic lithotripsy of a gallstone causing gallstone ileus. Gastrointest Endosc 1997; 45: 521-523. 24. Dumonceau JM, Delhaye M, Deviere J et al. Endoscopic treatment of gastric outlet obstruction caused by a gallstone (Bouveretâ&#x20AC;&#x2122;s syndrome) after extracorporeal shock-wave lithotripsy. Endoscopy 1997; 29: 319-321.
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CROSSWORD NO.137 2
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ACROSS 1. Muscle found in Cublic Epsilon (6) 4. Malaria in Prague (4)
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8. Which person is this TV doctor? (3) 9
8
9. Excited ally, hot in pursuit of fox, may shout this (7) 10. Basic unit of living organism finds room in prison (4) 11. Personal egg container (5)
10
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14. Would this little fellow be Happy or Grumpy? (5)
12
16. Prepare to put out with the turn of the tide (4) 13
18. Would a leperâ&#x20AC;&#x2122;s unscheduled return to his doctor be
14
due to this? (7)
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20. Illegal organisation has a difference to air! (3) 17
21. Sketched Ronnie? (4) 22. Though it rhymes with pharynx, it gives voice
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with a ... (6) DOWN 1. Cry loudly for a ball, we hear (4) 2. Acute infection of small intestine from leach or ingredients (7) 3. Broken plate is a bit of a bloomer (5) 5. Mr. Fawkes (3)
Name Address
6. My open confusion about one who gives his name to something (6) 7. Voice in a triumphal tone (4) 12. Hectic city aid leads to belly-ache! (7) 13. Dear, do change, beloved (6) 15. Dandies take part in infopsychology (4) 16. Colonic irrigation (5)
Entries should be sent to the Editor by 5th December 2008. Entries may be faxed to 01-678 0068 or posted to Modern Medicine, M&C Group Ltd. 7 Lower Fitzwilliam Street, Dublin 2, and should be marked for the attention of the Editor.
Congratulations to the winner of Crossword No. 136: Dr Fionnuala Toal, Cootehill, Co. Cavan
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17. Has such an islander got three legs but no tail? (4) 19. Fish coming back from southern river (3) Crossword No.136 - Answers
Across
Down
1. 7. 9. 10. 11. 13. 15. 16. 18. 21. 22. 23.
1. 2. 3. 4. 5. 8. 12. 13. 14. 17. 19. 20.
Inhaler Basic Flea Oklahoma Splint Pain Hive Bunion Alphabet Athy Andes Paisley
Anlke Bad apple Veto Oath Airmail Gluten Imbibe Prolapse Airline Three Heel Teat
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A bs trac t s fficacy and safety data from clinical trials has shown olmesartan medoxomil to provide effective and well-tolerated control of hypertension in elderly patients with either essential hypertension or isolated systolic hypertension. The appearance and progression of essential hypertension is associated with increasing age. Older patients also frequently have an abnormally elevated systolic blood pressure (SBP) [>140mmHg] without an elevated diastolic blood pressure (DBP) [<90mmHg], a phenomenon known as isolated systolic hypertension. Consequently, management of hypertension in elderly patients requires agents that can effectively treat isolated systolic hypertension as well as essential hypertension. The aim of this analysis was to assess the efficacy and safety of olmesartan medoxomil in elderly patients with either essential hypertension or isolated systolic hypertension. The efficacy of individually optimised doses of olmesartan medoxomil 20 or 40mg/day, with or without hydrochlorothiazide, in elderly patients (>65 years) was assessed in two separate randomised, double-blind studies. Researchers found that in patients with essential hypertension, 12 weeks of treatment reduced mean seDBP (primary efficacy parameter) by 17.9mmHg; mean seSBP was also significantly reduced. At study end (week 52), the proportion of diastolic responders (seDBP ≤90mmHg) was 93%. In patients with isolated systolic hypertension, mean seSBP was reduced by 30.0mmHg at week 12 (primary efficacy parameter); mean seDBP was only slightly reduced. At study end (week 24), the proportion of systolic responders (seSBP <135 mmHg) was 62.5%. Reductions in blood pressure (BP) were maintained throughout treatment in both patient populations. In each study, doubling the olmesartan medoxomil dose from 20 to 40mg/day or adding hydrochlorothiazide delivered additional BP-lowering efficacy without any tolerability concerns, and the Integrated Summary of Safety also showed that olmesartan medoxomil with or without hydrochlorothiazide was well tolerated.
Olmesartan medoxomil in elderly patients with essential or isolated systolic hypertension
ew research in China has found that metformin is safe in the treatment of elderly type 2 diabetes mellitus (T2DM) patients and that ageing is not a contraindication for metformin. The study by specialists at the Department of Elderly Endocrinology in the Chinese PLA General Hospital in Beijing evaluated the safety of metformin in the treatment of elderly T2DM over a 10-year period. Two-hundred and forty-three cases of elderly T2DM hospitalised from January 1996 to December 2006 were reviewed; the changes of fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), liver and renal function and blood lactic acid were evaluated before and after treatment. The mean time of treatment with metformin was (6.6 +/- 3.9) years (three months – 21 years) in these 243 cases. The study authors reported that the levels of FBG, PBG and HbA1c significantly reduced after treatment with metformin in 43 cases (17.7%), metformin combined with other oral hypoglycaemic drugs in 124 cases (51.0%) and metformin combined with insulin in 76 cases (31.3%). There were18.1% of the cases with normal range (>80ml/min) of creatinine clearance rate (Ccr), and 25.8% of the cases with Ccr ≤50ml/min. “The liver and renal function as well as the blood lactic acid had no significant change after treatment no matter in total cases or in different groups separated by Ccr,” they noted. The researchers recommended that for patients with high risk, doctors should monitor the level of blood lactic acid.
Safety of metformin in the treatment of elderly type 2 diabetes mellitus
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Drugs Aging 2009; 26(1): 61-76
Zhonghua Nei Ke Za Zhi 2008 Nov; 47(11): 914-8
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Phase III studies show that vandetanib (Zactima) brings clinical benefits to patients with lung cancer AstraZeneca has announced results from three phase III studies of Zactima (vandetanib) in combination with chemotherapy agents docetaxel (ZODIAC) and pemetrexed (ZEAL) and as monotherapy (ZEST) in non-small cell lung cancer (NSCLC). Results from the ZODIAC and ZEAL studies showed advantages for vandetanib in combination with chemotherapy, compared to chemotherapy alone. The addition of vandetanib to chemotherapy prolonged progression-free survival (PFS), the primary end point, which achieved statistical significance in the larger ZODIAC study, but not in the smaller ZEAL study. Clinical benefits were seen in secondary end points. Both studies showed that adding vandetanib to chemotherapy significantly improved objective response rate (ORR), which is a measurement of tumour shrinkage. Additionally, positive trends in prolongation of overall survival (OS) were seen, although these did not reach statistical significance. Importantly, the studies also showed that adding vandetanib to chemotherapy controlled the symptoms of lung cancer better than chemotherapy alone, allowing patients to maintain their quality of life for significantly longer. ZODIAC is a randomised, double-blind, placebocontrolled phase III study evaluating the combination of vandetanib 100mg with docetaxel versus docetaxel alone. The study enrolled 1,391 patients previously treated with one prior anti-cancer therapy for advanced NSCLC. ZEAL is a randomised, double-blind, placebo-controlled phase III study evaluating the combination of vandetanib
100mg with pemetrexed versus pemetrexed alone. The study enrolled 534 patients previously treated with one prior anti-cancer therapy for advanced NSCLC. ZEST, a randomised, double-blind, phase III study evaluating the efficacy of vandetanib 300mg versus erlotinib 150mg, did not meet the primary objective of demonstrating a statistically significant prolongation of PFS for vandetanib. However, vandetanib and erlotinib showed equivalent efficacy for PFS and OS in a pre-planned noninferiority analysis. The study enrolled 1,240 patients with locally advanced or metastatic NSCLC after failure of at least one prior anti-cancer therapy. The observed safety profile in these three phase III studies was consistent with previous studies with vandetanib in NSCLC. The most common adverse events associated with vandetanib included rash, diarrhoea and hypertension. John Patterson, Executive Director, Development, AstraZeneca, commented: “Non-small cell lung cancer is a truly debilitating disease. These studies have shown that vandetanib can offer clinical benefit to patients with lung cancer by extending the time a patient can live with their cancer under control, while managing symptoms and maintaining quality of life better than chemotherapy alone.” AstraZeneca plans to file a regulatory submission in the first half of 2009 following discussion with regulatory agencies. Full results from ZODIAC, ZEAL and ZEST will be presented at a forthcoming international medical congress. Vandetanib is also currently being investigated in another phase III monotherapy study in NSCLC (ZEPHYR) and in a number of other cancers, including thyroid cancer.
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New blood pressure educational booklet launched A new educational booklet for people with hypertension has been launched by MSD Ireland (Human Health). Your Guide to Blood Pressure contains vital information about the risks associated with hypertension, the key triggers and practical advice for lowering your blood pressure. Hypertension is one of the main causes of cardiovascular (CV) disease. Diseases of the CV system, including heart disease, stroke and related diseases, account for 43% of all deaths in Ireland. A recent Irish survey revealed that half the population over 50 suffers from hypertension and just onethird of these people are aware of their condition and are being treated. Hypertension is often known as the “silent killer” as most sufferers remain asymptomatic, yet it increases the risk of heart disease, kidney disease and stroke. Hypertension can affect almost all of the vital organs in the body. It is estimated that seven out of 10 people with hypertension do
not have their condition controlled to recommended levels. Your Guide to Blood Pressure explains the science of hypertension, risk factors for and symptoms of hypertension. Anne Copeland, Chairperson of the Volunteer Stroke Scheme, said: “Hypertension care and control are essential to ensure a healthy heart. Making changes to your diet and lifestyle can help to lower blood pressure and in turn significantly reduce the risk of stroke and heart attacks. This educational booklet is an excellent source of information for anyone with an interest in improving their heart health.” Your Guide to Blood Pressure will be made available through Age Action Ireland stores nationwide and distributed by the Volunteer Stroke Scheme and MSD Ireland (Human Health) sales representatives. Alternatively you may order copies by contacting Orla Barnewell on 01299 8708.
Studies confirm benefits of oestradiol-based oral contraceptive A truly novel oral contraceptive providing body-identical oestrogen (oestradiol valerate) has been found to be effective, well tolerated and associated with a high level of user satisfaction. This data was presented at the 11th World Congress on Controversies in Obstetrics, Gynaecology and Infertility (COGI). The study evaluated 1,377 women from three European countries (Germany, Austria and Spain) between the ages of 18 and 50 who received oestradiol valerate/dienogest over 20 28day cycles and showed an adjusted Pearl Index figure of 0.34 (upper limit of 95% CI=0.73). Treatment was well tolerated and associated with a generally well controlled and regular bleeding pattern. Most women (nearly 80%) receiving oestradiol valerate/dienogest said that they were either very satisfied or satisfied with the treatment. In addition to this data, a second study presented at COGI has shown a trend for oestradiol valerate/dienogest to have a positive metabolic effect, demonstrating a more favourable impact on lipid profiles. “This data provides convincing results to support the efficacy
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and tolerability of oestradiol valerate/dienogest,” commented investigator Dr Santiago Palacios, Director of the Palacios Institute of Woman’s Health. “Oestradiol valerate/dienogest represents an innovation in oral contraception; this is the first time that body-identical oestrogen has provided the basis for an oral contraceptive.” According to Bayer Schering Pharma’s Medical Director Brona O’Neill, “oestradiol valerate/dienogest is the first in a new class of oral contraception to provide the same oestrogen as that produced by the female body. Up to now, efforts to use oestradiol in oral contraception have failed to achieve a satisfactory level of bleeding control. Oestradiol valerate/dienogest is the first to achieve this through the combination of oestradiol valerate and an optimal endometrial-focused progestin, dienogest, delivered through a dosing regimen, which works in harmony with a woman’s biology.” Bayer Schering Pharma AG successfully completed the decentralised drug approval procedure in Europe for oestradiol valerate/dienogest in October 2008.
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Cimzia studies show significant clinical benefits for mono- and combination therapy in patients with rheumatoid arthritis UCB has announced the results of two phase III studies, published in the Annals of the Rheumatic Diseases Online recently, showing Cimzia (certolizumab pegol), the only PEGylated anti-TNFα (tumour necrosis factor alpha), provided significant clinical benefits as monotherapy, and in combination with methotrexate, in adults with active rheumatoid arthritis (RA). The six-month FAST 4WARD study met primary and secondary end points, and showed that 400 mg certolizumab pegol, given every four weeks as subcutaneous monotherapy, significantly reduced signs, symptoms and pain associated with RA, and improved physical function, compared to patients treated with placebo (p<0.001). “The positive outcomes of the FAST 4WARD study are exciting and demonstrate the potential for certolizumab pegol as a future therapy dosed every four weeks for patients with rheumatoid arthritis. While the RAPID studies have shown the benefits of certolizumab pegol as combination therapy, this is the first phase III trial to show a clinical benefit as monotherapy which becomes important when patients must discontinue treatment due to tolerability issues with conventional treatments, or have contraindications.” said Professor Roy Fleischmann, University of Texas Southwestern Medical Center, Dallas, US. Meeting the primary end point, patients treated with certolizumab pegol demonstrated significantly superior ACR20 response rates at week 24 versus those on placebo (p<0.001: 45.5% versus 9.3%). The response to treatment was rapid and significant with more than one-third (36.7%) of patients on certolizumab pegol achieving an ACR20 response as early as week one of treatment, compared to less than 10% on placebo (p<0.05), which was sustained throughout the study. Patients on certolizumab pegol also reported clinically significant improvements in physical function (HAQ-DI) from week 1 through to week 24, relative to placebo (p<0.001), consistent with significantly reduced pain scores (VAS) and disease activity (DAS28-3) (p<0.001). In the study, serious adverse events (SAEs) occurred in 2.8% and 7.2% of patients in the placebo and the certolizumab pegol groups, respectively. Reported SAEs included infections and benign tumours. The majority of AEs reported in both treatment groups were mild to moderate. The most commonly occurring AEs were headache, nasopharyngitis, and upper respiratory tract infections, diarrhoea and sinusitis. The incidence of injection site pain (1.8%) and discontinuations due to AEs (4.5%) were low in the certolizumab pegol group. A second six-month study called RAPID 2 showed that treatment with certolizumab pegol, together with methotrexate
(MTX), significantly improved the clinical signs and symptoms of RA, inhibited progression of disease, and improved physical function in adult patients with active disease. “The RAPID 2 study is important in demonstrating the benefits of certolizumab pegol in reducing the pain and symptoms of rheumatoid arthritis, and in helping to prevent joint damage associated with this debilitating condition in patients with active disease,” said lead author Professor Josef Smolen, Division of Rheumatology, Medical University of Vienna. In the RAPID 2 study, patients were randomly allocated to receive one of three treatment regimens: certolizumab pegol 400 mg at weeks zero, two and four, then 200 mg every two weeks (200mg); certolizumab pegol 400 mg every two weeks (400 mg); or placebo every two weeks, together with MTX. In RAPID 2, patients treated with Cimzia (200 mg or 400 mg), together with MTX, showed significantly superior ACR20 responses as early as week one, compared to patients treated with placebo and MTX (p<0.01), which were sustained throughout the study (p<0.001). Patients in both certolizumab pegol treatment arms reported clinically significant improvements in physical function (HAQ-DI) from week one, compared to placebo versus MTX, with improvements in quality of life sustained up to week 24 (p<0.001). In addition, certolizumab pegol, inhibited progression of structural joint damage, with significantly smaller mean change from baseline in modified total sharp score (TSS) at week 24, compared to MTX alone (p<0.001). There were no statistically significant differences in clinical efficacy on primary or secondary end points between the 200 mg and 400 mg certolizumab pegol treatment arms. The simultaneous studies, RAPID 2 and RAPID 1, are the first large, placebo-controlled phase III trials demonstrating the efficacy and tolerability of certolizumab pegol in the treatment of RA, as part of clinical trials programme involving more than 2,300 patients. Pooled safety data from both studies showed that the incidence of injection site pain (n=<3 new cases /100 patient years) and discontinuations due to adverse events (AEs) were low in the certolizumab pegol group. The US Food and Drug Administration (FDA) accepted a Biologics License Application for Cimzia for the treatment of adult patients with active RA in February 2008. UCB submitted a Marketing Authorisation Application to the European Medicines Agency in June 2008 requesting the approval of Cimzia as a subcutaneous treatment for adults with moderate to severe active RA.
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Crestor demonstrates dramatic CV risk reduction in a large statin outcomes study New data from the JUPITER study demonstrated that Crestor (rosuvastatin calcium) 20mg significantly reduced major cardiovascular (CV) events (defined in this study as the combined risk of myocardial infarction, stroke, arterial revascularisation, hospitalisation for unstable angina, or death from CV causes) by a dramatic 44% compared to placebo (p<0.001) among men and women with elevated hsCRP but low to normal cholesterol levels. Results also showed that for patients in the trial taking rosuvastatin: • The combined risk of heart attack, stroke or CV death was reduced by nearly half (47%, p<0.001); • Risk of heart attack was cut by more than half (54%, p<0.001); • Risk of stroke was cut by nearly half (48%, p=0.002); • Total mortality was significantly reduced by 20% (p=0.02). These results were accompanied by a median LDL-C reduction of 50% (p<0.001) resulting in an on-treatment median LDL-C of 1.4mmol/l. On the basis of the data, if the results are projected over a period of five years, 25 patients would need to be treated to prevent one major cardiovascular event (NNT=25). The JUPITER results were presented at the American Heart Association Scientific Sessions and were simultaneously published online by the New England Journal of Medicine.
“These results provide new information about Crestor’s effects on CV risk. The JUPITER trial confirmed that Crestor dramatically reduces LDL-C cholesterol levels and has now demonstrated a nearly 50% reduction in the risk of heart attack and stroke in a population of patients who had elevated hsCRP but low to normal cholesterol levels,” said Howard Hutchinson, Chief Medical Officer for AstraZeneca. “As is appropriate, the medical community, regulators, and guideline committees will now carefully consider these data and any implications for treating patients.” As previously guided, AstraZeneca expects to file a regulatory submission including the JUPITER data in the first half of 2009 and, if approved, will begin promotional activities within the approved labelling. Rosuvastatin is not indicated for the prevention of cardiovascular events. Rosuvastatin should be used according to the prescribing information, which contains recommendations for initiating and titrating therapy according to the individual patient profile. In Ireland, the usual recommended starting dose of rosuvastatin is 5mg or 10mg. Rosuvastatin 20mg was well tolerated in nearly 9,000 patients during the course of the study. There was no difference between treatment groups for major adverse events, including cancer or myopathy. There was a small increase in physician-reported diabetes consistent with data from other large placebo-controlled statin trials.
Rowex discontinuation of Valproat 300mg & 500mg prolonged-release tablets x 100’s Rowex Ltd wishes to announce its intention to discontinue Valproat 300mg and 500mg prolonged-release tablets x 100’s once existing stock is depleted. The expiry date of the last batch of the 300mg is September 2009 and the 500mg is
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November 2009. Further information is available from Rowex Ltd, Newtown, Bantry, Co Cork. Freephone 1800 304 400; telephone 027-50077; fax 027-50417; or e-mail rowex@rowapharma.ie.
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Irish companies first in Europe to receive coveted EuroRec seal 2008 The Health Informatics Society of Ireland (HISI) is proud to announce that Ireland has staked claim to the first recipients of the EuroRec Quality Label 2008 for electronic healthcare records systems (EHRs). As electronic health records continue to become increasingly entrenched in healthcare and ever more complex, the development of quality-assured advanced systems has become critical. Introduced last year, the EuroRec seal is a European-wide quality certification for advanced EHRs. The EuroRec seal validates the design, product quality, data portability and interoperability of EHRs. “In addition to recognising a quality standard in electronic healthcare records systems, the EuroRec seal will contribute to the future adoption of high-quality and more interoperable EHRs,” said Gerard Hurl, Chairman of the Health Informatics Society of Ireland. “This certification mitigates the risk for all stakeholders from policy makers to health authorities and ultimately the patient,” added Hurl. This is the first time in Europe that companies have been granted the EuroRec seal since its introduction. The recipients are: • CompleteGP, version 2.1 of Eircom, Cork;
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Health One, version 6 of Health Ireland Partners, Arklow; Helix Practice Manager, version 1 of Helix Health, Dublin; Socrates, version 1.5 of Technical Ideas.com, Ballinode.
The EUROREC Institute (www.Eurorec.org) is an independent not-for-profit organisation, promoting the use of high-quality EHRs in Europe. EuroRec is organised as a permanent network of National ProRec centres and ProrecIReland, founded by HISI, is Ireland’s national centre. As the European authorised certification body, it has been funded by the EU to create an efficient, credible and sustainable mechanism for the certification of EHR systems in Europe. HISI is affiliated to the Irish Computer Society and incorporates the Healthcare Informatics section of the Royal Academy of Medicine in Ireland and is concerned with promoting, supporting and developing the skills and knowledge base in health informatics in Ireland. There are currently 719 HISI members, drawn from information technology, medicine, nursing and other professions allied to medicine including education, government and industry. For further information, visit www.hisi.ie.
Ipsen expands its short-stature product portfolio
Ipsen Pharmaceuticals Limited has expanded its shortstature treatment portfolio with the launch of Increlex (mecasermin), a recombinant DNA-derived human insulinlike growth factor-1 (IGF-1). Increlex is the first and only product licensed in Europe for the long-term treatment of growth failure in children and adolescents with severe primary insulin-like growth factor-1 deficiency (IGFD). Severe primary IGFD is a complex condition where children’s IGF-1 levels are low, despite the presence of normal or elevated growth hormone (GH) levels. Without adequate IGF-1 these children cannot achieve normal height. Severe primary IGFD is defined in the licence approval by several key factors: • Height standard deviation scores <–3.0;
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Basal IGF-1 levels below the 2.5th percentile for age and gender; GH sufficiency; Exclusion of the secondary forms of IGF-1 deficiency, such as malnutrition, hypothyroidism, or chronic treatment with pharmacological doses of antiinflammatory steroids. An IGF-1 generation test can be used to confirm diagnosis. Ipsen’s short-stature treatment portfolio also includes NutropinAq, a liquid formulation of somatropin (recombinant DNA origin, Escherichia coli) for the treatment of growth hormone deficiency in adults and children, Turner syndrome and chronic renal insufficiency. Increlex is available in a 10mg/ml solution for injection. For further information please contact Ipsen Pharmaceuticals Limited, Phone: 01-668 1377, Fax: 01-660 2818, E-mail: info@ipsen.ie.
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Rasilez ASPIRE HIGHER clinical programme expands to 35,000 patients in 14 trials Novartis has announced details of two new long-term outcome studies in its landmark ASPIRE HIGHER clinical trial programme which has expanded to involve more than 35,000 patients in 14 trials. The series of trials that comprise ASPIRE HIGHER now form the largest and most far-reaching cardio-renal outcomes programme worldwide. The newly-launched studies will evaluate the organ protection potential of the first-in-class direct renin inhibitor Rasilez, for the treatment of heart failure and prevention of cardiovascular disease in the elderly, a patient segment that is predicted to grow. A third megatrial already under way is studying cardio-renal outcomes in diabetes. High blood pressure is a sign that many organs in the body could be under threat. Rasilez works by directly inhibiting renin, an enzyme that triggers a process leading to high blood pressure and organ damage. One-quarter of the world’s population, or approximately one billion people, are now affected by high blood pressure. This figure is projected to rise to 1.56 billion by 2025, a 60% increase over the current figure. “Patients with hypertension, diabetes, kidney disease and heart failure continue to experience adverse clinical events despite current best treatment,” said Professor John McMurray of the British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Scotland. “The ASPIRE HIGHER programme of clinical trials aims to build upon exciting proof-ofconcept studies with aliskiren to evaluate the role of this new agent in reducing morbidity and mortality in these very common and important disease states.” The ASPIRE HIGHER clinical programme includes three major outcome studies:
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ALTITUDE will determine whether Rasilez, added to conventional therapy, delays heart and kidney complications in around 8,600 patients with type 2 diabetes at high risk for cardiovascular and renal events. The study began in late 2007 with completion anticipated by 2012. ATMOSPHERE will evaluate the effects of Rasilez on cardiovascular morbidity and mortality in patients with acute and chronic congestive heart failure on top of standard therapy. APOLLO will assess the effectiveness of Rasilez in preventing cardiovascular morbidity and mortality in elderly patients with or without high blood pressure and other risk factors.
In addition to these megatrials, the ASPIRE HIGHER programme includes a comprehensive range of short-to-medium term studies to assess the potential organ protection benefits of Rasilez across a broad range of cardio-renal conditions including heart failure, post-acute coronary syndromes, post-myocardial infarction, left ventricular hypertrophy, coronary artery disease and diabetic nephropathy. Other studies are designed to further confirm the powerful blood pressure lowering effect of Rasilez. “ASPIRE HIGHER represents a major commitment to investigating this innovative therapy that can help physicians and patients better manage high blood pressure and its damaging effects,” said Trevor Mundel, MD, Head of Global Development Functions at Novartis Pharma AG. “Data already reported from the programme have shown the potential for Rasilez to protect organs such as the heart and kidneys. We look forward to the results of these additional long-term outcome studies that we hope will demonstrate the benefits of Rasilez independent of its powerful blood pressure reductions.”
Rowex announces launch of Vedixal Rowex Ltd has announced the launch of Vedixal tablets and Vedixal XL prolonged release capsules. Vedixal tablets and Vedixal XL prolonged release capsules are indicated for major depressive episodes. Vedixal tablets and Vedixal XL prolonged release capsules pricing details are as follows: • Vedixal 37.5mg tablets x 56’s: €21.26 • Vedixal 75mg tablets x 56’s: €35.45 • Vedixal XL 37.5mg prolonged release capsules: €3.58
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Vedixal XL 75mg prolonged release capsules: €20.55 Vedixal XL 150mg prolonged release capsules: €34.65.
This presentation is fully reimbursable under the GMS. The brand leader is 39% more expensive than Vedixal tablets and Vedixal XL prolonged release capsules, according to Rowex. For further information contact Rowex Ltd, Bantry, Co Cork. Freephone 1800 304 400, e-mail rowex@rowa-pharma.ie.
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Tapentadol immediate-release tablets approved for the treatment of moderate-to-severe pain by FDA German pain expert Grünenthal GmbH has announced that the US Food and Drug Administration (FDA) has approved tapentadol immediate-release tablets for the relief of moderate to severe acute pain for adults 18 years and older. The New Drug Application (NDA) had been submitted to the FDA by Grünenthal’s partner for developing and commercialising tapentadol in the US, Canada, and Japan, Johnson & Johnson Pharmaceutical Research & Development, LLC (J&JPRD), on January 23, 2008. Tapentadol is an oral centrally acting analgesic and will be the first new substance in its class for more than 25 years after successful registration. In the European Union, tapentadol is currently in phase III of the development programme for severe acute and chronic pain. Grünenthal plans the submission in Europe in the second quarter of 2009. The FDA approval was based on data from clinical studies involving more than 2,100 patients and showed that
tapentadol provided significant relief of moderate-to-severe acute pain compared to placebo. “Tapentadol represents a great success of the cooperation between Grünenthal and J&JPRD. Tapentadol is a major milestone in Grünenthal’s ambition to be one of the world leaders in providing patients suffering from pain with better therapeutic answers,” said Professor Pâques, Member of the Executive Board of Grünenthal. “Tapentadol is one of several exciting compounds we have in our pipeline.” Grünenthal is preparing the submission of tapentadol IR to regulatory authorities in Europe, Mexico, and South America. In the United States an NDA was submitted to the FDA for tapentadol immediate-release (IR) tablets by Grünenthal’s partner Johnson & Johnson Pharmaceutical Research & Development, LLC (J&JPRD) and has been approved by the FDA in November 2008. For more information visit www.grunenthal.com.
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Vimpat approved in Europe UCB (Pharma) Ireland has announced that the European Commission (EC) has approved Vimpat (lacosamide) as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older. Vimpat is the first new antiepileptic drug (AED) for partial-onset seizures in three years and offers a new treatment option for European patients living with uncontrolled partial-onset epilepsy. Professor Elinor Ben-Menachem, Clinical Trial Investigator, Department of Clinical Neuroscience, Goteborg University, Sweden, said: “Vimpat offers new hope for improved seizure control in adult patients with partial onset seizures. The novel mode of action of Vimpat makes it different from all other antiepileptic drugs currently available. Vimpat should be considered a valuable treatment option for adult patients with partial-onset seizures who need additional seizure control.” Roch Doliveux, Chief Executive Officer, UCB said: “The approval of Vimpat underscores the importance of UCB’s continued drive to develop innovative medicines that improve lives. UCB is pleased to make this important new antiepileptic drug available to European physicians and patients.” Preclinical studies indicate that Vimpat has a novel mode of action. While the precise mechanism by which Vimpat exerts its antiepileptic effect in humans remains to be fully elucidated, in preclinical studies Vimpat has been shown to modulate sodium channel activity differently compared with other sodium channel blocking AEDs. Sodium channels play a crucial role in regulating the activity of the nervous system to help nerve cells communicate. Sometimes sodium channels become abnormally overactive which may produce a seizure. Vimpat’s mode of action is thought to reduce this sodium channel overactivity. The regulation of the activity of nerve cells may contribute to the control of seizures. Preclinical studies also suggest that Vimpat binds to the collapsin response mediator protein-2 (CRMP-2), a phosphoprotein which is mainly expressed in the nervous
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system and is involved in neuronal differentiation and control of axonal outgrowth. The nature of the interaction between Vimpat and CRMP-2 is not completely known. Vimpat is the only AED known to interact with CRMP-2. The EC approval is based on data from three multicentre, randomised, placebo-controlled clinical trials that evaluated the efficacy and safety of Vimpat adjunctive treatment in over 1,300 partial-onset seizure patients aged 16 years and older who were not adequately controlled with between one to three concomitant AEDs and with or without additional vagus nerve stimulation. Patients entering these trials were experiencing on average 10 to 15 seizures per month and most patients (84%) were uncontrolled on two to three AEDs. In clinical trials Vimpat improved seizure control when added to a wide range of first and second-generation AEDs drugs. Pooled analysis shows that treatment with Vimpat 200 mg/day and 400 mg/day reduced seizures by half in 34% and 40% of patients with partial-onset seizures, respectively, compared with 23% in the placebo group. Vimpat was generally well tolerated with the most common adverse events (>10% and greater than placebo) reported in these trials including dizziness, headache, nausea and diplopia. In a long-term study, patients treated with Vimpat achieved sustained reductions in partial-onset seizures. Seventy-seven per cent of 370 patients who took part in this open-label trial completed at least 12 months of Vimpat treatment, 61% completed at least 24 months, and 56% completed at least 30 months of treatment. Vimpat has been approved as oral tablet (50mg, 100mg, 150mg, 200mg), oral syrup (15mg/ml) and solution for infusion (10mg/ml), to allow for additional dosage formulation options. Vimpat solution for infusion is an alternative for patients when oral administration is temporarily not feasible. For more information please contact Ms Emma Lynch on 01463 7395.