Neurology

Back pain is very common; it has a point prevalence of 25% and is the third most common reason for consultation in Australian general practice. A thorough history and examination can identify the minority of patients who require urgent neuroimaging or other targeted investigations. Careful correlation of clinical and radiological findings is required when abnormal neurological findings are detected. Radiological investigations may detect abnormalities at multiple levels but cannot confirm which level is primarily responsible for a patient’s symptoms. A trial of conservative treatment is appropriate, even in cases of radiculopathy. Most patients with an acute episode of back pain recover within 6–12 weeks, but at least a third go on to have a recurrent episode within 1 year. Various invasive treatments, such as transforaminal steroid injection and discectomy, may speed up recovery from radiculopathy, but the long-term benefits of invasive treatment are uncertain.

Timothy J Kleinig MB BS(Hons), FRACP, PhD · Brian P Brophy MB BS, FRACS · Chris G Maher BAppSc(Phty), PhD

Fast facts: brain tumours. 2nd ed. Lauren E Abrey, Warren P Mason. Oxford: Health Press, 2011 (143 pp, $19.50). ISBN 9781905832873. Brain tumours are the cause of the greatest loss of life-years per person from any cancer, but account for only 2% of all cancers. The first Australian Guidelines were published only in 2009. There is overwhelming consensus that brain tumours should be managed by a dedicated multidisciplinary team of neurosurgeons, medical and radiation oncologists, and nursing, social work rehabilitation and palliative care specialists. It is not clear who needs Fast facts. The authors, a neurologist and medical oncologist from major oncology centres in North America, have written it in a style that is only suitable for clinicians. Specialists will not find much that is new. Allied health practitioners new to neuro-oncology and medical students may be interested in a concise précis of current practice for the modest price of $20 but may prefer the Australian Guidelines, which are more detailed and are available for free from the Cancer Council Australia website. A version of the guidelines has been written for patients and carers. Fast facts discusses epidemiology, diagnosis and treatment and includes chapters on the more common types of brain tumours; however, rehabilitation, palliative care and supportive care are not covered. Brain tumour patients are rarely fit to drive, yet this important restriction is not mentioned. Older people are frequently undertreated because of concerns about their prognosis. The authors recommend treatment strategies based on the fitness of the patient rather than their age. The standard of illustration is good with many images of a wide range of clinical conditions. Brachytherapy, a disproved technique, is illustrated but radiosurgery is not. References are lacking but further reading is given at the end of each chapter, although some of the readings are over a decade old. The management of brain tumours should not be in the hands of those who need to fill gaps in knowledge “fast”. It is a complex and difficult area best managed by expert multidisciplinary teams.

Michael B Barton

Carpal tunnel syndrome, resulting from median nerve compression at the wrist, is a common and often disabling mononeuropathy. Risk factors include female sex, family history, repetitive hand use, obesity, pregnancy and a variety of medical comorbidities including diabetes mellitus, rheumatoid arthritis, and other connective tissue diseases. In many cases, an accurate diagnosis can be reached on the basis of clinical history and supportive examination findings alone. Neurophysiological investigations are essential for confirming the diagnosis, assessing severity and excluding more generalised neuropathies, as well as providing a baseline preoperative index of median nerve function. Wrist splinting and local corticosteroid injection are effective treatments in the short term, but long-term data are lacking. Surgical (endoscopic or open) carpal tunnel release is effective and nearly always required to enable a return to work for patients with occupationally induced carpal tunnel syndrome.

Marion A Simpson MB ChB(Hons), MRCP(UK) · Bruce Day MB BS, FRACP

A practical guide to common and important problems in clinical neurology It has been a long-held perception that neurology is a descriptive discipline, limited to careful diagnostic assessment but offering few therapeutic options for the care of patients, who are generally the responsibility of other medical practitioners. To some extent, these testaments hold true today: there has been distressingly little progress in the treatment of common and disabling neurodegenerative diseases — in particular, Alzheimer’s disease and motor neurone disease — despite tantalising clues to their aetiology. Major gaps remain in the availability of comprehensive specialist services, such as acute-care stroke units, despite nearly two decades of evidence from randomised trials supporting the benefit of such models of service delivery. However, considerable advances in many areas have transformed neurology into a very active discipline. For example, although the initiating factors for multiple sclerosis remain hidden, knowledge of the pathophysiological mechanisms has enabled development of treatments that target specific aspects of the immune system. The prognosis for young adults diagnosed with this chronic disease is, therefore, much more optimistic than it has been in the past. The development of sophisticated imaging technologies has radically increased the diagnostic certainty of a wide range of neurological conditions. Where neurologists once had to incrementally improve their diagnostic certainty by doing postmortem examinations months or years after a clinical encounter, there is now a range of investigations that can be used to determine the location and pathophysiological basis of lesions during life. This gives us a window of time during which therapeutic intervention may reverse an underlying process. The improvement in imaging techniques such as computed tomography, magnetic resonance imaging and ultrasound has dispelled much of the mystery of the neurological examination. Clinical neurophysiology, once a laboratory curiosity, is now widely available as the standard procedure to reliably diagnose nerve injuries and muscle disease. This technology has also enabled better use of surgical and medical therapies for conditions such as carpal tunnel syndrome, radiculopathies, and inflammatory myopathies and neuropathies. On a background of advances in neuroscience and neuroimaging has come enormous growth in the availability of therapeutic compounds. The pharmacology of neuroscience probably had its birth in the development of combination levodopa and dopa-decarboxylase inhibitor therapy for Parkinson’s disease in the 1960s. This was the first specifically targeted neuropharmacological treatment and heralded the subsequent arrival of a range of compounds that target specific receptors in the nervous system. In addition, recently developed high-potency biological compounds such as monoclonal antibodies offer the potential for unprecedented levels of efficacy, but those which target specific receptors in the immune system carry the risk of catastrophic side effects such as fatal opportunistic infection. The complexity of available therapies has meant that both doctors and patients need to be well informed to make appropriate management decisions. The unsung heroes of neurological therapies are epidemiological studies and clinical trials — these have formed an evidence base for practice that goes beyond knowledge derived from biological rationale, case series analyses and pattern recognition. Until recently, for example, every stroke admission provoked an arcane discussion about the role of heparin and/or aspirin, and other interventions to “thin the blood”. It took large, well controlled studies to show that the risks of such therapies, other than aspirin, outweighed any potential benefits in the acute-care setting. Similarly, such studies have debunked neurological dogma over the hazards of blood-pressure lowering in acute stroke and have established that such therapy is the most efficacious medical treatment for improving long-term outcomes. Large-scale clinical trials are usually funded by pharmaceutical companies, yet important questions have been, and will continue to be, solved by academics who work in collaboration and use public funding. Given that governments spend so much on health care, often with poor supporting evidence for how it should be best spent and monitored, the level of funding for such studies, and medical research in general, is parsimonious. Practical neurology is a series of articles that examine common and important problems in clinical neurology in the context of advances in basic neuroscience and neurological investigations. The quality of evidence that supports the available therapeutic options (see Box) is also included. Despite the advances in this discipline, neurology remains one of the bastions of clinical medicine, where simple but finely tuned bedside skills can readily establish a diagnosis, prognosis and management plan. The cases presented in this series therefore emphasise key aspects of patient history and clinical signs, which are still the most cost-effective way of establishing a neurological diagnosis and making management decisions. Grading system for recommendations in Practical neurology* Grade A: “Excellent” — evidence from large randomised controlled trials (RCTs), or systematic reviews with meta-analyses of multiple RCTs Grade B: “Good” — one or more RCTs with limitations, or high-quality and persuasive non-randomised cohort studies Grade C: “Satisfactory or poor” — non-randomised case series and opinions of experts * Adapted from the National Health and Medical Research Council.1

Leo Davies MB BS, MD, FRACP · Craig S Anderson MB BS, PhD, FRACP

Subacute unilateral visual impairment accompanied by pain on eye movement is characteristic of optic neuritis. Most cases of optic neuritis resolve spontaneously, and acute treatment with intravenous steroids hastens recovery but does not alter the ultimate visual outcome. Brain magnetic resonance imaging (MRI) may permit a diagnosis of multiple sclerosis (MS) to be made after a single clinical demyelinating event such as optic neuritis. Current evidence supports the introduction of disease-modifying therapy in patients with a single clinical event such as optic neuritis and brain MRI compatible with MS. The diagnosis of MS is a confronting life event associated with significant personal, social and financial burdens. The diagnosing neurologist should provide a detailed explanation of the disease and its clinical spectrum and introduce the patient to the wide range of support services, educational material and MS clinics.

Michael H Barnett MB BS, PhD, FRACP · Gurjit Chohan MB ChB · Leo Davies MB BS, MD, FRACP

A 35-year-old man sent us this self-portrait, taken with a digital camera, showing significant asymmetric flushing on the left side of his face after jogging. The episode resolved spontaneously after 30 minutes of rest. Harlequin syndrome consists of flushing limited to one side of the face due to sympathetic disturbance on the contralateral side.1 Although most cases are benign, imaging and neurological examination should be performed in patients with this condition to rule out serious structural lesions of the sympathetic pathway, such as mediastinal neurinoma, spinal invasion by lung cancer and brainstem infarction.

Agustín Toll · Alberto Gálvez-Ruiz

Fast facts: Parkinson’s disease. 3rd ed. K Ray Chaudhuri, Christopher G Clough, Kapil D Sethi. Oxford: Health Press, 2011 (144 pp, $25.00). ISBN 9781905832880. Since the first description of Parkinson disease in 1817 as the “shaking palsy”, it has become increasingly known that this common condition is not simply a motor disorder but a complex neurodegenerative process that requires a holistic approach to management. This book aims to provide an easy guide for doctors who are not necessarily specialists in neurology for managing the motor and non-motor symptoms of the disease. All three authors are leaders in the field — Chaudhuri is professor of neurology and movement disorders at King’s College Hospital, London; Clough is medical director of King’s College Hospital; and Sethi is Director of the Movement Disorders Program at Georgia Health Sciences University in the United States. The book presents information on the diagnosis, pathogenesis, genetics and treatment of the condition in a concise and readable form, as well as on the psychosocial aspects of the disease and palliative care. This third edition has a chapter on new developments and gene therapy. It includes an excellent table on drugs currently undergoing trials to treat the non-motor symptoms of the disease. Recent advances in neuroprotection are reviewed, such as the findings of the ADAGIO study (N Engl J Med; 361: 1268-1278) that suggest that early treatment with the monoamine oxidase inhibitor rasagiline confers benefits not seen with delayed treatment with the same agent. The book lists some useful resources for those managing the disease, and contact details of Parkinson disease associations in several countries including Australia. The only shortcoming is that it would benefit from more detail about the management of the gastrointestinal and autonomic symptoms of Parkinson disease. This book is certainly good value. In a world of limited time, it can be read quickly and carried in your pocket to read when you have a spare moment.

Rebekah M Ahmed · Simon Lewis

Promising outcomes from the Australian register include a fall in fetal malformation rates associated with changes in antiepileptic drug prescribing The burden of epilepsy for those with the disorder is significant. For women of childbearing age, the uncertainty surrounding their ability to bear children who are free of the disorder, without birth defects, and cognitively and psychologically normal adds to this burden. Although factors other than medication exposure influence these questions, there is no doubt that antiepileptic drugs (AEDs) used to prevent seizures, such as valproate, have a significant, and possibly preventable, role in teratogenicity.1 Pregnancy registers are now showing promising results in elucidating this role and influencing changes in practice for the benefit of women with epilepsy and their children. Some detailed information on the relative risks associated with AEDs has emerged over the past three decades,2 but it has largely been based on small-scale retrospective studies, with various and incomplete methods of recording data, no set protocols, and other shortcomings. It was clear that better information regarding teratogenicity, preferably from prospective studies, was needed. It was also clear that the expectant mother, as well as the infant, should be a primary consideration. The process of studying pregnancies in women with epilepsy should start well before conception and requires extensive consultation with the expectant mother about the planned management of her pregnancy and medication administration.3 In the late 1990s, these issues provided the rationale for setting up registers of pregnant women with epilepsy who were taking AEDs. There are now several international collaborative, independent and pharmaceutical company-initiated registers. The latter are concerned with single drugs and are not prospective. The collaborative and independent registers generally aim to collect prospective observational data from participating women according to an extensive protocol, with the data computerised for subsequent analysis. None of the registers dictate treatment and all have ethics approval, as well as informed consent from the participating women.4 The major registers are the International Registry of Antiepileptic Drugs and Pregnancy (EURAP),4 which includes data from 46 countries in Europe and elsewhere, and registers in North America, Denmark and the United Kingdom that publish reports independently. The Australian Pregnancy Register of Antiepileptic Drugs for Women in Pregnancy with Epilepsy and Allied Conditions (the Australian Pregnancy Register), established in 1999, is affiliated with EURAP, but also publishes its findings independently. It collects data from women who have volunteered to participate through a series of five interviews held at various times during pregnancy and after the infant’s birth.5 Over the past decade, all these registers have contributed considerable knowledge, improved prescribing practices and, although they were initially intended to focus on teratogenicity, have been extended to examine maternal wellbeing and seizure control, and cognition of the offspring. In terms of teratogenicity, the data collected in the registers can be used to assess the contributing roles of heredity, social factors, substance misuse, alcohol consumption, social status, intake of other medications, and accurately defined type and activity of epilepsy. The registers represent prospective studies on treatment efficacy and compliance, seizure freedom before pregnancy, interactions between AEDs and hormones, the role of folate supplementation, and many other factors involved in producing normal pregnancies and outcomes. The international registers have not used untreated control groups until recently — the North American register has used historical controls but is now enrolling a control group of pregnant untreated women, while EURAP compares the effects of different drugs. The Australian Pregnancy Register has from the outset collected data from a control group of untreated women with epilepsy, comprising about 10 per cent of the total, as well as (less successfully) women receiving AEDs for non-epileptic indications such as pain or bipolar disorder. Although there is no ideal control group, collecting data from untreated women with epilepsy provides an important comparison baseline.6 Recent analyses of data from the Australian Pregnancy Register have examined the role of AEDs in teratogenicity. For several decades, the use of AED polytherapy has been enshrined in the international literature as being harmful to the fetus, but our recent analysis of register data casts doubt on this, suggesting that it is the specific composition of polytherapy that is critical, not intake of multiple drugs per se.7 Most recently, analysis of register data has focused on dose issues that are associated with most of the AEDs, and examined the question of whether lower doses of drugs such as valproate may be effective in achieving seizure control without posing a higher risk of teratogenicity than other, less effective drugs.8 The role of AEDs in teratogenicity has become even more complicated as a series of new second-generation drugs have become available, because it takes a long time with many participants to define their role compared with the traditional drugs.9 Findings from the Australian Pregnancy Register have shown that seizure freedom before conception is demonstrably important in predicting the course of future pregnancies; the longer a woman is seizure-free, the better the outlook. The question of repeated pregnancies in women who have had a malformed baby while taking an AED, and advice to women contemplating extending their family, has also been studied. Findings such as these are of immediate importance to women and their babies, contribute to medical knowledge and have demonstrably altered prescribing practices in Australia and internationally. Recent data indicate that, while prescribing of valproate has risen in the general Australian population, possibly as a result of increasing use for patients with psychiatric illness, especially bipolar disorder, there has been a fall in the number of prescriptions and doses of valproate for women of childbearing age.10 This change in prescribing, which was influenced by register data, has been associated with a fall in fetal malformation rates.11 Increasing the number of women enrolled in the Australian Pregnancy Register is highly desirable to continue study of these important and complex topics. Pregnancy is an important health issue, and we must all collaborate to make it safer for women and their children.

Frank J E Vajda MD, FRCP, FRACP · Terence J O’Brien MB BS, MD, FRACP · Cecilie M Lander MB BS, FRCP, FRACP · Mervyn J Eadie MD, PhD, FRACP

Objective: To assess the influence of area-level socioeconomic status (SES) on incidence and case-fatality rates for stroke.Design, setting and participants: Analysis of pooled data for 3077 patients with incident stroke from three population-based studies in Perth, Melbourne, and Auckland between 1995 and 2003.Main outcome measures: Incidence and 12-month case-fatality rates for stroke.Results: Annual age-standardised stroke incidence rates ranged from 77 per 100 000 person-years (95% CI, 72–83) in the least deprived areas to 131 per 100 000 person-years (95% CI, 120–141) in the most deprived areas (rate ratio, 1.70; 95% CI, 1.47–1.95; P < 0.001). The population attributable risk of stroke was 19% (95% CI, 12%–27%) for those living in the most deprived areas compared with the least deprived areas. Compared with people in the least deprived areas, those in the most deprived areas tended to be younger (mean age, 68 v 77 years; P < 0.001), had more comorbidities such as hypertension (58% v 51%; P < 0.001) and diabetes (22% v 12%; P < 0.001), and were more likely to smoke (23% v 8%; P < 0.001). After adjustment for age, area-level SES was not associated with 12-month case-fatality rate.Conclusions: Our analysis provides evidence that people living in areas that are relatively more deprived in socioeconomic terms experience higher rates of stroke. This may be explained by a higher prevalence of risk factors among these populations, such as hypertension, diabetes and cigarette smoking. Effective preventive measures in the more deprived areas of the community could substantially reduce rates of stroke.

Emma L Heeley MSc, PhD · Jade W Wei BPharm · Kristie Carter PhD · Md Shaheenul Islam MB BS, MPH, MSc · Amanda G Thrift PhD · Graeme J Hankey MD · Alan Cass PhD · Craig S Anderson MD, PhD

We report two Australian patients with possible cobalt toxicity related to metal-on-metal total hip replacements. Both patients were treated for osteoarthritis with a DePuy ASR (articular surface replacement) XL Acetabular Hip System prosthesis, which contains cobalt and chromium, and which has recently been recalled from the market. (MJA 2011; 194: 649-651) Clinical recordsPatient 1A 73-year-old woman presented to our orthopaedic clinic in February 2011 for follow-up of a right total hip replacement that had been performed 5 years previously because of osteoarthritis. At review, she had neurological symptoms, including cognitive decline, memory difficulties and depression, which had been present for 7 months since a cerebrovascular episode. She also had a continuous metal taste in her mouth and complained of severe headaches, anorexia and weight loss. She had mild groin pain but otherwise no symptoms related to her hip. X-rays showed a well fixed, well aligned implant, with mild osteopaenia around the acetabular component. Her serum cobalt level was 410 nmol/L (reference range, 0–20 nmol/L) and chromium level was 240 nmol/L (reference range, 0–100 nmol/L). The cerebrovascular episode had occurred in July 2010, when the patient experienced symptoms consistent with a stroke: dizziness, disorientation, nausea, vomiting and being “off balance on the left side”. She had particularly noted difficulty in remembering names and registering information (both written and aural), headaches and cerebellar signs (ataxia and dysdiadochokinesis). She had been admitted to the stroke unit and treated with ongoing clopidogrel. A computed tomography (CT) scan at this time showed a hypodensity in the right anterior commissure, although it could not be confirmed whether this represented a lacunar infarct or a perivascular space. CT angiogram, echocardiogram and thyroid function test results were all normal and she had no previous history of depression or dementia. The patient’s original hip replacement had been done in 2006 with an ASR (articular surface replacement) hip prosthesis (ASR XL Acetabular Hip System [DePuy Orthopaedics, Warsaw, Ind, USA]), comprising a large-diameter metal (cobalt and chromium) cup with a large modular metal head on a titanium Corail stem (Box). A revision total hip replacement was performed in March 2011, principally because of her systemic symptoms and elevated cobalt and chromium levels. The ASR metal cup and head were removed and the stem retained. Her acetabulum was revised with an all-polyethylene cemented cup and the head was changed to a ceramic one. At the time of surgery, 30 mL of turbid fluid was aspirated from the joint and debridement of metal stained tissue was undertaken. The concentration of cobalt in the joint fluid was 4218 nmol/L and chromium was 217 000 nmol/L. Cerebrospinal fluid (CSF) collected at surgery showed a cobalt level of 9 nmol/L and a chromium level of 13 nmol/L (no reference ranges for these in CSF), showing that the ions had crossed the blood–brain barrier. At 8-week follow-up after the revision surgery, the patient felt much improved. She had regained a normal appetite and gained weight, the metallic taste in her mouth had gone, and she had less fatigue and greater energy. The hip pain had completely resolved and she was walking up to 2 km a day. Her serum cobalt level had reduced to 60 nmol/L. Patient 2A 60-year-old male professor of engineering presented in January 2011 with systemic symptoms, for follow-up after a right total hip replacement with a DePuy ASR XL Acetabular Hip System prosthesis 4 years previously. He had no hip symptoms, but an x-ray showed quite marked bone loss around the acetabular component. Before his hip replacement surgery, the patient had been working full time and enjoyed excellent general health, apart from pain and stiffness in his right hip secondary to osteoarthritis. Three years after the surgery, he developed symptoms that steadily increased in severity: painful muscle fatigue in all limbs associated with cramps in the hands and feet, particularly at night; dyspnoea and feeling faint when performing simple tasks; inability to climb a flight of stairs without needing to rest; and a decline in cognitive function (although this was not quantified). He particularly noted problems with remembering names and poor concentration. His previously stable hypertension had become uncontrolled and required additional medication. The patient’s serum cobalt level had been measured in September 2010 and found to be 185 nmol/L, and subsequently remained consistently elevated at between 213 nmol/L and 258 nmol/L. His chromium level was never elevated. In February 2011, the patient had a revision total hip replacement performed because of his systemic symptoms, in spite of having no hip symptoms. At revision surgery, the titanium stem was retained, and the metal head and cup were changed to ceramic and polyethylene versions, respectively. There was no metal debris or localised tissue reaction. Immediately before the revision surgery, the patient’s serum cobalt level was 258 nmol/L, with a normal level of chromium (88 nmol/L). At 8-week follow-up after the revision surgery, the patient reported significant improvement in his energy levels and a decrease in muscle pains. He had significantly improved exercise tolerance and was able to walk without restriction. His serum cobalt level had fallen to 42 nmol/L. DiscussionTotal hip replacement is generally a successful operation, with a long clinical history of good outcomes. Conventional total hip prostheses consist of a metal head that fits into a polyethylene cup. Concerns have been raised, particularly in younger patients, that the plastic cup suffers wear and tear with time and may require revision. In an attempt to decrease wear at the interface of the articulation, metal-on-metal bearings (Box), composed of cobalt and chromium, have gained widespread popularity and have been used extensively, particularly in the United States. However, some of these metal-on-metal prostheses have not lived up to the promise of increased durability. The Australian National Joint Replacement Registry (NJRR) notes large differences in the performance of different types of metal-on-metal hip prostheses. An acceptable upper rate of failure of hip prostheses is considered to be below 1% per year, with the vast majority of implants studied by the NJRR falling well below this failure rate.1 The ASR prosthesis originally implanted in both patients reported here has recently been withdrawn from the market, after about 100 000 were implanted worldwide. Its revision rate reported on the NJRR in 2010 was 6.4% at 3 years when inserted with a Corail stem and 10.9% at 5 years when inserted as a resurfacing.1 Updated guidance from the British Hip Society’s 2011 conference noted a higher than anticipated early failure rate [in large-diameter metal-on-metal hip replacements]. These range from [a] 21% revision rate at 4 years (potentially rising to 35% if all currently known painful implants progress to revision) to 49% at 6 years for the ASR XL device. Other devices have a revision or impending revision rate of 12 – 15% at 5 years.2 An additional problem with metal-on-metal bearings is that they release a variety of metal ions into local tissue and the general circulation, with chromium being the most widely reported of these. Increased cobalt levels have been reported to be associated with neurological3,4 (hand tremor, incoordination, cognitive decline, depression, vertigo, hearing loss and visual changes), cardiac (arrhythmias and cardiomyopathy) and endocrine5,6 symptoms. Symptoms of cobaltism have been previously described when cobalt was used to treat refractory anaemia in patients 40 years ago.7 The term “arthroprosthetic cobaltism” has been coined to describe these manifestations in patients with joint replacements.3 The direct effect of cobalt on cells has recently been explored. Exposure to cobalt ions was found to significantly inhibit osteoblast function by reducing alkaline phosphatase activity and calcium deposition, and to rapidly induce the secretion of proteins IL-8 and MCP-1 in primary human osteoblasts.8 This may have implications for bone ingrowth onto implants and osteolysis around the hip replacement. Other reported effects of elevated cobalt levels on cells include abnormal lymphocyte function,9,10 chemokine secretion11 and ischaemic changes in rat brains.12 A relationship between symptoms and peak cobalt levels, or the length of exposure to cobalt, has not been established. We believe our patients’ symptoms were related to their elevated cobalt levels, resulting from cobalt leaching out of their hip prostheses. Both patients had metal-on-metal hip prostheses, and both patients’ cobalt levels were reduced after removal of the metal-on-metal prosthesis. We are concerned that cobalt toxicity may be under-recognised, particularly if patients consult doctors who may not be aware of the details of the patient’s hip replacement and the potential for release of cobalt into the circulation. The British Hip Society recommends regular follow-up of patients with metal-on-metal hip replacements for at least 5 years and probably for the life of the prosthesis.2 Clinical manifestations of cobalt toxicity may occur many years after implantation of the prosthesis and appear to stay elevated over extended periods of time.13 Long-term exposure to cobalt may also be associated with cancer.14 Patients should therefore be followed up carefully, with specific questioning about alterations in neurological, cardiac, respiratory and endocrine function. In the presence of persistently elevated metal ion levels and symptoms consistent with metal toxicity, once other causes have been excluded, revision hip replacement is the only method available to decrease the ion levels. X-ray of Patient 1’s right metal-on-metal articulation hip replacement, with well fixed cementless femoral and acetabular implant

Xinzhan Mao MD · Andrew A Wong MB BS, PhD, FRACP · Ross W Crawford MB BS, DPhil(Oxon), FRACS(Orth)

Murine typhus (MT) occurs worldwide, but, in Australia, is only regularly diagnosed in south-west Western Australia. Meningoencephalitis is an uncommon complication of MT, often accompanied by rash or systemic involvement. We report a case of MT presenting exclusively with meningoencephalitis, raised intracranial pressure, papilloedema and bilateral 6th cranial nerve palsies. MT should be considered in patients with “aseptic” meningitis or meningoencephalitis, even in the absence of other typical features of a typhus-like illness. (MJA 2011; 194: 652-654) Clinical recordIn June 2010, a 20-year-old man who worked as an apprentice chef developed a progressively severe, non-pulsatile global headache without report of additional neurological symptoms, rash, fever or other constitutional features. After 3 days of headache he woke with severe headache and associated nausea and vomiting. A short time later, while standing in the shower, he developed paraesthesiae, starting initially in his fingers and toes, then spreading quickly up his limbs, trunk and finally involving his face and tongue. He subsequently collapsed onto the bathroom floor and was unable to move or speak, although he did not lose consciousness. While he was being transported to hospital, a speech disturbance was noted, with fluent but nonsensical speech. On initial assessment he was noted to be febrile at 39°C and confused, but without rash, organomegaly, lymphadenopathy or other signs on complete physical examination. There were no additional findings on neurological examination. This patient was normally well, had no prior significant medical history and took no regular medications or complementary therapies. He did not smoke, drank alcohol rarely and denied using cannabis or other recreational substances. He lived with his family on a small acreage in a rural area of the mid-north coast of New South Wales. Two dogs and two horses lived on the property, and an aviary containing parrots and an enclosure housing chickens were contained within the yard. There were no cats on the property. The patient reported that rats and mice were frequently seen around the chicken enclosure, but he had not been in its vicinity for several weeks before his illness. About a week before the onset of the headache, he had visited a friend who kept a pet rat indoors. He had never travelled outside NSW, and his travel within NSW was limited almost exclusively to infrequent travel between his home and Sydney. He did not recall any flea or other insect bites. He was diagnosed with meningoencephalitis after a lumbar puncture on the day of admission showed a predominantly lymphocytic pleocytosis of 180 lymphocytes/mm3 (reference range [RR], < 5 lymphocytes/mm3) with an elevated protein level of 1.7 g/L (RR, < 0.45 g/L) and a normal glucose concentration (Box 1). He was admitted to the intensive care unit (ICU) and remained there for a week because of fluctuating confusion and fever. During that week he had two further episodes like the one described before his presentation, including on Day 10 of admission requiring readmission to the ICU. Empiric treatment with a number of antimicrobial medications was commenced at standard doses in the following order: ceftriaxone (intravenously, Days 3 to 17 of illness); ampicillin (intravenously, Days 4 to 9); aciclovir (intravenously, Days 4 to 17); vancomycin, oseltamivir and azithromycin (intravenously, Days 10 to 17). Phenytoin therapy (1000 mg intravenous loading dose, followed by 300 mg orally, daily) was commenced on the day of admission owing to the possible seizure activity before presentation. He was discharged from hospital on Day 17 of the illness after the fever and headaches resolved. On presentation, the results of blood investigations including a full blood count, liver function tests, a C-reactive protein test, renal function tests and electrolyte level measurements were normal. A transient leukocytosis developed after admission and peaked on Day 6 of admission at 14.0 × 109/L, with a predominant neutrophilia. At no time was there significant derangement of liver function tests. Findings on brain imaging, including gadolinium enhanced magnetic resonance imaging of the brain on two occasions, magnetic resonance venogram and magnetic resonance angiogram were all normal. Serial lumbar punctures were performed (Box 1) showing the reducing white cell count and protein level. Cerebrospinal fluid (CSF) opening pressure was elevated to 30 cmH2O (RR, < 18 cmH2O) measured on Day 5 and this normalised by Day 27. Results of serological tests for human immunodeficiency virus, leptospirosis, Q fever, mycoplasma, brucellosis, psittacosis, and Ross River fever, which were performed during both the acute and convalescent phases of the illness, were negative. Repeated tests of the CSF for cryptococcal antigens were negative. CSF cultures for bacteria, fungi and mycobacteria were also negative, as was polymerase chain reaction testing for herpes viruses and enterovirus. Indirect immunofluorescence detecting total antibody against rickettsiae in the typhus group (Rickettsiae typhi and R. prowazekii), spotted fever group (R. honei and R. australis) and scrub typhus (Orientia tsutsugamushi) was performed in parallel on serum collected on Days 9 and 41. Antibodies against R. typhi were detected at a titre of 1/256 on Day 9, rising to ≥ 1/1024 on Day 41. Antibodies in each CSF specimen showed cross-reactivity with R. prowazekii at equivalent titres, but not with other rickettsial species. The patient first noticed diplopia and reduced visual acuity on Day 10, which peaked on Day 20 of his illness. At this point, bilateral partial 6th nerve palsies and papilloedema were noted. Because of persistent visual symptoms and papilloedema, therapy with 250 mg acetazolamide orally, twice daily was commenced on Day 26. Papilloedema was documented on Day 28 by ocular coherence tomography (OCT), a measure of retinal nerve fibre layer thickness and indicative of the degree of optic disc swelling (Box 2). The 6th nerve palsies resolved after Day 30 and regular fundoscopy and repeat retinal OCT showed the papilloedema continued to resolve (Box 2). Acetazolamide therapy was ceased on Day 35. The patient had not experienced recurrence of the headaches or neurological symptoms at 6 months after the onset of the illness. DiscussionWe present the first case of murine typhus (MT) reported in NSW since the 1940s. Perhaps even more notably, we have now reported the first case of MT causing proven, isolated meningoencephalitis with raised intracranial pressure (ie, rarely reported complications without other typical clinical features) in Australia. MT (endemic typhus) was first described in 1922 with a series of cases from South Australia.1 There have been further outbreaks in the Darling Downs region of south-east Queensland and south-west Western Australia.2 In each series, exposure to rodents was reported in a significant proportion of cases. MT has been reported worldwide in diverse geographic areas.3 Several areas continue to regularly report new cases including Perth in WA,4 South-East Asia,5 and Texas in the United States.6 The first case of MT in Victoria was recently reported,7 and no locally acquired cases of MT have been reported from NSW since 1944.8 The disease is caused by R. typhi, which is an obligate intracellular gram-negative bacterium with an incubation period of 7–14 days. There are two major sources of transmission. The major route of infection worldwide is the rat–flea–rat cycle.9 Rat fleas (Xenopsylla cheopis) transmit R. typhi to a roof or Norwegian rat (Rattus rattus and Rattus norvegicus, respectively). Humans are infected when flea faeces containing R. typhi are inoculated into the site of a flea bite. Alternatively, the organism may be inhaled from an environment contaminated with flea faeces. Another transmission cycle has been identified, which involves predominantly cats and opossums and their fleas (Ctenocephalides felis).10 In the case we present here, it is likely that the patient was infected as a consequence of close contact with rodents, with a respiratory route of infection being most likely. Although serological testing does not separate MT and epidemic typhus, MT has been distinguished by its milder course and the lower associated mortality.1 Fever is almost universal, and about 75% of affected patients complain of headache. Rash is observed in about 50% of cases, and is usually a macular or maculopapular rash that starts on the trunk and spreads to the extremities. A number of other features may accompany the illness, including myalgia, arthralgia, gastrointestinal symptoms, jaundice and hepatic dysfunction.11 Among the antibiotics given to our patient, azithromycin was the only one with activity against rickettsiae, and may have altered the course of the illness. However, without treatment, MT is usually a self-limiting illness, with symptoms resolving after 2 weeks.1 Neurological complications like those described in this report are uncommon in MT. Aseptic meningitis or meningoencephalitis has been reported in 2%–14% of cases.12,13 There is often a coexisting rash or other systemic features of typhus,12 and isolated meningitis or meningoencephalitis has been reported previously in only six patients.13,14 Papilloedema and raised intracranial pressure can occur with the meningitis, and 6th nerve palsy has been reported in a single case.13 Facial nerve palsy has also been described in association with meningitis in MT.14 Neurological dysfunction is usually reversible. but long-lasting deficits have been reported.13,15 In affected patients, the CSF typically shows a predominantly monocytic pleocytosis with variable elevation of protein concentration.13 The raised intracranial pressure and optic disc swelling in our patient were transient, and it is likely that intracranial pressure changes associated with meningitis are monophasic like MT infection generally. This has important implications for the extent and duration of treatment of associated raised intracranial pressure. This is the first report of MT causing proven, isolated meningoencephalitis with raised intracranial pressure in Australia. The clinical manifestations documented represent rarely reported complications of MT without other typical clinical features. The case illustrates that MT should be considered in the differential diagnosis of a patient presenting with “aseptic” meningitis or meningoencephalitis with or without raised intracranial pressure. This is particularly relevant in areas where MT is regularly observed, like south-west WA. However, it should also be considered in other areas of Australia. The absence of other typical features of a typhus-like illness such as rash should not preclude testing for R. typhi, as antibiotic therapy may reduce the duration and severity of the illness, and establishing the diagnosis of MT provides valuable information about the likely course and prognosis of the illness. 1 Serial findings on examination of the patient’s cerebrospinal fluid (CSF) Reference ranges: white cell count, < 5 cells/mm3; protein concentration, < 0.45 g/L; CSF opening pressure, < 18 cmH2O. 2 Serial ocular coherence tomography of retinal nerve fibre layer thickness showing improving papilloedema from Day 29 to Day 48

Neil G Simon MB BS(Hons), BSc(Med)Hons · Phillip D Cremer MB BS(Hons), PhD, FRACP · Stephen R Graves MD, PhD, FRCPA

New results from an Australian collaborative randomised trial will change practice Every year in Australia, 1000 people are admitted to intensive care units with severe traumatic brain injury, mostly as a result of motor vehicle accidents.1 Despite high standards of prehospital and medical care, 50% of these people either die or survive with severe lifelong disability.2 Most of the survivors with severe disability are young men aged in their mid 20s;2 they cannot return to work and will never be able to live independently. The cost of severe traumatic brain injury in human terms is huge, and in economic terms has been recently independently calculated to be $4.8 billion every year in Australia.1 In the United States, the annual economic burden of traumatic brain injury is $60 billion.3 Half of patients with severe traumatic brain injury have haematomas that may require neurosurgical evacuation; management of these patients before and after surgery is not controversial. However, about 10% of patients have diffuse brain injury,4 and also have persistent brain swelling that cannot be effectively controlled in intensive care units by airway management, mechanical ventilation, intracranial pressure monitoring, heavy anaesthesia, resuscitation fluids, osmotherapy, and drainage of cerebrospinal fluid from ventricular catheters. Over the past decade, management of these patients has been shifting in many centres from barbiturate therapy, and sometimes hypothermia, to decompressive craniectomy5 — a well established neurosurgical procedure in which a large piece of skull bone is removed (stored for 1–2 months, and then replaced) to enable better control of intracranial pressure and a more rapid decrease of sedation, with the ultimate goal of improving patients’ long-term functional outcomes. About 20 case series of adult patients from many countries have reported mainly favourable results from this procedure.6 However, all suffer from a lack of prospective randomised control groups and of objective blinded outcome assessment at defined time points. To objectively assess decompressive craniectomy for the first time and to establish its true efficacy in adult patients with traumatic brain injury, intensivists and neurosurgeons in Australia, New Zealand and Saudi Arabia collaborated between 2003 and 2010 to conduct the Decompressive Craniectomy (DECRA) randomised trial. The results of the DECRA trial have recently been published.7 This was the first randomised trial of any neurosurgical technique to be completed in complex adult neurotrauma patients. Patients were randomly assigned to receive decompressive craniectomy plus standard care (maximised intensive care therapies, which could include barbiturate anaesthesia) or standard care alone. The study found that early decompressive craniectomy clearly and dramatically achieved its short-term goals: it decreased intracranial pressure, markedly decreased medical therapies required for intracranial pressure, shortened mechanical ventilation time, and shortened stay in the intensive care unit by 5 days compared with the standard care group. The dramatic short-term effects meant that the study was difficult to complete because neurosurgeons and intensivists were aware of group allocation, could see the early benefits, and increasingly preferred to conduct early surgery rather than recruit patients to the trial. However, despite these positive short-term effects, the findings in relation to patients’ eventual functional outcome, measured carefully at 6 months, were startling and the reverse of what had been expected. There were 19% more patients with poor functional outcomes (odds ratio, 2.21; 95% CI, 1.14–4.26; P = 0.02) and 23% more survivors with severe disability in the decompressive craniectomy group compared with patients who received standard care alone. The cause of these poor outcomes is speculative. They may have related to the surgery itself or to surgical complications (including hydrocephalus), but surgical complications seem an unlikely explanation given that the rates overall were less than those reported in published case series. A more likely explanation is that “axonal stretch” that occurred during swelling of the brain outside the skull through the craniectomy defect8 exacerbated brain injury in a way that has not previously been described in humans and was not anticipated. Multimodal magnetic resonance imaging may enable confirmation of this. We might now coin the term “brain volutrauma”, analogous to the “lung volutrauma” observed in mechanically ventilated patients with acute lung injury. A second ongoing randomised trial — the Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) — is addressing similar questions in the United Kingdom and Europe. The RESCUEicp trial also includes patients with brain haematomas and intervenes at a slightly higher intracranial pressure threshold,9 so the results will be complementary to the DECRA trial and are likely to be equally important. What is unequivocal is that functional outcomes of future patients with severe diffuse traumatic brain injury in Australia and New Zealand can be substantially improved by choosing best intensive care medical and surgical therapies, based on established guidelines,10 without early decompressive craniectomy, despite increases in intracranial pressure that may be concerning to clinicians. The role of decompressive craniectomy as a rescue therapy in the context of very high intracranial pressure has not been resolved by this study, but is now clearly uncertain. It is also unequivocal that the Australian health care system will save many tens of millions of dollars annually when the less invasive treatment regimen is chosen. Although careful cost–benefit analyses are urgently required (and can be done using existing databases), it is already clear from independent costing analyses, which confirmed that most of the traumatic brain injury cost burden relates to rehabilitation costs of survivors with severe disability,1 that the savings to Australia of choosing intensive medical therapies instead of craniectomy in appropriate patients will be greater than $100 million annually. Savings in the US and Europe are likely to be proportionately greater. Finally, the DECRA trial illustrates with new clarity that carefully designed randomised controlled trials are the only way to correctly advance clinical practice, even in complex, critically ill patients, and despite the clear inherent difficulties of such trials.11 Recent calls for “comparative effectiveness research” in neurosurgery,12 based on aggregations of non-randomised databases, do not represent a valid substitute. In the DECRA trial, a collaborative network of clinician-investigators (the Australian and New Zealand Intensive Care Society Clinical Trials Group), which was supported by the National Health and Medical Research Council (NHMRC) and co-funders, unfettered by industry, and motivated by a strong desire to improve the quality of outcomes in critically ill patients, enabled the trial to be supported to completion and to influence clinical practice for the better. These are the essential ingredients needed to make meaningful improvements in health care.

D James Cooper MD, FRACP, FCICM · Jeffrey V Rosenfeld MD, MS, FRACS

Clinical record A 64-year-old woman who had never consumed alcohol presented to hospital with a several-day history of vomiting and severe diarrhoea, secondary to Clostridium difficile colitis. She had suffered a similar episode 3 months earlier. Her symptoms settled after 7 days’ treatment with vancomycin and metronidazole, but her admission was complicated by nosocomial pneumonia and her oral intake was poor. Fifteen days into her stay, she became drowsy and less communicative and developed generalised weakness. Clinical examination revealed signs of encephalopathy. She had slowed mentation, paucity of facial expression and slow limb movements. She could follow one-stage commands but only slowly and with significant prompting. Her eye movements were normal. She had mild generalised weakness in all four limbs, but her deep tendon reflexes were intact and plantar responses were downgoing. Ataxia could not be assessed reliably due to impaired consciousness. Electroencephalography showed generalised slowing without focal features. Magnetic resonance imaging (MRI) of the patient’s brain revealed symmetrical changes of high signal in the periaqueductal grey matter, superior colliculi and medial thalami, most evident on the fluid-attenuated inversion recovery (FLAIR) sequences (Box 1, A–C). These symmetrical periventricular changes were consistent with typical findings recently described for Wernicke’s encephalopathy.1 Given the clinical history of dietary deprivation and colitis, together with the typical radiological changes, a diagnosis of Wernicke’s encephalopathy was strongly suspected. Hence, intravenous thiamine 500 mg three times a day was administered, after which the patient made a dramatic clinical and radiological recovery (Box 1, D–F) over a period of about 7 days. Despite this, her pretreatment (Day 15) blood thiamine pyrophosphate level, measured using high-performance liquid chromatography, was eventually reported as being normal (136 nmol/L [reference range, 67–200 nmol/L]). However, given her clinical history, the changes noted on MRI and the dramatic improvement in her condition with thiamine, the diagnosis of Wernicke’s encephalopathy remained the most likely explanation. Wernicke’s encephalopathy is caused by thiamine deficiency and is most commonly associated with heavy alcohol intake paired with poor nutrition.2 However, the same phenomenon can occur in non-alcoholic patients with a very low dietary thiamine intake — for example, in patients who undergo prolonged therapeutic fasting or gastrointestinal (particularly bariatric) surgery, and in patients with recurrent vomiting or diarrhoea.3 It has also been reported after prolonged febrile illnesses, where thiamine requirements may be increased and where there is also inadequate oral intake.3 If not recognised, Wernicke’s encephalopathy can progress to Korsakoff syndrome, resulting in profound working memory deficits, or may even be fatal.4 In a healthy person, reserves of thiamine are estimated to be exhausted after only 2–3 weeks of dietary deprivation.3 In this case, we hypothesise that nutritional deficiency developed due to the patient’s ongoing vomiting and diarrhoea, combined with a catabolic state from her severe pneumonia, and that thiamine stores may already have been depleted from her previous bout of Clostridium difficile infection. Clinically, patients with Wernicke’s encephalopathy classically present with the triad of global cognitive deficits, eye signs (nystagmus and/or ophthalmoplegia) and ataxia,4 although there are also less common clinical features (Box 2). However, autopsy reports of pathologically confirmed cases of Wernicke’s encephalopathy indicate that only 16% of patients have the triad, 19% have no clinical signs at all, and the most common presentation is isolated cognitive changes (eg, impaired consciousness or disorientation).4,5 This is consistent with the clinical findings in our patient and emphasises the need to consider Wernicke’s encephalopathy as a diagnostic possibility even when the classic triad is absent. In the past decade, magnetic resonance imaging (MRI) has been recognised as a useful adjunct in Wernicke’s encephalopathy diagnosis.6 Wernicke’s encephalopathy typically causes symmetrical alterations in MRI signal intensity (increased on fluid-attenuated inversion recovery [FLAIR] images) in the periventricular regions of the brain, including the medial thalami, periaqueductal grey matter, tectal plate (inferior and superior colliculi), and mamillary bodies.1,7 It has been suggested that MRI changes which occur in alcoholic and non-alcoholic patients with Wernicke’s encephalopathy may differ, with contrast enhancement of the mamillary bodies and thalami occurring more frequently in the alcoholic patients, suggesting that these areas may be selectively susceptible to alcohol toxicity.7 Our patient’s normal thiamine level is also of interest. Thiamine functions as a coenzyme in the metabolism of carbohydrates, lipids and some amino acids and is involved in myelin sheath maintenance and neurotransmitter production.2 One would, by definition, expect a low thiamine level in Wernicke’s encephalopathy. However, thiamine assays have well recognised limitations. Serum thiamine levels are a poor measure of thiamine status.2 Until recently, many laboratories have used thiamine transketolase activation assays; however, these have also been reported to lack specificity, as well as being technically difficult.3 Many laboratories in Australia have moved to using high-performance liquid chromatography with fluorescent detection to measure thiamine pyrophosphate — the physiologically active form of thiamine — in whole blood, as done for our patient. This assay is thought to have improved reproducibility,2 but has also been noted to have weaknesses relating to the standardisation process of its complicated chromatographic methods (Ronda Greaves, Chair, Vitamins Working Party, Australasian Association of Clinical Biochemists, personal communication). In addition, although these assays give an estimate of whole-blood thiamine levels, they do not necessarily reflect intracerebral thiamine levels. Thiamine is predominantly transported across the blood–brain barrier by a slow, carrier-mediated process,8 hence Wernicke’s encephalopathy cannot be diagnosed simply by measuring the circulating thiamine level.9 In our case, the patient’s clinical presentation, MRI changes and rapid clinical and radiological recovery in response to administration of thiamine provide support for the diagnosis of Wernicke’s encephalopathy, despite the normal thiamine level. Further, it is critical to remember that while thiamine assays usually take several days, early initiation of thiamine is vital to prognosis9 and clinical response to thiamine is the most reliable diagnostic test.3 In conclusion, this case highlights the challenges of recognising Wernicke’s encephalopathy and the importance of prompt diagnosis. Given the underdiagnosis of Wernicke’s encephalopathy,4 the often incomplete clinical presentation of the condition, and the low toxicity of thiamine,2 a low clinical threshold is warranted for initiating thiamine therapy in patients with cognitive changes and significant predisposing factors for dietary thiamine deficiency. Clinicians should maintain a high index of suspicion when such risk factors are present. The characteristic MRI changes should also be looked for. Thiamine assays may help confirm suspicions but a normal thiamine level does not exclude the diagnosis. As this case demonstrates, early thiamine replacement can fully reverse the clinical and radiological features of this potentially devastating condition. 1 Magnetic resonance imaging scans of the patient’s brain before and after thiamine administration Axial fluid-attenuated inversion recovery (FLAIR) sequence images from when the patient was encephalopathic (A–C) show symmetrical changes of abnormal high signal in the periaqueductal area (arrows, A), superior colliculi (arrows, B) and posterior medial thalami (arrows, C). These changes resolved completely following thiamine administration (D–F). 2 Less common clinical features of Wernicke’s encephalopathy2,3 Autonomic: hypotension and tachycardia; hypothermia; bradycardia Ocular: sluggish pupillary reactivity; light–near dissociation; bilateral visual disturbances due to papilloedema and retinal haemorrhages Aural, vestibular: hearing loss; vestibular dysfunction; tinnitus Seizures: generalised tonic–clonic seizures Movement disorders: myoclonus; orthostatic tremor; choreic dyskinesias Motor system: acute peripheral neuropathy; increased muscular tone and spastic quadriparesis Mental status: hallucinations and behavioural disturbances; psychosis; coma Lessons from practice Wernicke’s encephalopathy can occur in non-alcoholic patients with other risk factors (eg, dietary deprivation of thiamine). In a previously healthy individual, thiamine stores can be depleted by 2–3 weeks of dietary deprivation. Although Wernicke’s encephalopathy is classically described as the clinical triad of cognitive deficits, eye signs and ataxia, this triad is much less common in practice than presentation with cognitive deficits alone. Magnetic resonance imaging is a useful diagnostic aid, showing symmetrical increased signal on fluid-attenuated inversion recovery (FLAIR) images in the periventricular regions of the brain. A normal thiamine level does not exclude a diagnosis of Wernicke’s encephalopathy.

Sarah B Davies BSc(Med)Hons · Fredrick F Joshua MB BS, FRACP, PhD · Alessandro S Zagami MB BS, FRACP, MD

To the Editor: We read with interest the recent letter by He and colleagues.1 The authors described a case of ischaemic stroke in a patient with scurvy and considered whether there was a connection between the two conditions. They referred to evidence that vitamin C deficiency may be a risk factor for cerebrovascular disease, but acknowledged that a direct causal link is unlikely to be established. We propose adiponectin as the causal link between vitamin C deficiency and stroke. Adiponectin is an adipokine, secreted in multimers by adipose tissue, with insulin-sensitising, antiatherogenic and cardioprotective properties.2 A decrease in adiponectin levels — particularly the more biologically active, high molecular weight (HMW) multimers — is implicated in a number of disease states, such as obesity, type 2 diabetes, heart disease and some cancers. Adiponectin has also been reported to have cerebroprotective properties,3 and there is some evidence that levels may be reduced in patients with cerebrovascular disease.4 A recent study demonstrated that vitamin C supplementation increases the proportion of HMW adiponectin secreted from human adipocytes.5 Vitamin C levels are lower in obese and diabetic patients, and the patient reported by He et al had also been recently diagnosed with type 2 diabetes. While scurvy is admittedly rare, He and colleagues noted that subclinical vitamin C deficiency is not uncommon in the general population (about 10%). We suggest that it would be worthwhile to assay plasma vitamin C levels and total and HMW adiponectin levels in patients presenting with cerebrovascular events, and to undertake prospective studies to determine whether vitamin C supplementation improves patients’ adiponectin levels. Increased HMW adiponectin levels could be explained, at least in part, by the role of vitamin C in the multimerisation of adiponectin. Adiponectin levels are also reduced in other vascular conditions, such as ischaemic heart disease and peripheral vascular disease.4 As plasma vitamin C levels of patients with these diseases are also reduced, it is tempting to posit that vitamin C supplementation could have a role as a treatment, or even a prophylactic, in populations at risk of a range of adiponectin-related vascular diseases.

Felicity J Rose · Jonathan P Whitehead

Visual field defects typically caused by lesions in the optic nerve or optic chiasm may be caused indirectly by subdural haematomas. A 61-year-old man survived transtentorial herniation caused by subdural haematomas that resulted from shaking his head in an attempt to remove a cockroach impacted in his external auditory canal. Bilateral incomplete posterior cerebral artery infarction of both inferior tips of the occipital lobe resulted in bilateral superior quadrantanopia. There are no previous reports of tentorial herniation causing this permanent outcome. (MJA 2011; 194: 420-422) Clinical recordA 61-year-old man presented to the emergency department with a 3-day history of worsening headache and drowsiness. He had a past medical history of renal calculi and gout and was not taking any regular medication. He had a history of consuming 5–6 standard units of alcohol per day, but no antecedent falls or head injury were reported. On physical examination, his Glasgow Coma Scale (GCS) score was 15/15 and his vital signs were normal, apart from mild hypertension (154/80 mmHg). His right pupil measured 4 mm, and his left pupil, 3 mm. His reflexes were documented as brisk in the upper limbs. Results of liver and coagulation studies were normal. A cerebral computed tomography (CT) scan showed large bilateral frontoparietal subdural haematomas (Box 1, A). The right-sided haematoma had mixed hyperdense and isodense areas suggestive of acute on subacute bleeding, while the left frontal haematoma was isodense. The CT scan also showed marked mass effect (Box 1, B) and early tentorial herniation of the uncus (Box 1, C) without tonsillar descent. There was a delay of 8 hours, including transfer of the patient to a neurosurgery centre, before surgery. The patient’s medical notes showed that before undergoing surgery he had developed bilateral extensor Babinski responses and had a GCS score of 14/15. One hour before the operation, the nursing records indicated “GCS 13/15, patient too drowsy and disoriented to consent [to surgery]”. No further imaging was undertaken and no further notes were made before surgery. The patient made an uneventful recovery after bilateral craniotomy and drainage. A CT scan of the brain on discharge about a week later confirmed evacuation of the haematomas and normalisation of brain position. During routine follow-up 10 weeks later, the patient reported persistent difficulty with reading since the operation and that he was experiencing problems differentiating colours. His visual acuity was found to be 6/5 in the right eye and 6/18 in the left, with symptoms of defective colour vision (3/14 Ishihara plates correctly identified with the right eye, and 4/14 with the left). A minor cataract was found in his left eye, but there was no other intraocular abnormality in either eye. His optic discs appeared healthy without pallor in both eyes (and remained so on further follow-up several years later). Computerised visual field perimetry testing conducted at 10 weeks showed bilateral superior altitudinal defects (Box 2). Routine visual evoked potentials showed normal latencies. However, multifocal visual evoked potentials showed normal latencies with decreased amplitude in superior fields bilaterally. Magnetic resonance imaging (MRI) of the brain and orbits conducted 6 months after the surgery showed chronic infarction involving the inferior tip of both occipital lobes medially, more marked on the right side (Box 1, D and E). There was evidence of residual blood products from the evacuated bilateral subdural haematomas, with no evidence of new bleeding. There was no abnormality of the optic nerves or optic chiasm, and venous drainage on magnetic resonance venography was normal. Upon further questioning at this time, a reason for the apparent spontaneous subdural haematomas became evident. The patient described an incident 7 weeks before admission when he awoke with an insect inside his ear. Despite, in his words, “shaking my head from side to side and banging on the side of my head with my fist”, the patient was not able to get the insect out. He was seen at the emergency department, where his ear was syringed and, eventually, a German cockroach (Blatella germanica) was removed with further shaking of the head (which was documented in the hospital records). He recalled a marked headache for the next 2 weeks, which gradually subsided. Recurrence of the headache 5 weeks later prompted him to present to the emergency department again, and the subdural haematomas were detected. DiscussionThis is an unusual and to the best of our knowledge a novel case of bilateral visual field defects related to earlier impaction of a cockroach in the external auditory canal. Subdural haematoma is an uncommon cause of bilateral homonymous hemianopia.1 It can occur as the result of direct local injury to the occipital lobes, or alternatively, mass effect from subdural haematoma can result in tentorial herniation, potentially compromising the blood supply of the posterior cerebral artery (PCA) and placing the regions it supplies at risk. Visual field defects as a consequence of this indirect effect of subdural haematoma have been reported in some surviving patients, but posterior cerebral infarction is more commonly recognised in postmortem examinations of the brain.2-4 Altitudinal visual field defects are typically due to optic nerve lesions and are usually unilateral. Theoretically, the minimal lesion required to produce a bilateral superior quadrantanopia is one located in the inferior optic chiasm; however, this occurs rarely. Typically, injury causes splaying of the chiasm, which is more commonly associated with bitemporal hemianopia. Transtentorial herniation is a well recognised cause of uncal and brainstem displacement and third cranial nerve palsy, but it can also cause stretching and compression of the PCA — thereby compromising the blood supply and leading to infarction.4,5 Survival from tentorial herniation with residual bilateral homonymous hemianopia has been occasionally reported in the literature.6-9 To date, there is no documentation of it causing bilateral superior quadrantanopia. The regions of the brain at risk secondary to PCA ischaemia or infarction are the inferior and medial temporal and occipital cortices. The actual area of involvement depends on which tributaries (and distributions) are affected. The calcarine branch of the medial occipital artery, which supplies the medial occipital lobe, is most commonly involved.10,11 In our patient, there was evidence of mass effect and tentorial herniation secondary to the enlarging subdural haematoma. This would have placed the PCA blood supply at risk. The MRI findings of bilateral infarction of the inferior tip of the medial occipital lobe, together with field test findings of bilateral superior altitudinal defects, confirm the involvement of the visual cortex, which is topographically organised with the cortical representation of the superior field localised inferiorly.5,12 The affected region corresponds to the striate cortex and most posterior part of the prestriate cortex. Both areas are involved in aspects of colour visual processing, suggesting an explanation for the patient’s defective colour vision despite a normal optic chiasm and optic nerves, although a congenital cause cannot be excluded.13 The patient’s history of daily alcohol consumption may have predisposed him to bleeding tendencies and subdural haematomas, although results of his liver and coagulation studies were normal. A diagnosis of acute on subacute subdural haematoma fits well with the timing of the patient’s violent attempts to remove a foreign body from his ear about 7 weeks previously, and with subsequent delayed re-bleeding and increasing supratentorial pressure resulting in uncal herniation and infarction of the part of the primary visual cortex known to correlate with the superior visual fields. A preferred method of removing a cockroach from the ear canal is to drown it with non-toxic vegetable or mineral oil so it can then be easily extracted with forceps. Cautious suction can also be used, taking care not to cause barotrauma by occluding the canal. Lignocaine 2% also rapidly kills the insect or results in it leaving the canal, but entry of lignocaine through any perforation into the middle ear can produce severe sustained vertigo with nystagmus for some hours.14-17 1 Initial computed tomography scan of the brain (A–C), and magnetic resonance images 6 months later (D, E) A: Isodense subdural haematomas (arrows) extending over the convexities longitudinally with effacement of sulci. B: Right hyperdense frontal acute component of a subdural haematoma (arrows) consistent with delayed re-bleeding. C: Uncal herniation, particularly on the left (arrow). D, E: Sagittal fluid-attenuated inversion-recovery magnetic resonance image 6 months later, left and right of midline, respectively (arrows), showing inferior occipital pole infarction. 2 Computerised visual field perimetry of the right eye (A) and left eye (B) The left superior and right superior visual fields are abnormal for both eyes (black areas). The left superior quadrant is slightly worse for both eyes, suggesting this is homonymous and that the lesion is posterior to the chiasm. We describe this as a bilateral superior quadrantanopia rather than a hemianopia to distinguish this circumstance from the normally lateral hemianopias, and because the lesion required to cause this finding is bilateral.

Wan Yi Ng BBus, MB BS · Brian E Chua MB BS, BSc, MPH · Todd A Hardy MB BS, PhD · David Wechsler MB BS · Stephen W Reddel MB BS, PhD

To the Editor: A middle-aged male night-shift driver experienced dizziness, vomiting, sudden onset of limb weakness, and then collapsed and became delirious. He had no past history of renal impairment or hypertension. At presentation in an emergency department, he was hypertensive (blood pressure, 220/140 mmHg) and hyperglycaemic. An upper motor neurone pattern of persistent dysarthria and left hemiparesis was evident. An electrocardiograph and transthoracic echocardiogram confirmed sinus rhythm and left ventricular hypertrophy. Magnetic resonance angiography of the brain showed subacute basal ganglia haemorrhage (Box) and an anterior communicating artery aneurysm. Renin levels were elevated at 124.7 mU/L (reference range, 4.5–46.0 mU/L) but renal artery stenosis was absent on ultrasound. Evaluation of an elevated initial normetadrenaline level of 1610 pmol/L (reference range, < 900 pmol/L) with a diagnostic algorithm1 suggested that phaeochromocytoma was unlikely. Hypertension, proteinuria, suboptimal renal function, inactive urine sediment and normal fasting blood glucose suggested hypertensive nephropathy. Antihypertensives were initiated to mitigate the risk of further stroke, nephropathy and cardiomyopathy. Results of an electroencephalogram were normal. Further history revealed that the patient had nicotine dependence with occasional amphetamine and cannabis exposure. Before admission, he had an estimated intake of 1–2.5 bottles of cough mixture episodically (600–1500 mg of pseudoephedrine). A pattern of ingesting excessive amounts of various brands of over-the-counter combination pseudoephedrine and codeine cough mixture developed over 20 years, and he suffered cravings when abstaining. He visited various pharmacies, provided identification, was repeatedly cautioned, but rarely consulted doctors. A Naranjo score2 of 7 indicated a probable adverse drug reaction to pseudoephedrine, resulting in a disabling hypertensive haemorrhagic stroke. During 2.5 months of inpatient rehabilitation, he regained full independence in self-care and mobility. His unstable employment was interdependent with pseudoephedrine misuse. He accepted counselling regarding constructive, non-pharmacological coping strategies for social stressors. Financial, legal and housing difficulties complicated his discharge plan. He planned to return to work as a driver. Pseudoephedrine is associated with a modest elevation in blood pressure3 and hypertensive crises.4 Intracerebral haemorrhage associated with pseudoephedrine usage is anecdotally reported.5 Dependence and chronic psychoses have been reported6,7 but their prevalence is unknown. Night-shift workers, students, recreational or self-medicating users, and athletes are potentially vulnerable to misuse. Project STOP is an initiative of the Pharmacy Guild of Australia (http://www.projectstop.com.au/index.html) to curb diversion of pseudoephedrine-containing medications from retail pharmacies into illegal amphetamines. However, it is not mandatory and the National Drugs and Poisons Schedule Committee has rejected the Pharmacy Guild’s proposal to enhance Project STOP’s capabilities using an electronic messaging tool for pharmacists (NotifyRx, RelayHealth, Atlanta, Ga, USA) to regulate codeine sales (excluding cough mixtures). In contrast, New Zealand authorities now restrict the supply of pseudoephedrine to prescription only. A concerted effort from all relevant parties, including tighter regulation or legislation, is essential for harm minimisation. We urge regulatory bodies to review the effectiveness of current practice. Magnetic resonance angiogram of the patient’s brain showing likely hypertensive right basal ganglia haemorrhage

Ajay Bharatula · Peter W New

To the Editor: The report by Leyden and colleagues highlights the value of examining the total experience of stroke thrombolysis in one population.1 The results are devastating: protocol violations in more than a third of cases (consistent with other reports of up to 50%2), and a 10% symptomatic intracranial haemorrhage (ICH) rate (representing a number needed to harm [NNH] of 10). As a clinician, I would be “gutted” if my treatment harmed every 10th patient. The 22% mortality at 3 months is consistent with real-world evidence that stroke thrombolysis increases mortality.3 Although the authors state that the rate of symptomatic ICH was not statistically significantly different to that in the National Institute of Neurological Disorders and Stroke (NINDS) study, an absolute increase of 3.6% (10% versus 6.4%) is clinically important to patients and their families. Presumably, this is largely related to the age protocol violations: 10 of 53 resulted in symptomatic haemorrhage (19%; NNH = 5), including seven cases of intracerebral haemorrhage and five deaths. In all, there were 39 cases of any ICH (25%; NNH = 4). The article highlights that 54% of thrombolysis cases were not on the Safe Implementation of Thrombolysis in Stroke (SITS) registry. This result adds to the concerns of a selection bias in the SITS registry. As the authors point out, the sample size is small — too small, in my opinion, to draw any rigorous conclusions. This highlights that registry results should, at best, be hypothesis generating. However, it has also been highlighted that patients in the SITS International Stroke Thrombolysis Register do worse than those in the placebo group of the European Cooperative Acute Stroke Study III (ECASS III).4 The authors also refer to the ECASS III results, which contend that the time window for stroke thrombolysis should be extended to 4.5 hours. However, methodological and analytical flaws in this study, as well as the NINDS study, cast doubt on this statement.5 A recently published independent review of evidence on stroke thrombolysis concluded, “There is no consistent or proven benefit to thrombolytics”; it included all 11 clinical trials, of which nine had no benefit (with four of these causing harm).6 There are multiple examples in medicine where small studies suggest a benefit, but larger more definitive studies confirm otherwise. Hence, it is very important to look at the totality of the evidence.7 While I agree with the authors that poor access to acute stroke units is deplorable, the real challenge is to define the role, if any, for thrombolysis in acute stroke. Pronouncements that we need to be thrombolysing more are a disservice to those who seek the truth.

Daniel M Fatovich

In reply: To a carpenter, everything looks like a nail, and to a stroke thrombolysis sceptic, every study seems to confirm their opinion. A result cannot be “clinically important” yet statistically not so. We found no difference in symptomatic intracranial haemorrhage rates between our study and others using the same definition. The most widely accepted estimates of the true number needed to harm (for functional outcome at 3 months, following treatment within 3 hours) is about 30, as opposed to a number needed to benefit of around three.1 Our study does not suggest that thrombolysis increases mortality. Mortality cannot be compared between different populations, with different aetiology and severity. We have demonstrated a large number of relative “protocol violations” according to 2007 guidelines, the most common of which was that the patient was older than 80 years, but there is robust evidence that thrombolysis is safe and effective in this cohort.2 The benefit of a therapy cannot be assessed by a tally of “positive” and “negative” trials. A recent meta-analysis of all tissue plasminogen activator trials (seven trials, 2199 patients),3 and the relevant Cochrane review,4 confirm benefit in appropriate patients treated with tissue plasminogen activator within 4.5 hours. Stroke thrombolysis is effective. We must overcome the barriers to administering it frequently, safely and rapidly.

Tim Kleinig · James M Leyden · Andrew Lee · Jim Jannes

To the Editor: In their editorial, Terpening, Hodges and Cordato argue for routine screening for dementia in Australia.1 Most of the editorial is devoted to discussing which test should be used, and the authors contend that the most-used test — the mini-mental state examination — has such poor test characteristics that it would be a very poor basis for routine screening. However, the discussion about which test to use ignores the elephant in the room — should we screen for dementia in the first place? In their 1968 World Health Organization public health paper on screening for disease, Wilson and Jungner stipulate that “There should be an accepted treatment for patients with recognized disease”.2 There is no evidence whatsoever that this is the case with dementia. Terpening and colleagues cite an article in their editorial in support of their assertion that “development of effective dementia treatments depends on earlier and more accurate identification of disease”.3 However, that article only states that early intervention might help to slow some forms of cognitive decline or progression to dementia. This is a very slim evidence base for routine mass screening. The development of effective treatments can never be a justification for routine population-wide screening. Even in a study environment, screening the study population with a view to developing treatments rather than testing them, would struggle to find ethics approval. The evidence is clear — there is no basis for screening for dementia. It would produce many false positives and false negatives, and would cause much anxiety without any benefit from early treatment. As long as no effective treatments are available, the case for screening for dementia is void.

Jan J Barendregt

Longer life expectancies lead to increases in the prevalence of age-associated illnesses. The number of Australians with dementia is predicted to rise, from 234 000 in 2009 to over 1 million by 2050, as a result of the increased prevalence of Alzheimer’s disease (AD), the leading cause of dementia in the elderly. Early diagnosis of AD will become more important as disease-modifying therapies emerge within the next decade. Advances in molecular neuroimaging with amyloid-β-specific radioligands for positron emission tomography, aided by magnetic resonance imaging techniques, allow detection of AD years before symptoms of dementia develop. Longitudinal prospective studies, such as the Australian Imaging Biomarkers and Lifestyle (AIBL) study of ageing, will determine the sensitivity and specificity of these analysis techniques for diagnosing AD and predicting cognitive decline.

Kathryn A Ellis BAppSc(Hons), PhD · Christopher C Rowe MB BS, FRACP, MD · Cassandra E I Szoeke MB BS, PhD, FRACP · Victor L Villemagne MD · David Ames MD, FRCPsych, FRANZCP · Gaël Chételat PhD · Ralph N Martins BSc(Hons), PhD · Colin L Masters MD, FRCPath, HonDLitt · Jurgen Fripp PhD · Oscar Acosta PhD · Parnesh Raniga BSc(Hons) · Pierrick T Bourgeat PhD · Olivier Salvado PhD

Clinical neurology: a primer. Peter Gates. Sydney: Churchill Livingstone, 2010 (450 pp). ISBN 9780729539357. NEUROLOGY is regarded as a difficult specialty but, paradoxically, neurological illnesses are common. Clinicians will come across a large number of patients with neurological symptoms — headaches, strokes, dementia and a variety of pain syndromes, to name a few — in their day-to-day practice, irrespective of their scope of practice. I have been looking for a good clinical neurology textbook to recommend to my students for several years now, and Associate Professor Peter Gates, neurologist at Geelong Hospital and the University of Melbourne, Victoria, has come up with a gem. I read the book from cover to cover and thoroughly enjoyed it. I also gained new skills in teaching neurology. Gates has successfully demystified neurology. Clinical neurology will help cure students and health care practitioners of their “neurophobia” for good, and readers will discover how easy and enjoyable it really is to study and practise neurology. The book starts with an introduction to clinically oriented neuroanatomy that has a novel approach. The author likens the nervous system to a map grid with longitudes (ascending sensory pathways and descending motor pathways) and latitudes (cortical signs, brainstem cranial nerves, nerve roots and peripheral nerves). He uses a number of cases to explain the concepts involved in diagnosis in a way that is easily accessible to the novice. Subsequent chapters take the reader through the neurological examination process and common neurological presentations from a symptom-oriented perspective. Gates then poses the question, “After the history and examination, what next?”, and goes through all possible answers from “no idea what the clinical problem is” to “seeking a second opinion” and “understanding the principles of solving complex clinical problems”. The book is accompanied by a DVD that demonstrates how to perform a neurological examination and includes a series of high-resolution videos on some abnormal neurological signs. Both undergraduate and postgraduate students will find this to be a valuable resource for mastering clinical neurology skills by observing an experienced neurologist in action. The book is aimed at medical students, young doctors and general practitioners; however, clinicians and neurologists should also find it useful.

Tissa Wijeratne

To the Editor: Waxman’s prompt recovery after a stroke was probably a stroke of luck,1 unless perhaps Saint Mary MacKillop was involved. Amid the conflicting evidence on the effect of thrombolysis on recovery in ischaemic stroke, one fact is beyond doubt — thrombolysis gives no greater improvement at 24 hours than placebo.2 It is the various measures of recovery at 3 months, and the risks of adverse outcomes from protocol violations in administering thrombolysis, that are less clear. The European Cooperative Acute Stroke Study III (ECASS III) showed that there is a benefit from administering thrombolysis up to 4.5 hours after stroke onset,3 and the complete Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register (SITS-ISTR) data showed that this benefit can be reproduced in non-trial hospital practice.4 Simpson and colleagues say that the Australian data support this conclusion, even though outcomes show slightly higher mortality compared with rest-of-world data.5 There are several gaps in that line of reasoning. A modified Rankin score (mRS) of 0–1 (zero or minimal disability) is the standard measure of a good outcome. In ECASS III, an mRS of 0–1 was seen in 52.4% of patients who received thrombolysis compared with 45.1% of patients who received placebo.3 However, the SITS-ISTR data showed an mRS of 0–1 in just 40% of patients treated within 3 hours of stroke onset and 44% of patients treated at 3–4.5 hours.4 This is despite lesser stroke severity (National Institutes of Health Stroke Scale score: 10 in the SITS-ISTR cohort v 11.6 in the ECASS III placebo group), selective patient inclusion, and exclusion of patient data with protocol violations known to give worse outcomes. Achieving a worse result than placebo is hardly evidence for safe and effective use of thrombolysis in normal clinical practice. However, the Australian study presents the data differently, using an mRS of 0–2 and thereby concluding good outcomes in patients with greater disability than is the accepted good outcome measure.5 Rather than providing the actual data and the percentage of patients with good outcomes, a novel measure of odds ratio comparison with rest-of-world data is made. Publishing data in the same format as for the full SITS-ISTR report would allay concerns of what may be unfavourable outcomes compared with clinical trial data. Patients deserve to be told what their likely prognosis will be in hospitals that are less experienced in stroke thrombolysis than The Alfred, where Waxman received world-class stroke care.

Brendon J Smith

In reply: We were delighted to hear of Waxman’s “miraculous” recovery, and admire the world-class standard of stroke care which was delivered at The Alfred.1 The Australian data in the Safe Implementation of Thrombolysis in Stroke (SITS) database up to 2008 included tertiary referral centres and outer metropolitan hospitals, and centres with varying experience of using recombinant tissue plasminogen activator (rt-PA) in clinical practice. There was no difference in outcomes according to experience of the treating centres. We believe that the non-trial clinical data presented in our article are a realistic indication of expected outcomes for all patients receiving thrombolysis for stroke in Australia. The choice of a modified Rankin score (mRS) of 0–2 as an outcome measure in our article was largely dictated by the SITS international analysis. The aim of our study was to compare outcomes in Australia with those in the rest of the world; these were also not significantly different when an mRS of 0–1 was used as an outcome measure (mRS 0–1 at 3 months, 34.6% for Australia v 37.8% for the rest of the world; P = 0.13). The original National Institute of Neurological Disorders and Stroke (NINDS) trial data,2 now more than 15 years old, have been analysed and re-analysed and, arguably, it is time to move on from rehashing the data. However, if one wishes to follow this path, there was in fact a significant difference in improvement at 24 hours between patients in the rt-PA and placebo groups. Smith’s statement that thrombolysis gives no greater improvement at 24 hours than placebo is correct in terms of the proportion of patients with an improvement in National Institutes of Health Stroke Scale (NIHSS) score of 4 or more, but this is a low benchmark and many untreated patients also show a relatively mild improvement at 24 hours. If one considers major neurological improvement (MNI, defined as an improvement in 24-hour NIHSS score of 8 or more), this was seen in a greater proportion of patients in the rt-PA group compared with the placebo group.3 Patients with MNI have a much greater chance of achieving minimal or no disability at 3 months, which is by far the most accepted outcome measure for thrombolytic therapy. This major early recovery is frequently seen in patients who receive rt-PA, and has been termed the “Lazarus effect”. Waxman was fortunate enough to experience this effect — but it occurs far too often with rt-PA in stroke to pass the Catholic Church criteria for a miracle.

Marion A Simpson · Helen M Dewey · Mark W Parsons

Objective: To report the rate of thrombolysis for treating acute stroke in South Australia from October 2007 to September 2009. We hypothesised that the rate of thrombolytic therapy would be related to distance from an acute stroke unit.Design, setting and patients: An observational, population-based, retrospective review of case notes and imaging, using multiple case-ascertainment methods. Patients administered a thrombolytic agent by any method for suspected ischaemic stroke in urban, rural, public and private hospitals in SA (covering a population of 1.5 million people) were included.Main outcome measures: Absolute and relative contraindications for thrombolysis administration in each case, according to the 2007 National Stroke Foundation guidelines; incidence of haemorrhage; and population thrombolysis rates according to distance from an acute stroke unit.Results: A total of 158 cases of thrombolytic therapy for suspected acute ischaemic stroke were identified in 157 patients. Fifteen patients (10%) had symptomatic intracranial haemorrhage, of whom eight (5%) died within 3 months. Seven patients had symptomatic extracranial haemorrhage. Five patients (3%) received thrombolysis despite absolute contraindications. Patients living closer to stroke units were more likely to receive thrombolysis.Conclusions: Rates of symptomatic haemorrhage after thrombolysis were similar to those in voluntary registries. A large proportion of South Australians are currently missing out on acute stroke therapy as a result of poor access to acute stroke units in both urban and rural settings. It is estimated that fewer than 2% of ischaemic stroke patients are administered thrombolysis in SA.

James M Leyden MB BS, FRACP · Woon K Chong MB BS, FRANZCR · Tim Kleinig MB BS(Hons), FRACP, PhD · Andrew Lee MB BS, MPH, FRACP · John B Field PhD, AStat · Jim Jannes BM BS, FRACP, PhD

Objective: To determine the predictive value of the ABCD2 score for early risk of stroke in Australian patients who have had transient ischaemic attack (TIA).Design, participants and setting: Cohort study of 512 consecutive patients with suspected TIA referred by the emergency department to the acute stroke unit (in accordance with the TIA pathway) of an urban tertiary hospital in Melbourne, Victoria, between 1 June 2004 and 30 November 2007.Main outcome measures: Overall accuracy, estimated by the area under the curve (AUC) of receiver operating characteristic plots (of true positive rate v false positive rate), and sensitivity, specificity, predictive values and likelihood ratios at prespecified cut-off ABCD2 scores for stroke within 2, 7 and 90 days.Results: 24 patients were excluded because their symptoms lasted more than 24 hours. All included patients were reviewed by a stroke physician; TIA was confirmed in 301/488 (61.7%). Most (289/301; 96.0%) had complete follow-up. Stroke occurred in 4/292 patients (1.37%; 95% CI, 0.37%–3.47%) within 2 days and 7/289 (2.42%; 95% CI, 0.98%–4.93%) within 90 days; no patient had a stroke between 2 and 7 days. The AUCs for stroke in patients with confirmed TIA were 0.80 (95% CI, 0.68–0.91) and 0.62 (95% CI, 0.40–0.83) for stroke within 2 days and 90 days, respectively. At a cut-off of ≥ 5, the ABCD2 score had modest specificity for stroke within 2 days (0.58) and 90 days (0.58), but positive predictive values (2 days, 0.03; 90 days, 0.04) and positive likelihood ratios (2 days, 2.40; 90 days, 1.71) were both poor. The score performed similarly poorly at other prespecified cut-off scores.Conclusions: Given its poor predictive value, the use of the ABCD2 score alone may not be dependable for guiding clinical treatment decisions or service organisation in an Australian tertiary setting. Validation in other Australian settings is recommended before it can be applied with confidence.

Lauren M Sanders MB BS · Velandai K Srikanth FRACP, PhD · Helen Psihogios FACEM · Kitty K Wong SRN, MPH · David Ramsay RN · Thanh G Phan FRACP, PhD