Neurology

Considering the clinical implications of new research data on migraine and brain lesions Migraine has received considerable attention in the past 15 years as it has come to be better understood as a brain disorder with new and efficient treatment strategies.1 The World Health Organization considers a day with severe migraine to be in the highest category of disability, comparable to quadriplegia.2 Migraine is classically described and defined as an episodic disturbance manifest primarily as head pain and sensitivity to afferent stimuli, such as light (photophobia), sound (phonophobia) and head movement.3 Against this background, new data have emerged that open the issue of whether migraine may be progressive in some way. Kruit and colleagues recently published a cross-sectional, population-based study of Dutch adults aged 30–60 years. They compared the prevalence of brain infarctions and white-matter lesions between people with migraine and control subjects matched for age, sex, place of residence and potential risk factors for cerebrovascular disease.4 Overall, there was no difference between people with migraine and controls in prevalence of infarction. There was an increase in posterior circulation lesions in patients with migraine with aura, and more deep white-matter lesions in women with migraine. The authors concluded that some patients with migraine are at increased risk for subclinical lesions in certain brain areas. These data come at a time when others have suggested a link between migraine and right-to-left cardiac shunts5 (which may predispose to stroke), and when there are known risks for stroke in women under 35 years with migraine.6 It has been suggested that these data may mark migraine as a progressive, rather than simply episodic, disorder.7 This is not a trivial question for migraineurs or their physicians. A progressive disorder is one where there is a continuous increase in severity or extent (Oxford English Dictionary). This may relate to symptoms or some objective measure, such as brain imaging. Migraine certainly does not, in general terms, increase in severity with time, as the natural history is to abate and disappear in later life.8 So, with very few exceptions, it could not be called progressive on the basis of increasing severity with time. This does not negate the fact that some migraine sufferers go through enormously disabling periods of frequent attacks — chronic migraine. 9 This smaller group10 needs attention, but progression should not be ascribed to the vast majority of sufferers. Whether migraine causes permanent, progressive brain lesions is also not established. The relationship between migraine and cardiac right-to-left shunts is at best cloudy. These shunts may arise from a patent foramen ovale (found in about a quarter of the population), atrial septal defects and arteriovenous malformations; they have been implicated in stroke and decompression illness as a result of paradoxical embolism. However, studies of the association with migraine were not population-based, and case definitions were very poor, mixing migraine with aura with isolated aura. The latter makes it impossible to be sure whether the events described were migrainous or ischaemic in nature. Stroke risk is certainly increased for women under 35 with migraine with aura, but the increase is small, and one wonders if this highlights a prothrombotic or vasculopathic comorbidity in a particular subset, rather than a general pathophysiological principle for all patients. The new study by Kruit and colleagues4 gives pause for thought, but, as it is cross-sectional, it provides a hypothesis, not proof. It certainly does not provide evidence that lesions in the brain produce chronic migraine. Only a longitudinal study would give information on accumulation of lesion load that would provide evidence for a progressive course. While the authors of a recent meta-analysis of observational studies of ischaemic stroke risk in migraine conclude that there is an association,11 their review, unfortunately, adds nothing to our understanding. Most studies show an association, and half of the 14 studies in the meta-analysis did not divide their patients with migraine into those with and without aura. Thus, the really interesting possibility suggested by Kruit and colleagues4 of patients with migraine with aura being at increased risk of subclinical brain lesions could not be explored. What are the clinical implications of the new data? First, we can assure patients with migraine without aura that there seems little risk of any progressive or serious problem in terms of brain lesions. Unfortunately, we can also assure them that they will suffer, losing time from work and their personal life, year on year, unless we can help them manage their attacks properly by appropriate advice and use of acute attack and preventive medicines. For patients with migraine with aura, I explain that the risk of stroke is small. Indeed, it is smaller, even for those taking oral contraceptives, than the risk of stroke during pregnancy itself. The available data do not, in my view, justify antiplatelet agents in patients with migraine with aura, nor do they provide intellectual justification for paternalistic limitations on patient choice in, for example, contraceptive use. As a rule, I investigate the unusual: one might target those with prolonged aura (ie, over an hour3) with standard stroke investigations. Migraine is a horrible, disabling, biologically determined, inherited brain disorder rendering life much less tolerable, but for the moment there is no sustainable position that it is progressive for most patients. We can look forward to new data with which to qualify and quantify the issue.

Peter J Goadsby MD, PhD, DSc FRACP, FRCP

A 66-year-old man presented with a 12-month history of progressive gait disturbance with cerebellar ataxia and extrapyramidal features. Computed tomography of the head showed calcification of the basal ganglia and dentate nuclei of the cerebellum, and periventricular calcification (Box). Biochemical testing showed serum level of calcium, 1.19 mmol/L (reference range [RR], 2.15–2.55 mmol/L); ionised calcium, 0.61 mmol/L (RR, 1.14–1.29 mmol/L); phosphate, 1.8 mmol/L (RR, 0.8–1.5 mmol/L); and parathyroid hormone, 0.9 pmol/L (RR, 1.5–8.0 pmol/L). The patient was diagnosed with hypocalcaemia caused by idiopathic hypoparathyroidism. He was treated with calcitriol (2 μg daily) and calcium carbonate (6.0 g daily). His gait showed some improvement, and serum calcium levels became normal over several weeks. The pathophysiology of intracerebral calcification in hypoparathyroidism, which appears paradoxical, is unknown. It is usually asymptomatic. When neurological effects occur, they are thought to be caused by microvascular degeneration from massive perivascular calcium deposition in high-metabolic areas. Computed tomography of the head, showing cerebral calcification A: Calcification of the basal ganglia. B: Calcification of the dentate nuclei of the cerebellum. C: Periventricular calcification.

Huong Van Nguyen MB BS · Seng Khee Gan FRACP

Angelo Labate,* Mark R Newton,† Graeme M Vernon,‡ Samuel F Berkovic§ * Research Fellow, Brain Research Institute, † Neurologist, § Director, Epilepsy Research Centre, ‡ Drug Information Pharmacist, Austin Health, Heidelberg West, VIC 3081. s.berkovicATunimelb.edu.au To the Editor: Tramadol is a synthetic, centrally acting analgesic that was approved for use in Australia in 1998. Seizures have been reported in patients receiving the drug in overdose and, rarely, at the recommended dose.1-4 Over a one-year period, we observed a number of tramadol-associated seizures in the First Seizure Clinic at Austin Health, an outpatient service for rapid evaluation and diagnosis of patients with new-onset seizures.5 We evaluated 197 patients from April 2003 to April 2004. One hundred had alternative diagnoses to epileptic seizures: syncope (n = 56), convulsive syncope (n = 27), panic attacks (n = 3) and other events (n = 14). Of 97 patients with confirmed seizures, 8 (5 male; median age, 34 years [range, 18–51 years]) were associated with tramadol (Box). Two patients who had received high doses of tramadol (600–750 mg/day [maximum recommended dose, 400 mg/day]) had developed seizures within 24–48 hours. Among the other six patients, who had received tramadol in the recommended dose range (50–300 mg/day), seizures had occurred 2–365 days after commencing therapy. Long-term psychotropic medication was taken by two patients. Seizures were generalised tonic–clonic seizures, without auras or focal features. No patient had a prior history of seizures, and none had a recurrence after they had ceased taking tramadol for a median of 9 months’ follow-up (range, 2–14 months). Electroencephalographic studies were normal in seven patients, with only one isolated sharp slow-wave in one patient. Computed tomography scans were all normal, and magnetic resonance imaging was normal in five patients. Previous US studies suggest a relatively low risk of seizures with tramadol, unless it is taken by people with epilepsy or taken with other drugs that reduce the seizure threshold.2-4 Tramadol is now widely prescribed in Australia, with 1.65 million prescriptions for oral tramadol issued under the Pharmaceutical Benefits Scheme in 2003.6 The Australian Adverse Drug Reactions Advisory Committee had received 83 reports of convulsions associated with tramadol to March 2004, although in only three cases was the association classified as “certain”. In our First Seizure Clinic, tramadol is the most frequently suspected cause of provoked seizures. We cannot calculate the exposure risk in our population, but the frequency of tramadol-related seizures suggests that they may be under-reported. It is important to consider tramadol as a possible cause of seizures — even when used at recommended doses. This may avoid inappropriate use of anti-epileptic drugs and unnecessary restrictions on driving and choice of vocation that might apply in cases of new-onset epilepsy. Details of eight patients with tramadol-related seizures at the First Seizure Clinic, Austin Health, April 2003–April 2004 Patient 1 2 3 4 5 6 7 8 Age (years) 18 35 31 33 48 51 25 45 Sex M F F M M M F F Tramadol dosage (mg/day) 750 600 100 300 100 50 100 300 Treatment duration (days) 1 2 7 365 21 90 2 180 Concomitant psychotropic drug taken No No No Yes* Yes† No No No Duration of follow-up (months) 12 9 14 9 9 3 3 2 * Chlorpromazine hydrochloride 200 mg/day. † Haloperidol 1 mg/day.

Angelo Labate · Mark R Newton · Graeme M Vernon · Samuel F Berkovic

Daniel M Fatovich Specialist in Emergency Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847 daniel.fatovichAThealth.wa.gov.au To the Editor: I have read with interest the debate in the MJA on the use of tPA in acute ischaemic stroke. Most recently, Levi et al published a position statement stating that it is a major advance.1 This was probably in response to Hoffman’s critical editorial.2 At the 10th International Conference on Emergency Medicine in June 2004, a session on the use of tPA in acute ischaemic stroke clearly portrayed thrombolysis as not standard care.3 I have attended other emergency medicine conferences where thrombolysis was seen as risking more harm than good. Conversely, I expect that stroke physicians attend stroke conferences that endorse thrombolysis. In my experience, when such divergent views exist, it usually means that we don’t have enough answers. I would like to outline here some other viewpoints that are not often considered. Number needed to harm (NNH): The best results to date were from the NINDS study that reported a number needed to treat (NNT) of 8.4 With their findings of an intracranial haemorrhage rate of 6.4%, the NNH is about 16. Hence, for every 16 patients treated with tPA, two may derive much benefit, but one much harm. These odds are worse than Russian roulette. The Cleveland study reported an intracranial haemorrhage rate of 22%.5 Hence, the worst possible NNH is about 5. Other authors have expressed similar ethical concerns.6 Risk tolerance is an individual judgement, but, when faced with the above issues, my practice is to ask what I would want for myself. Knowing that the earlier thrombolysis is given the better,7 my personal choice would be to only have thrombolysis if it is administered within 90 minutes of stroke onset (ie, maximal benefit and minimal risk). Unfortunately, it is rare for patients to present early enough for this to occur. Furthermore, many of my colleagues do not know what they would want for themselves, so how can we advise our patients? Pathophysiology: Heart muscle is relatively robust, whereas the brain is a softer structure. A haemorrhagic complication is very different in the two organs. Mode of thrombolysis: Giving thrombolysis by infusion is an outdated approach. Furthermore, thrombolysis is almost a forgotten therapy for acute myocardial infarction in tertiary centres because of the use of primary angioplasty. When thrombolysis is used, the agent is given as a bolus. Uptake of this mode of administration would be rapid if it were shown to be effective and safe for acute ischaemic stroke. Obviously, consensus among care providers on the use of tPA does not exist. This means that more research needs to be done to work out the answers to these difficult questions. I believe there is much support for this, as we need to define who should be receiving thrombolysis, and, perhaps more importantly, who should not. We all want something that works! However, we need greater knowledge to overcome the safety issues. The answer to Levi’s question “Why did it take so long?” is “Because it is a complex problem”.

Daniel M Fatovich

Ian R Rogers,* George A Jelinek,† Ian Jacobs* * Associate Professor, † Professor, Discipline of Emergency Medicine, Queen Elizabeth II Medical Centre, Nedlands, WA 6009. Ian. RogersAThealth.wa.gov.au To the Editor: We applaud the call of Levi and his co-contributors for collegiate communication and consensus regarding the use of tissue plasminogen activator in acute ischaemic stroke.1 Emergency care providers are acutely aware of their role at the centre of the acute healthcare system. Daily, we interact with colleagues from other disciplines in the course of seeking the best clinical care for our patients. However, the views expressed by Hoffman2 are shared by many emergency physicians and prehospital care providers. We remain unconvinced of the role of thrombolysis in acute ischaemic stroke outside the setting of properly constituted clinical trials. On review of the contributors list in Levi’s article, we are unable to identify a single specialist emergency medicine or prehospital care provider. Consensus is not likely to be achieved until position statements from expert groups include a strong representation from all the specialty disciplines involved in the care of stroke patients. We look forward to developments in this direction.

Ian R Rogers · George A Jelinek · Ian Jacobs

Christopher R Levi (on behalf of the Australasian Stroke Unit Network, the New South Wales Greater Metropolitan Clinical Taskforce Stroke Initiative, and the Towards A Safer Culture Stroke Expert Working Group) Director, Acute Stroke Services, John Hunter Hospital, Locked Bag No. 1, Hunter Region Mail Centre, NSW 2310. christopher.leviAThunter.health.nsw.gov.au In reply: We thank the authors for their comments on our recent position statement.1 We fully agree and accept the view of Rogers and colleagues that emergency physicians are central to the timely and safe delivery of emergency medical care in our health system. This is especially the case for a therapy such as intravenous tPA, given the narrow therapeutic window and coordination challenges. We view the development of linkages with our colleagues in emergency medicine as crucial in implementing not only tPA but also a number of acute stroke therapies showing great promise in the advanced stages of development.2 Our position statement is a starting point for broader discussion, and we are pleased that discussions between the key groups are under way. We agree that, when considering patient suitability for intravenous tPA, a number of uncertainties remain, and we fully support the rationale for the ongoing clinical trials of thrombolysis in acute ischaemic stroke (see www.astn.org.au/epithet/index.html and www.ist3.com/). The risk–benefit ratio will be improved in the 0–90-minute window, as indicated by Fatovich. However, it is likely that some patients at much later time points will also gain benefit. We would emphasise, however, that according to Australia’s independent arbiter of therapeutic safety and efficacy, the Therapeutic Goods Administration, intravenous tPA is an approved therapy if given within a 3-hour window, under appropriate clinical circumstances and within appropriate healthcare settings. Regarding the comments by Fatovich on number needed to harm, it is important to recognise that the most serious adverse outcome of intravenous tPA — fatal intracerebral haemorrhage — is already accounted for in the calculations of number needed to treat (for patients to survive free from dependency). Intra-arterial thrombolytic therapy in the form of prourokinase has been found to be effective in reducing dependency in acute ischaemic stroke, shown angiographically to be caused by middle cerebral artery occlusion.3 Feasibility issues, however, presently limit the application of the intra-arterial approach, and the relative risk of intracranial haemorrhage, even with this more targeted approach, is similar to that seen with intravenous therapy. The importance of cross-disciplinary teamwork in the effective application of current and future acute stroke therapies cannot be underestimated. Central to this is the need to develop an effective dialogue between the leaders of these teams — stroke physicians and emergency physicians. The Australasian Stroke Unit Network, the New South Wales Greater Metropolitan Clinical Taskforce Stroke Initiative, and the Towards A Safer Culture Stroke Expert Working Group are committed to the task of helping to build better links between stroke units and emergency departments.

Much has been written about false memories — memories that are a distortion of an actual experience, or a confabulation of an imagined one. Memory and its reliability or otherwise have profound implications for us all, not only in our daily lives, but clinically and medicolegally. How often does a medical negligence or misconduct allegation boil down to “he said, she said” evidence? And we have all experienced the mismatch of memories of events shared in the distant past by more than one person. This personal anecdote records the same event as recalled by two people. Quite fortuitously in this instance, objective contemporaneous evidence settled the disagreement. Being a borderline student in Chemistry I, my poor performance in the practical examination was enough to secure a fail mark and a repeat of first-year medicine. During my rerun of Chemistry, I consistently failed to identify the colours of certain metals when held in the Bunsen flame. The Ishihara chart confirmed partial red–green colour blindness. Four years later, in 1959, I bumped into a medical school colleague in Paris, and we visited an art gallery together. Throughout the ensuing 45 years, my memory has been that the gallery was the Louvre. I have a clear memory of our standing before an impressionist painting by Manet, with mainly blue to purple hues, of Paris in the rain. My companion commented how wonderfully the red roofs contrasted with the overall bluish colours. I asked, “What red roofs?”. I could not see them until she pointed them out, and was intensely disappointed by this aesthetic consequence of my red–green handicap. That night I recorded the unhappy event in my diary. I have since visited perhaps no more than two or three art galleries, and then only as a reluctant companion to my wife. Van Gogh’s bedroom in Arles Van Gogh’s bedroom in Arles (oil on canvas — Musée d’Orsay, Paris; photo RMN © Gérard Blot) — one of three versions of the same painting, and most likely the one I saw. This one, painted while Van Gogh was voluntarily confined to a mental asylum in Saint-Rémy, includes a self-portrait as one of the paintings above the bed. In a letter to his brother, Théo, Vincent wrote “. . . it’s just simply my bedroom, only here colour is to do everything . . .” Fast forward to 2002. By chance, I re-established communication with my student colleague, now a psychiatrist in England. I commented how she had been someone I had always remembered, in large measure because of our joint experience at the Louvre. She replied that our gallery visit had made its mark on her, too. In subsequent decades of lecturing, she had taken care, when preparing slides, overheads and PowerPoint presentations, to avoid colours that might be confusing to men like me. However, the painting had not been in the Louvre, she said, but at a museum of impressionist art near the Place de la Concorde. Furthermore, the red I had not been able to see in the painting was not Parisian roofs in the rain, but the red heads of birds! Quite fortuitously, at the time of this correspondence, I was transcribing my 1959 European travel diary into typescript. I quickly checked my entry for the day at the art gallery. Yes, my colleague was right: it was a museum at the Place de la Concorde, not the Louvre. (The museum was, in fact, the Musée du Jeu de Paume at the Place de la Concorde, which housed the collection of impressionist paintings of the Louvre before they were relocated to the Musée d’Orsay in 1986.) But the painting in question? No red roofs in a rainy Paris. No birds with red heads. It was the famous Van Gogh painting of his bedroom in Arles, with the large, red coverlet on his bed! I had been familiar with Van Gogh’s bedroom painting for many years before going to Europe. But my memory, over nearly five decades, remains of rainy red roofs. No matter that I have searched the catalogues of the Impressionists and have not found such a painting. No matter that I now know that the painting with the invisible reds was the Van Gogh pictured here, my memory remains undiminished — red roofs in the rain! I still “see” them clearly. As for my colleague, despite my presenting her with the contemporaneous evidence of my diary, she, in turn, “knows” that the picture was of birds with red heads!

Peter C Arnold BSc, MB BCh, BA

Raised plasma homocysteine (tHcy) concentrations are caused by genetic mutations, vitamin deficiencies, renal and other diseases, numerous drugs, and increasing age. Raised tHcy concentrations are associated with laboratory evidence of atherogenesis (eg, endothelial dysfunction) and thrombosis, and epidemiological evidence of an increased risk of atherothrombotic vascular disease. An association between raised tHcy concentration and an increased risk of atherothrombosis is independent of other vascular risk factors, strong, dose-related and biologically plausible, but has not been proven to be causal in randomised controlled trials. A recent trial identified no significant benefit from lowering tHcy concentration by folic-acid-based multivitamin therapy among 3680 patients with recent ischaemic stroke, but did not reliably exclude a modest but important reduction in the relative risk of stroke of up to 20%; a difference of only 2 mmol/L in tHcy concentration between the two treatment groups was probably due to widespread vitamin use and fortification of grains and staple foods with folate in North America. There is currently insufficient evidence to recommend routine screening and treatment of high tHcy concentrations with folic acid and other vitamins to prevent atherothrombotic vascular disease.

Graeme J Hankey MD, FRACP, FRCP · John W Eikelboom MSc, FRACP, FRCPA · Wai Khoon Ho MB ChB, FRACP, FRCPA · Frank M van Bockxmeer PhD, FAHA

Clinical record A 36-year-old man was found semiconscious in a park. He was carrying a syringe which was later found to contain high-purity amphetamine. He became combative, and was sedated and intubated on arrival at a hospital emergency department. Preliminary examination revealed proptosis of the left eye, which was surrounded by swelling and erythema, and a small conjunctival laceration on the nasal aspect. Pupillary light reflexes were normal. Examination revealed track marks in both cubital fossae suggesting intravenous drug use, but no other abnormalities. Non-contrast computed tomography (CT) of the brain revealed two minute areas of high density in the left frontal lobe, interpreted as evidence of early infection. CT of the orbits revealed left-sided swelling of the subcutaneous soft tissue, interpreted as preseptal cellulitis. A fracture of the left orbital roof was also noted adjacent to a superior orbital phlegmon (Box 1A). A lumbar puncture was performed, and, with a provisional diagnosis of preseptal cellulitis and meningitis, the patient was empirically treated with broad-spectrum intravenous antibiotics (vancomycin, ceftriaxone, gentamicin and metronidazole), while remaining intubated in the intensive care unit. However, as the cerebrospinal fluid appeared normal on microscopy and biochemical examination and showed no growth on culture, the initial diagnosis was questioned. Magnetic resonance imaging of the brain and orbits was performed the day after presentation. This showed a 5 cm tract extending obliquely from the roof of the left orbit into the white matter of the left frontal lobe, associated with a fracture of the orbital plate of the frontal bone (Box 1B). Inflammatory changes, presumed infective, were noted superiorly within the left orbit, resulting in proptosis. It was concluded that the patient had incurred a penetrating injury of the left orbit entering through the nasal conjunctiva and extending superiorly to the globe, through the orbital plate of the left frontal bone, and into the frontal lobe. Treatment with vancomycin, ceftriaxone and metronidazole was continued, and the patient was successfully extubated after 5 days. He was then able to recount jumping over a fence and landing on bushes, a branch of which penetrated his orbit. Re-examination revealed a marked decrease in the soft-tissue swelling around the left globe, but significant limitation of movement of the left eye in all directions (Box 2). These findings, along with the known intracranial penetration and the possibility of retained organic fragments, necessitated surgical exploration. A superior orbitotomy revealed an abscess containing tiny fragments of organic matter. This was washed out. The abscess was sterile on culture. The orbital tract was explored, and further small fragments of organic matter were retrieved. A left frontal craniotomy and repair of the roof of the left orbit were performed concurrently. Over the ensuing 10 days, the patient’s ocular movements improved to near full range, but he had intermittent temperature spikes. Multiple blood cultures showed no growth. Transthoracic echocardiography revealed a vegetation on the tricuspid valve. Intravenous antibiotics were continued for a further 6 weeks to treat presumed infective endocarditis. Although the patient developed no further symptoms, magnetic resonance imaging of the brain 11 days after the initial surgery revealed an elongated abscess in the frontal lobe, its inferior end abutting a small fragment of intracranial bone. The left frontal craniotomy was reopened, and the abscess drained. Culture of the abscess again showed no growth, and the patient required no further surgical intervention. Transorbital intracranial penetration by a wooden foreign body is unusual.1 The resilience of the sclera and ability of the globe to be displaced usually protect the eye from perforation.2 Metallic objects and glass fragments are the foreign bodies most often encountered in the orbit.3 Although computed tomography is excellent for identifying these high-density objects, it is much less sensitive for low-density organic objects.4 Magnetic resonance imaging is more sensitive for delineating the extent of orbital injury and is safe when non-magnetic foreign bodies, such as wood, are suspected.5 Because of its porous organic nature and frequent proximity to soil, wood is an ideal reservoir for bacteria and fungi and is likely to provoke inflammation. A narrow deep tract, such as occurred in our patient, is conducive to the proliferation of anaerobic bacteria.6 The most usual complications of an orbital foreign body are proptosis of the eye, development of a chronic fistula, orbital abscess or cellulitis, and damage to the extraocular muscles or optic nerve.7 Intracranial extension of the foreign body is associated with a 48% incidence of brain abscess and a 25% mortality rate.1,6 This case illustrates the possibility that a seemingly trivial lesion, such as a conjunctival laceration, can be associated with severe lesions in the orbital region. This case demonstrates the need to suspect intracranial penetration in orbital injuries, as intra- and extracranial complications often lead to prolonged hospital admission and carry a significant risk of mortality . Lessons from practice The diagnosis of transorbital intracranial penetration of a foreign body requires a high index of suspicion, as it can present with trivial findings on examination. Intracranial penetration carries significant morbidity and often leads to local and systemic complications. Early magnetic resonance imaging is recommended when there is a possibility of transorbital intracranial penetration. 1 Imaging in a patient with an orbital fracture A. Computed tomography showed a fracture of the roof of the left orbit (F), adjacent to a superior orbital phlegmon (P). B. Subsequent magnetic resonance imaging showed a 5 cm oblique tract extending from the fracture of the orbital plate of the left frontal bone into the white matter of the left frontal lobe. 2 Limitation of movement of the left eye The patient is attempting to look to his right.

Dana Robaei MB BS(Hon), MPH · Glen T Fernando MB BS(Hon) · Charmaine MacDonald MB BS · Michael G Branley FRACO, FRACS

Objective: To determine risk factors for ischaemic stroke recurrence among patients admitted to hospital for a first-ever occurrence of ischaemic stroke.Design, setting and patients: Retrospective study involving linked hospitalisation and death records. The cohort comprised 7816 people who were hospitalised for first-ever ischaemic stroke between July 1995 and December 1999 in Western Australia. Cox’s proportional hazards model was used to identify risk factors for stroke recurrence.Main outcome measures: Time to first recurrence; cumulative recurrence risk; risk factors for recurrence.Results: The median time to first stroke recurrence was 255 days. The cumulative probability of first recurrence was 5.1% (95% CI, 4.6%–5.7%) at 6 months, 8.4% (95% CI, 7.6%–9.1%) at 1 year and 19.8% (95% CI, 18.1%–21.4%) at 4 years. The risk of first recurrence was increased by advancing age (hazard ratio [HR], 1.03; 95% CI, 1.02–1.04), Aboriginality (HR, 1.50; 95% CI, 1.02–2.22), diabetes (HR, 1.27; 95% CI, 1.07–1.51), a history of cardiac conditions (HR, 1.18; 95% CI, 1.01–1.38), post-stroke urinary incontinence (HR, 1.27; 95% CI, 1.03–1.57) and transfer to another hospital on index admission (HR, 1.26; 95% CI, 1.08–1.46). Admission at first stroke occurrence to a hospital maintaining a stroke unit reduced the risk of recurrence (HR, 0.84; 95% CI, 0.72–0.99).Conclusion: The risk factors identified in our study have implications for planning secondary prevention strategies. In particular, Aboriginality and transfer to another hospital upon admission for first-ever ischaemic stroke were important risk factors. Research into the level of compliance and access to stroke treatment by Aboriginal patients to prevent further strokes is required.

Andy H Lee PhD · Peter J Somerford BSc · Kelvin K W Yau PhD, AStat

Clinical record A 32-year-old woman presented to the Royal Brisbane Hospital immediately on disembarking from a flight from Bangkok. She had a 5-day history of gastrointestinal symptoms, fever and altered mental state. She was a university graduate and had travelled for 2 months across south-east Asia before becoming unwell in Phnom Penh, Cambodia. Her illness began with mood elevation, hallucinations, muscle spasms and paraesthesiae, shortly after ingestion of a “herbal pizza”. Within 24 hours, nausea, vomiting and profuse watery diarrhoea ensued. Despite empirical treatment for bacterial gastroenteritis, symptoms progressed to lethargy with altered mental state. The patient had been taking doxycycline for malaria prophylaxis, and had been vaccinated against viral hepatitis, tetanus, poliomyelitis and typhoid. She was aware of the availability of a Japanese encephalitis vaccine, but had been advised that it was not essential. On presentation, the patient was drowsy and dehydrated, with a temperature of 38°C and tachycardia. There was peripheral leukocytosis (white cell count, 17.9 x 109 cells/L; reference range [RR], 4.0–11.0 x 109 cells/L) with dominant neutrophilia, as well as hyponatraemia, but renal function was preserved. Fever and lethargy persisted over 48 hours despite rehydration and regular paracetamol. Increasing obtundation and a fine tremor were observed. The patient complained of persistent headache, mild photophobia and neck discomfort. Her partner commented on her slow mentation, reduced concentration and personality change. Investigations for malaria, typhoid, rickettsial disease and infectious diarrhoea were all negative. Magnetic resonance imaging of the brain detected no abnormalities. Cerebrospinal fluid (CSF) showed mononuclear pleocytosis (white cell count, 12 x 106 cells/L; 92% mononuclear cells [RR, < 5 x 106 mononuclears/L]), with mild elevation of protein level (0.62 g/L [RR, <0.45 g/L]), but was negative for herpes simplex virus by polymerase chain reaction. Flavivirus-specific IgM was detected in CSF and subsequently blood. The diagnosis of Japanese encephalitis was confirmed by a rise in titre of specific IgG in blood, from 80 (8 days after onset of illness) to 1280 (4 weeks after onset). The fever resolved spontaneously by Day 4 after presentation, and the patient was discharged after 10 days. At the time of discharge, her level of alertness had improved, but global impairment of higher cognitive functioning and tremor persisted. After a period of convalescence of approximately 5 months, during which she was cared for by her partner, the patient was able to return to work. Japanese encephalitis is the leading cause of viral encephalitis in Asia, with recent epidemics in India, Malaysia and Nepal.1 An outbreak of Japanese encephalitis in the Torres Strait Islands and the northern extremity of Cape York in March 19952 raised concern that this arbovirus may become established in feral pigs in northern Australia. Although the overwhelming majority of infections are asymptomatic, the case-fatality rate of symptomatic infection is 25%–30%, with neuropsychiatric sequelae seen in 30%–50% of survivors.3 The incubation period ranges from 4 to 21 days. The earliest symptoms are lethargy, high fever, headache and gastrointestinal symptoms.4 Japanese encephalitis should therefore be considered among unwell travellers returning from endemic areas, including those with undifferentiated fever.4 Blood and CSF are positive for flavivirus antibodies by 10 days after symptom onset. Specific IgM antibody may appear earlier in the CSF. Treatment is symptomatic. A vaccine is available for Japanese encephalitis and is administered as three doses over 30 days, at a material cost of over $300. Vaccination is recommended for: Travellers spending at least one month in rural areas of Asia or the Western Province of Papua New Guinea, particularly during the wet season, or if there is considerable outdoor activity, or suboptimal accommodation. It is possible that this recommendation will be expanded to include all areas of Papua New Guinea.5,6 Travellers spending a year or longer in Asia (except Singapore), even if lifestyle is predominantly urban.7 All permanent residents of the outer Torres Strait Islands over the age of 1 year and all non-residents who will be living in the region for 30 or more days during the wet season (December–May). Vaccine uptake among travellers in whom it should be considered has been hindered by the cost of the vaccine, and by occasional reports of delayed and (rarely) life-threatening adverse reactions.8 Overall, local injection-site reactions occur in about 20% of recipients. Systemic reactions, such as fever, rash, myalgia and gastrointestinal symptoms, are seen in about half that number.9 A new live, attenuated vaccine that allows a simpler administration regimen and is likely to produce fewer of these adverse reactions than the current vaccine is undergoing Phase II testing.10 Statistics on vaccine use include military personnel and residents of northern Cape York and the Torres Strait Islands, who receive free vaccinations under the Queensland Government Vaccination Programme. Separate statistics on vaccine use by travellers are unavailable. Adventure travel is popular among Australians. Uncertainty about disease risks and the financial burden of vaccination and antimalarial prophylaxis combine to make pre-travel counselling a challenge. This case of a rare vaccine-preventable infection with a potentially devastating outcome exemplifies these issues. As an efficacious vaccine for Japanese encephalitis is available, it should be considered for all at-risk travellers. This case also highlights the need to emphasise mosquito avoidance in pre-travel counselling, and to consider a broad differential diagnosis in unwell returning travellers. Lessons from practice Japanese encephalitis is a potentially devastating illness; it can be fatal and can have permanent neurological effects in survivors. Vaccination is indicated for many Australians who seek pre-travel counselling; they should be counselled about their risk of contracting Japanese encephalitis and the benefits of the vaccine. Mosquito avoidance is a key message in pre-travel counselling. Japanese encephalitis may present as an undifferentiated fever; gastrointestinal symptoms may be prominent.

Catherine M Geraghty MB BS · James S McCarthy FRACP, MD

Objective: To compare differences in functional outcomes between urban and rural patients with traumatic brain injury (TBI).Design: A longitudinal, prospective, multicentre study of a 2-year cohort from the Brain Injury Rehabilitation Program (BIRP) for New South Wales, with follow-up at 18 months after injury.Participants: 198 patients (147 urban, 51 rural) with severe TBI from the 11 participating rehabilitation units.Main outcome measures: Demographic and injury details collected prospectively using a standardised questionnaire, and measures from five validated instruments (Disability Rating Scale, Mayo–Portland Adaptability Inventory, Sydney Psychosocial Reintegration Scale, Medical Outcomes Study Short Form and the General Health Questionnaire – 28-item version) administered at follow-up to document functional, psychosocial, emotional and vocational outcomes.Results: Demographic details, injury severity, lengths of stay in intensive and acute care wards were similar for both rural and urban groups. There were no significant group differences in functional outcomes, including return to work, at follow-up.Conclusions: Our findings contrast with previous research that has reported poorer outcomes after TBI for rural residents, and suggest that the integrated network of inpatient, outpatient and outreach services provided throughout NSW through the BIRP provides effective rehabilitation for people with severe TBI regardless of where they live.

Peter G Harradine MB BS, FAFRM (RACP) · Julie B Winstanley PhD, CStat · Robyn Tate MPsychol, PhD · Ian D Cameron MB BS, PhD · Ian J Baguley MB BS, FAFRM · Ross D Harris PhD, MA

Systematic reviews of randomised trials of tPA in acute ischaemic stroke indicate a clear benefit of treating selected patients within 3 hours of stroke onset. Moreover, a net benefit remained after adjustment for chance baseline imbalances between subgroups in stroke severity within one of these trials (National Institute of Neurological Disorders and Stroke [NINDS]). Rates of favourable outcomes and intracranial haemorrhage comparable with those in randomised trials can be achieved in routine clinical practice; however, translation of net benefit from tPA therapy requires organised and coordinated stroke management across the continuum of care. Prerequisites for well organised and coordinated acute stroke care are: consensus among care providers on the use of tPA; stroke-care teams spanning the gaps between pre-hospital care, emergency departments and stroke units; and collegiate relations and effective communication networks between care providers.

on behalf of the Australasian Stroke Unit Network, the New South Wales Greater Metropolitan Transition Taskforce Stroke Initiative, and the Towards A Safer Culture Stroke Expert Working Group

Attempted repair of human spinal cord injury by transplantation of stem cells depends on complex biological interactions between the host and graft. Extrapolating results from experimental therapy in animals to humans with spinal cord injury requires great caution. There is great pressure on surgeons to transplant stem cells into humans with spinal cord injury. However, as the efficacy of and exact indications for this therapy are still uncertain, and morbidity (such as rejection or late tumour development) may result, only carefully designed studies based on sound experimental work which attempts to eliminate placebo effects should proceed. Premature application of stem cell transplantation in humans with spinal cord injury should be discouraged.

Jeffrey V Rosenfeld MS, FRACS · Grant R Gillett PhD, FRACS

As part of the Clinical Support Systems Program, the Monash University Consortium conducted a project to identify factors influencing the implementation of clinical evidence into routine hospital practice. Training was required in the process of clinical practice improvement (CPI) and the nature of evidence. One of the most helpful instruments for change was to point to active models of quality assurance as exemplars. Staff can be trained to be good managers, but leadership is less susceptible to training and is better obtained by selective recruitment. CPI requires rapid feedback on the effectiveness of the implementation. Access to this information and the confluence of management skill, an ability to translate research evidence into routine clinical behaviour and an understanding of the process of quality assurance are central. Effective CPI is only possible when the larger hospital administrative culture is committed to providing the necessary resources.

Malcolm K Horne MB BS, PhD, FRACP

Towards a Safer Culture (TASC) aims to provide a safer culture in hospital departments by introducing clinical pathways for the management of patients with acute coronary syndromes or stroke. Specific clinical pathways have been implemented for patients with different levels of risk to guide the most appropriate evidence-based medical care for each patient. Pathways facilitate continuity of care across different clinical departments by identifying gaps in care, and clarifying tasks and responsibilities. A multidisciplinary and interdepartmental approach to managing patients is seen as an effective way of effecting change. A system for “point-of-care” data acquisition, a centralised database and web-based reporting enable benchmarking for participating hospitals. A comprehensive range of educational/training strategies is used to facilitate multidisciplinary teamwork and promote clinical leadership. Phase 1 of TASC was successfully piloted at four hospitals in New South Wales, Victoria and Queensland. TASC is currently being rolled out to 29 hospitals in NSW and three hospitals in Western Australia.

Catherine T Ferry BN, GradDipPubHlth · M Andrew Fitzpatrick BSc(Med), MD, FRACP · Paul W Long GradDip(CommMgt) · Christopher R Levi BSc(Med), FRACP · Roderick O Bishop BSc(Med), MPH, FACEM

Although infectiousness is a feature of Creutzfeldt–Jakob disease (CJD), only a small proportion of cases are linked to transmission through healthcare provision. As of January 2003, over 120 cases of CJD associated with use of human cadaveric dura mater had been recognised worldwide; almost all were associated with the commercial product Lyodura. Most cases (97) have occurred in Japan, giving an overall risk estimate of around 1 per 2268 patients treated with Lyodura (0.04%) in that country. In Australia, five cases of CJD have so far been linked to Lyodura, but, given the protracted tails of previous epidemics of transmissible spongiform encephalopathies, further cases are possible. Results of surveys of Lyodura use in Australia are incomplete, but information from the manufacturer suggests that 2208–2478 sheets of Lyodura may have been used here. This use translates to a relatively high incidence of Lyodura-associated CJD, with current overall rates appearing around five times higher than those reported in Japan; reasons for this difference are unclear.

Fiona J Brooke BA(Hons) · Alison Boyd PostGradDipGenCoun · Genevieve M Klug BSc(Hons), PostGradDipEpiBiostat · Colin L Masters FRCPA · Steven J Collins FRACP

David J Blacker Neurologist and Stroke Physician, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009. davidblackermdAThotmail.com To the Editor: I respect the opinion of Hoffman1 and others who have recently expressed concerns about the use of tissue plasminogen activator (tPA) in patients with ischaemic stroke. However, it is critical that these views do not dampen the enthusiasm for better stroke treatments. The Therapeutic Goods Administration recently approved tPA for ischaemic stroke patients with symptoms of less than 3 hours’ duration. This approval has catalysed collaboration between stroke units around Australia and may provide benefits to patients who do not receive tPA, by improving clinical pathways, as well as a more coordinated approach to treatment. Internationally acclaimed Australian stroke experts have already rebutted the arguments of opponents of the National Institute of Neurological Disorders and Stroke (NINDS) trial, 2,3 and an independent reanalysis of the NINDS data showed tPA to be more effective than originally reported.4 It is time to stop bickering about the NINDS trial5 and move forward, by focusing on a collaborative effort between emergency departments and stroke teams. In the near future, there will surely be better data on new-generation thrombolytics and other agents; all will operate on similar “time is brain” protocols, as did the NINDS trial. Obviously, more data would be useful, but when clinicians are faced with patients with acute stroke today they must give the patients and their families the facts about tPA, regardless of their personal opinion. These are best expressed in terms of the absolute risk reduction for disability seen in the NINDs trial. It is interesting to note the widespread discomfort with the 6.4% risk of intracerebral haemorrhage (half of which were fatal) in this trial of a “medical” therapy. Surgeons quote similar morbidity and mortality risks every day to patients undergoing procedures such as coronary artery bypass grafting. Additionally, many surgical procedures became established on much less solid evidence than the NINDs trial, and yet there is no outcry. For example, many thousands of carotid endarterectomies were performed before the publication of controlled-trial data. In properly selected patients in expert hands, we now have a treatment that works. Its risks should not be underestimated, but should also be placed into context when compared with other powerful therapies for serious illnesses. Patients presenting with acute ischaemic stroke in Australia today have the chance to benefit from tPA, but future patients will benefit even more, partly because of the process that is being undertaken to institute pathways for using this drug.

David J Blacker

Jerome R Hoffman Professor of Medicine and Emergency Medicine, UCLA School of Medicine, Los Angeles, California, USA. jrhATucla.edu In reply: I agree with Blacker that enthusiasm generated by thrombolytic therapy could lead to benefit for stroke patients, independent of whether the therapy is actually useful, or even whether they receive it. However, I believe there are better ways to encourage rational stroke care. I also acknowledge that some experts believe thrombolysis is proven to be beneficial if used in accordance with NINDS (National Institute of Neurological Disorders and Stroke) guidelines. Others believe the question is not yet settled and are concerned that widespread adoption of the guidelines will lead to more harm than good. It is one thing to enthuse about possible benefits of a treatment, particularly for a devastating disease for which we have traditionally had little to offer. It is entirely different to embrace this therapy, even though it may be harmful overall, simply out of this frustration. I disagree with Blacker that the best way to inform patients about thrombolysis is “in terms of the absolute risk reduction for disability seen in the NINDS trial”. Regardless of concerns about the trial itself, it is always foolhardy to accept data from one small study as “the truth”. Many other trials have found far worse results — it would be equally inappropriate to base all estimates on their worst outcomes. Finally, there is strong evidence that, even if NINDS-like “success” could be achieved under optimal circumstances, routine use in the community might well lead to overall harm. I am also cautious about Blacker’s comparison of thrombolysis and some surgical procedures in terms of adverse effect rates. No single adverse effect rate is or is not acceptable for all interventions — a 90% rate of intracerebral haemorrhage could be acceptable in a disease with 100% mortality, while a 2% rate would be completely unacceptable in a disease with no long-term morbidity. Furthermore, the adoption of many surgical interventions in the absence of persuasive evidence does not justify repeating this mistake. Of course we must routinely make decisions without definitive evidence, based on our best estimates of benefits and harms. We should never take such decisions lightly, and should in general embrace the precautionary principle, which tells us not to adopt new therapies without reasonable evidence of their safety (especially when any benefit is likely to be extremely small). Although some advocates support thrombolysis based on current knowledge, my reading of available evidence is far less sanguine. That is why I continue to argue that this treatment should not be introduced into routine practice until far better evidence of its benefit outweighing its harm becomes available. Given the possibility that this treatment will harm stroke patients overall, and the likelihood that any potential benefit is very limited for the stroke population as a whole, I ask once again, why is so much being made of so little?

Jerome R Hoffman

Migraine and other headaches. Your questions answered. Andrew J Dowson. Edinburgh: Churchill Livingstone, 2003 (256 pp). ISBN 0 443 07339 2. Andrew Dowson is a general practitioner and Director of Headache Service at King's College Hospital, London. This puts him in a good position to write a book that answers questions about headaches that patients present with in the course of a busy practice. His pocket-sized book is part of a Churchill Livingstone series called Questions answered. The emphasis is naturally on migraine, which can be a burden for doctors as well as for their patients. A key question posed is “How well is migraine managed in primary care today?” and the answer given is “less than 50% of migraine sufferers receive effective treatment from their healthcare provider”. This deplorable situation probably applies in Australia as well as in the United Kingdom. The author intends this book to be delved into when required, rather than read from cover to cover. Most answers are not supported by references to original sources, and this makes one apprehensive at times, but in general they reflect current opinion. Some answers are deceptively simple. For example, “thunderclap headache” at orgasm is not always benign, or an occasion for “a certain amount of amusement”, but may signal a subarachnoid haemorrhage and requires immediate investigation when it happens for the first time. I found a particularly helpful table in the Appendix summarising the many medications used in the treatment of headache with their trade names, dosages and side-effects. On the other hand, I found some illustrations unnecessarily complex: for example, the multiple diagrams included in Figure 2.7 do not clarify the mechanism of migraine. However, my overall impression is that it will prove interesting and useful in the care of headache patients. The price is higher than one might wish, but, if every doctor had the answers to these questions at his or her fingertips, there would be far fewer disgruntled patients in the community. James W LanceNeurologist Woollahra, NSW

James W Lance

Shall quips and sentences and these paper bullets of the brain awe a man from the career of his humour? — Shakespeare, Much Ado About Nothing (II.iii.260) In 1993, when interviewing me for the archives of the Royal College of Physicians, Dr Max Blythe suggested that I write my autobiography. Never reluctant to take pen to paper, I put this suggestion to my family. Their answer was unequivocal — “No, Dad, no. Nothing exciting has ever happened to you. You’ve led a charmed life”. However, as a person who even enjoys filling in questionnaires, I found it hard to resist the invitation of the Editor of the Journal to reminisce about my decision to undertake a medical career, the mentors who guided me and the influences in my chosen pathway to become a clinical investigator. Why medicine?I wanted to be a doctor from the age of 12 years; why, I am not sure. I had no medical forebears but admired an uncle by marriage, Justin Markell, a physician at St Vincent’s Hospital and a keen skier. As a boy I read everything medical I could lay hands on — “The Citadel”, “Viewless Winds”, “The Story of San Michele” and “The Healing Knife” come to mind — and many other books about the history and challenges of the medical life. I found their messages stirring and thought that this was the life for me. I have never regretted my decision. As a medical student I was fortunate in my introduction to clinical work at the Royal Prince Alfred Hospital (RPAH). Frank Mills, debonair and charming, was a kind and understanding tutor in surgery. Keith Harrison, our tutor in medicine, was a first class clinician, caring and courteous. The senior physicians included dedicated teachers such as Archy Collins, C G McDonald, Tom Greenaway and Bill Morrow, all of whom were later knighted, and Professor Lambie, who improved our history taking and physical examination with the rigour of the Scottish discipline he imposed. Cotter Harvey ran the only specialist medical unit in RPAH, the Thoracic Unit, which was of world standard. The pathway to researchAfter graduation I knew that I wanted to undertake research work. My uncle, Justin Markell, exclaimed “Why would you want to do research? You don’t have any deformity or handicap. You could go into practice.” I approached Hugh Ward, Professor of Bacteriology, to discuss my aspirations. When Sir Howard Florey visited Sydney, Professor Ward introduced Henry Harris, another recent graduate, and me to him as possible candidates for a research career. Florey advised us to work in the Physiology Department of Melbourne University and then to do the honours course in physiology at Oxford. Henry Harris followed this advice, and eventually succeeded Florey as Director of the Sir William Dunn Institute in Oxford. I did fly to Melbourne, but was not excited by the work in progress. It was not until I met Peter Bishop, newly returned from London and setting up the Brain Research Unit in the Department of Surgery, University of Sydney, that I focused my research ambitions on neurophysiology. Peter was an enthusiast and transmitted that enthusiasm to others. I have written elsewhere about his influence on the development of neurology in Australia.1 It is necessary not only to make a discovery but to repeat the findings at intervals to prevent the results from sinking into oblivion and to deter others from going through the same motions. While in Peter’s laboratory I kept in touch clinically by seeing patients at the Northcott Neurological Centre, Cammeray, under the guidance of George Selby. George was a superb clinician and teacher who patiently imparted his art, which stood me in good stead when I departed for the then customary 2 years of postgraduate training in London. Marking timeOn returning from Queen Square (now The National Hospital for Neurology and Neurosurgery) in 1956, I looked for an appointment combining clinical work with research. There were none. I was appointed Superintendent of the Northcott Neurological Centre and an Honorary Assistant Physician to the Sydney Hospital. I was one of a group of young specialist physicians who were astounded when informed that we could not conduct a clinic in our own speciality but had to rotate throughout all the clinics so that we could work in our own speciality clinic for 6 months every three years or so. We naturally rebelled against this mad manifestation of entrenched antagonism to specialisation until it was conceded that we could all work for a half day each week in our speciality, provided that we ran a general medical clinic on another half day and took fourth year students on physical examination 2 other half days in the week. As all hospital work was honorary this left three days a week to earn an income. Having completed training in neurology, I had thought that I might reasonably be asked to lecture in this discipline. I gave a series of lectures in physiology at Sydney University but the task allocated to me at Sydney Hospital was to give lectures to nurses on hygiene. The neurological topics were covered by the senior general physicians. When the opportunity arose for Sydney Hospital to be rebuilt on the Prince of Wales site at Randwick, the main teaching hospital of the new University of New South Wales Medical School, my spirits rose. They were dashed when the honorary staff voted by a small margin in favour of the status quo. I decided to jump ship. Sir Kenneth (“Bob”) Noad, senior physician at Sydney Hospital, kindly wrote to Dr Raymond Adams in Boston on my behalf and supported my application for a Lilley Travelling Fellowship. Dr Adams was the Bullard Professor of Neuropathology and Chief of the Neurology Service at the Massachusetts General Hospital. I was accepted to start there in August 1960. There were 2 events worth recording in my four years as an “Honorary” before going to Boston. Bob Noad had looked after four members of a family with epilepsy that he passed on to my care. They had myoclonic jerks and falling attacks with cerebellar signs, known then as the Ramsay Hunt syndrome (a form of familial myoclonic epilepsy). Bob Noad and I reported the family in Brain.2 This experience aroused my interest in myoclonus, which I was later able to investigate in Boston. The second was the suggestion by George Selby that we analyse the case histories of patients with migraine headache. The resulting article3 was published in 1960 and is still quoted today. That work started me on the headache road. My wife Judy and I arrived in Boston with our daughter Fiona in September 1960. While I was working in the centrally heated comfort of the Massachusetts General Hospital, Judy trudged through the snow of a cold New England winter, dragging one reluctant daughter and pregnant with another. While in Boston I followed up my interest in myoclonus, working and publishing with Ray Adams on a group of patients with myoclonus after hypoxia, and on the cause of myoclonic falling attacks (Box 1).4 I completed another interesting project with Dr Robert Schwab, who ran the Parkinson’s disease clinic at the Massachusetts General Hospital, on the relationship between action and resting tremors and cogwheel rigidity.5 Neurological grand rounds were held in the Ether Dome, where ether was first used as a general anaesthetic in 1846 (Box 2). Foremost among the clinicians were Raymond Adams, Miller Fisher and Maurice Victor. From Boston, I applied for the position of Chairman of Neurology at the Prince Henry and Prince of Wales Hospitals, which were to become the teaching hospitals of the Medical School of the University of New South Wales. To my great joy I was appointed. There are many legacies of the year in Boston — a lasting friendship with Raymond Adams, one of the great neurologists of the twentieth century, continuing contact with my colleagues in training at the Massachusetts General who went on to chair most of the major neurology departments in the US, honorary membership of the American Neurological Association, being a foundation member of the editorial board of Annals of Neurology and becoming the proud father of our second daughter, Sarah. Re-entryThe task of creating a teaching hospital out of a rundown infectious disease hospital (Prince Henry) and a collection of wooden huts dating back to the First World War (Prince of Wales) was challenging. The great merit of Prince Henry was that it was a very happy hospital, superbly situated between the Pacific Ocean and Botany Bay with its own golf course. I set up a modest laboratory in a disused ward where our work on the neurophysiology of movement disorders began. In investigating reflex actions we discovered that it was the vibration wave set up by percussion which was the essential trigger for tendon jerks, and this led to the discovery of the tonic vibration reflex, which had important clinical implications, and which led to collaboration with Karl-Erik Hagbarth in Sweden, who had recently discovered the same phenomenon. Studies on the mechanism of spasticity and the control of movement were carried out with David Burke, David Gillies, Colin Andrews, Carlo Tassinari (visiting from Marseilles) and Peter Ashby (from Toronto). I have summarised the early motor studies and their clinical implications in the Wartenberg Address that I gave to the American Academy of Neurology in 19806 and in my book on clinical neurophysiology in which I collaborated with Jim McLeod.7 I wish that the findings were more widely known to guide clinical neurologists today. It is necessary not only to make a discovery, but to repeat the findings at intervals to prevent the results from sinking into oblivion and to deter others from going through the same motions. David Burke and Simon Gandevia later joined Ian McCloskey in founding the Prince of Wales Institute of Medical Research. The motor program, which started in a disused ward and moved to a basement under the EEG Department and then to an abandoned operating theatre at Prince Henry Hospital, now resides in handsome villas on the Prince of Wales site at Randwick. Headaches and serotoninMy interest in headache was reignited by observations made in 1959 and 1961 by Federigo Sicuteri in Florence and by a group at the Montefiore Hospital in New York in 1960. It appeared a paradox that a serotonin antagonist, methysergide, could prevent attacks of migraine and yet an infusion of serotonin itself could ease the headache. We had the good fortune to have a biochemist at Prince Henry Hospital, Herta Hinterberger, who was an expert amine chemist, to teach Don Curran (our first Research Fellow), and then Michael Anthony (our second), the mysteries of estimating serotonin (5-hydroxytryptamine, 5-HT) in blood. We found that serotonin was discharged from blood platelets at the onset of migraine headache. An intravenous infusion of serotonin would constrict cranial blood vessels and relieve the headache (Box 3).8 These and other of our observations on blood vessels in migraine came to the attention of Dr Patrick Humphrey in the Glaxo laboratories in England. He set out to find an analogue of serotonin that had its beneficial effects without its side effects of chest tightness and lightheadedness. At the time of our early studies, there were only 2 receptors known for serotonin. Now there are at least seven main groups with many subdivisions. Patrick Humphrey came up with a substance that was active at the B and D subtypes of the serotonin1 receptor and named this sumatriptan. This and the other triptans developed later have proved to be highly effective agents in cutting short or preventing the development of migraine headache. It is gratifying that our observations qualify us to be godfathers to the triptans. Our initial concentration on the vascular aspects of migraine was carried on by Ewan Mylecharane, pharmacologist, with Paul Spira, John Duckworth, Michael Welch (from the UK and US) and Jusef Misbach (from Indonesia) who quantified the effects on the monkey cranial circulation of various vasoactive agents and their antagonists with a potential use in migraine. Geoff Lambert took over the pharmacological reins in 1978 as the emphasis in migraine research moved to determining the cerebral mechanisms that could underlie vascular changes and be of significance in the genesis of migraine. Some of the headache research team are shown in Box 4. Peter Goadsby and Richard Piper joined the team as BSc(Med) students in the early 1980s, followed by Rick Adams and Sandrino Zagami as Higher Degree candidates. A series of papers established the way in which the cerebral circulation of cat and monkey could be controlled by brainstem structures,9 thus filling a gap in the hypothesis of migraine mechanisms.10 Peter Goadsby continued research as a PhD and MD candidate investigating the pathophysiology of migraine, including a collaborative study of peptide neurotransmitters with Lars Edvinsson of Lund, thus forming our second Swedish connection. Peter later accepted an invitation from the Wellcome Foundation to set up a research department at the National Hospital, Queen Square, London. He joined me as a co-author for the sixth edition of my headache book,11 which outlines the research that has led to the current hypothesis of the mechanism of migraine. We have participated in many therapeutic trials including the triptans. Two early publications are worth mentioning. Don Curran and I conducted a double-blind controlled trial of amitriptyline for chronic tension headache in 1964,12 which has been accepted as a main line of treatment since then. Michael Anthony and I13 reported in 1969 on a successful open label trial of phenelzine for migraine patients resistant to other treatment which opened the door for the use of monoamine oxidase inhibitors when all else had failed. Odd neurological syndromesIn parallel with the research programs, our clinical work grew apace. We had close relationships with our neurosurgical colleagues under the leadership of Alex Gonski. Among the routine case load unusual problems appeared from time to time.14 We studied patients with phaeochromocytoma15 to define the headache and “funny turns” of this disorder, as well as benign sex headache, “neck–tongue syndrome”, visual hallucinations and paroxysmal dystonia.16 The arrival of Dr Peter Drummond, an experimental psychologist, brought a new dimension to our group’s studies of the autonomic nerve system. He worked out the part that the sympathetic nervous system played in facial flushing and the mechanism of the unilateral flushing in harlequin syndrome17,18 and clarified the nature of autonomic deficits in migraine and cluster headache. There are always new diagnostic and therapeutic challenges arising from our patients’ histories. Recent examples are the red ear syndrome19 and the “blip” syndrome.20 EpilogueSurely neurologists must have one of the most exacting and exciting occupations in the world. I have been fortunate in being able to set up the first Academic Department of Neurology in Australia and being appointed a Professor of Neurology rather than Professor of Medicine. The struggle to have neurology regarded as a discipline separate from general medicine has been long, hard and eventually rewarding. I want to emphasise that the research described here is very much the result of a team effort, and I regret that I have not had enough space to record all of it or to mention here all those that have been involved. I am indebted to my wife Judy for so many things, not least for her tolerance of my deskbound habits. I have been shielded from the uglier side of paperwork and helped over the years by three wonderful secretaries — the late Margaret Kendall, Patricia Miller and Carol Flecknoe. New techniques of studying cerebral function and dysfunction are granting us deeper insight year by year. I have no wish to be young again, but would not object to a 20 per cent discount so that I could observe further into the future. I am cheered by the fact that bright eyes and brighter minds are carrying on the exploration of the unknown. 1: Myoclonus In 1960, the cause of myoclonic falling attacks was not understood. Our investigations established that it was not the violence of the myoclonic jerking that caused the fall, but the following period of silence in all muscle groups. (a) Myoclonic jerk and falling attack. (b) Sharp and slow wave seen in an electroencephalogram (upper trace) and myoclonic jerk followed by a silent period in an electromyogram (lower trace). Reproduced with permission from Brain.4 2: The Ether Dome of the Massachusetts General Hospital. Dr Miller Fisher on my right and Professor Raymond Adams on my left during a lecture visit in 1989. 3: Serotonin and migraine Our investigations of migraine in the 1960s clarified the role of serotonin and paved the way for others to find serotonin analogues that would be safe and effective in treating and preventing migraine. (a) Levels of platelet serotonin in a migrainous patient. The injection of reserpine releases serotonin from body stores. Platelets discharge serotonin at the onset of a migraine headache, whether spontaneous or induced. Both spontaneous and induced headaches were relieved by intravenous infusion of serotonin. Reproduced with the permission of the Editor of Archives of Neurology. (b) The vasoconstrictor effect of intracarotid serotonin on the superficial temporal artery pulsation. The upper trace in each pair shows respiratory function, the lower, arterial pulsation. Reproduced with the permission of Karger Publishers (New York, Basel). 4: Members of the headache research team, 1987, in front of the Clinical Sciences Building, Prince Henry Hospital. From left to right: (front row) Professor Michael Anthony, Professor James Lance, Mr. Mark Hellier (Technical Officer), Mr. Basil Daher (Biochemist); (middle row) Mrs Patricia Miller, Mrs Francine Skane (Secretaries), Mr Paul Charalambous (Histology Technician); (back row) Dr Geoff Lambert (Pharmacologist), Dr Peter Goadsby, Dr Alessandro Zagami (Research Fellows), Mr John Duckworth (Technical Officer).

James W Lance MD, FRCP, FRACP

A 62-year-old woman with longstanding, well controlled type 2 diabetes mellitus and hypertension initially presented with a 2-day history of acute, partial right-sided facial weakness. The facial paralysis was not accompanied by hyperacusis, and taste sensation was preserved. The patient presented again 2 weeks later with complete paralysis of the left facial nerve and only partially resolved right-sided symptoms. No other central or peripheral neurological signs or symptoms were elicited during either presentation. As bilaterality makes facial neuropathy a more ominous sign of various known conditions,1,2 we carried out prompt further investigation. Results of haematological and biochemical assays, including liver function tests, were unremarkable. Specifically, the serum angiotensin-converting enzyme (ACE) level was 42 U/L (normal range, 30–50 U/L). Results of urinalysis and cerebrospinal fluid examination were also normal (although the latter did not include oligoclonal IgG and ACE assays). Nerve conduction studies and electromyography findings were consistent with denervation of the facial nerves. Electroneurography of lower limb nerves showed normal nerve conduction bilaterally. No abnormality was detected on chest x-ray or brain magnetic resonance imaging. However, a computed tomography scan of the chest showed bilateral hilar lymphadenopathy with bilateral basilar lung infiltrates (Box, A). A transbronchial biopsy revealed a single, non-caseating granuloma (Box, B). The patient was discharged from hospital with instructions to take 30 mg prednisone daily for a month (because of her diabetes, she was given half the ideal dose of 1 mg/kg per day). After 1 month of treatment she showed marked improvement, and the dose was gradually reduced over the following month. DiscussionThis is an unusual case of sequential or “consecutive” bilateral facial paralysis — in which unilateral facial palsy was followed by contralateral facial palsy before the side affected first had recovered — in association with biopsy-proven pulmonary sarcoidosis. This case makes the point that a normal chest x-ray does not, unequivocally, exclude hilar lymphadenopathy. Although sarcoidosis is known for its unusual and protean manifestations, including neurosarcoidosis, we are aware of only two other case reports of bilateral facial paralysis as the sole presenting feature of sarcoidosis.3,4 However, we cannot exclude the possibility that the facial weakness seen in this case was related to type 2 diabetes or another aetiology, such as Bell’s palsy. A: Computed tomography scan of the chest, showing hilar lymphadenopathy. B: Transbronchial biopsy, showing a single, non-caseating granuloma (haematoxylin–eosin stain).

Ali A Haydar MD · Nabil M Hujairi MD · Aiman Tawil MD · Raja A Sawaya MD

We understand the molecular basis, and a cure may soon be possible The French neurologist Duchenne de Boulogne (1806–1875) originally described paralysie hypertrophique de l’enfance in 1861, outlining the key clinical features, including lordosis and calf hypertrophy.1,2 Although the English physician Edward Meryon had recognised similar cases 10 years earlier, Duchenne’s name became associated with this condition through a series of illustrated articles in which he described key features, including male predominance, progressive course, waddling gait, pseudohypertrophy of calf muscles, loss of ambulation by adolescence, and early death. Duchenne devised a muscle biopsy needle and established that hyperplasia of fibrous connective tissue and destruction of the muscle cytoarchitecture (arrangement of cells) are key abnormalities. By the 1880s, the English neurologist Sir William Gowers was able to identify 81 case reports confirming the clinical features established by Duchenne. Clinicians established the clinical heterogeneity of the muscular dystrophies, and various disorders were identified, including facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy and myotonic dystrophy. Importantly, Becker muscular dystrophy (BMD) was identified as a much less severe condition with some similarity to Duchenne muscular dystrophy (DMD). Success in delineating the basis of the dystrophies awaited the molecular era. Kunkel and coworkers identified a patient with a cytologically recognisable deletion on the X chromosome (Xp21) and realised that, if they allowed this to hybridise (pair) with normal DNA, they could find the gene.3 By ingenious use of their novel techniques, they created probes containing part of the Duchenne gene and found that one detected submicroscopic deletions in some affected boys.3 This led to the identification of the gene and eventual delineation of its sequence. Boys with DMD were found to have mutations that produced non-functional dystrophin protein.4 BMD patients were identified as having mutations that produced dystrophin protein with some function.4 The structure of the functional protein was predicted from the genetic sequence,5 and immunocytochemical investigation revealed a close relationship to the sarcolemma.6 Dystrophin’s function as a key cytoskeletal protein was subsequently defined in elegant studies in many laboratories, but especially by Kevin Campbell and colleagues.7 Dystrophin links the actin filament of the contractile apparatus to a complex series of linking proteins in the cell membrane, and hence to the extracellular matrix (Box). It was found that the C-terminus of dystrophin, which binds it to the sarcolemma, is crucial, as is the actin-binding zone, but the helical zone can be shortened with some preservation of function, explaining the differences between BMD and DMD. Subsequently, defects in the dystrophin-associated glycoprotein complex were found to underlie many other types of muscular dystrophy, including the limb-girdle syndromes and the congenital muscular dystrophies. Indeed, it was through pursuit of the cause of DMD that an understanding of much of what we now know about the muscle cytoskeleton has been achieved.7,8 Much new knowledge, but what has been achieved of practical importance for the patients and their families? Diagnosis has improved a great deal. Established DMD is not difficult to diagnose, but molecular causation can now be defined in most cases, allowing accurate confirmation of female carrier status and, with in-vitro fertilisation techniques, selection of a healthy embryo for implantation.9 Advances in clinical management include the use of steroid therapy to improve muscle strength,10 orthopaedic techniques, especially Luque rods, to prevent kyphoscoliosis,11 and regular respiratory monitoring, including sleep studies, to maximise use of non-invasive ventilatory techniques to improve quality of life. Later, depending on patients’ wishes, tracheostomy-dependent ventilation can be used to prolong duration of life. What of new potential treatments? The aim is to develop curative treatments, and it is somewhat disappointing that, more than 20 years after Kunkel’s pioneering discoveries, this is yet to be achieved. Studies with cell therapy (myoblast transfer therapy) have not fulfilled initial promise, although they are still proceeding in several laboratories.12 Major effort in gene therapy has led to an understanding of the key parts of the dystrophin gene that must be incorporated to achieve reasonable function.8 New techniques of gene repair are under evaluation in several laboratories, including our own.8 Skeletal muscle has an enormous capacity for regeneration, and there is every chance that effective strategies to achieve functional muscle remodelling will be achieved, especially if applied before irreversible fibrosis has occurred. Indeed, skeletal muscle, by virtue of its relatively simple structure, enormous capacity for regeneration, and easy and safe accessibility, is an ideal tissue for many of the new therapies in the cell and gene area. Correction of causative mutations through gene repair in autologous mesenchymal stem cells derived from bone marrow, manipulation to a committed myogenic lineage, and systemic delivery, once a concept in the realm of science fiction, may be practical in the years ahead. However, even with the promise so close, there need to be further advances in several areas to achieve this. For example, we need better understanding of the factors that drive pluripotent stem cells into myogenic lineages, and of other factors, mainly immunological, that have limited stem cell survival in vivo. Gene vectors capable of encompassing the whole dystrophin gene are likely to be tested in human studies, and promising new techniques of gene repair are likely to reach clinical trials. It is important that various potential treatments be pursued in parallel, as it is not currently possible to determine which of the approaches available will enjoy most success. Equally important to the search for a cure is the maintenance of quality of life for people who currently have muscular dystrophy. This necessitates adequate funding for clinical care in key paramedical areas, including access to state of the art wheelchair and ventilatory equipment. The role of the Muscular Dystrophy Association in providing support for carers and families is especially important. The next decade is full of promise for robust advances in the management of the dystrophies, and there is real hope that by 2011, the 150th anniversary of Duchenne’s landmark description, a cure for DMD will have been found. Dystrophin: the key protein in Duchenne muscular dystrophy Dystrophin links actin filaments to a complex of transmembrane proteins and hence to the extracellular matrix. Mutations that affect the C-terminus or actin-binding region cause Duchenne muscular dystrophy. Mutations that shorten the a helix cause Becker muscular dystrophy. Other muscular dystrophies are caused by defects in the dystrophin-associated glycoprotein complex.

Edward Byrne DSc, MD, FRCP, FRACP · Andrew J Kornberg MB BS, FRACP · Robert Kapsa PhD

A 17-year-old man presented with a history of several months of constant, throbbing headaches. He had always had long hair, concealing an obvious skull deformity that had not previously been noticed. Examination revealed a visible occipital deformity of the skull (Box, A). He had chronic papilloedema, with a visual acuity of 6/60 within markedly contracted visual fields. There were no other neurological abnormalities. ImagingX-rays, computed tomography and magnetic resonance imaging further delineated the anatomy of the lesion (Box, B,C). Volume estimation1 yielded a total volume of 1094 cm3, making this one of the largest meningiomas ever reported. ManagementThe patient was given high-dose corticosteroids, and surgical excision was undertaken in two stages. At the first operation, the extracranial component and most of the hyperostotic bone were removed (Box, D). A week later, the remainder of the tumour was removed and the involved (and occluded) superior sagittal sinus resected. The postoperative period was complicated by a cerebrospinal fluid (CSF) leak and meningitis, requiring replacement of the artificial dural graft with fascia lata and CSF diversion with a lumbar drain. Histopathological examination of the tissue revealed a meningothelial meningioma with no atypical features. As a Simpson grade II removal (complete resection of macroscopic tumour with diathermy of the dural origin)2 had been achieved, no adjuvant treatment was given. Six months later, an acrylic cranioplasty was performed, and at 2-year follow-up the patient was well. His visual acuity had returned to 6/36 and his visual fields had expanded. DiscussionMeningiomas account for about 20% of all intracranial tumours3 and, as slow-growing tumours that display benign behaviour, can escape notice. Hyperostosis is often palpable through the scalp, but this patient had an unusually large extracranial volume of tumour (more commonly associated with malignant meningiomas,4 which often lack a significant intracranial component). Complete surgical excision of meningiomas has been shown to offer the best long-term outcome compared with subtotal excision with or without radiotherapy.5 However, even with optimum surgical excision, recurrence rates of up to 20% can be expected over a 20-year period.6

Rodney S Allan MB BS(Hons) · Peter J Spittaler FRACS · Lindsay J Rowe FRANZCR

Has enthusiasm overwhelmed judgement? Although advocates of the use of tissue plasminogen activator (tPA) in acute ischaemic stroke suggest that this “is one of the most important advances in stroke medicine”,1 a recent Cochrane meta-analysis also supports “clinicians who choose . . . not to use the treatment at all”,2 and all three major emergency medicine associations in North America have declined to endorse it as “standard of care”.3 In a recent issue of the Journal, Szoeke and colleagues’ audit of tPA use in a tertiary-care hospital concluded that “favourable outcomes . . . were similar to those achieved in international . . . trials in specialised centres”,4 while an accompanying editorial highlighted that “the absolute benefits of stroke care unit management clearly outweigh those of . . . tPA administration”.1 Several letters in this issue of the Journal raise important concerns about the report of Szoeke et al, as well as the overall risks and benefits of the use of tPA in ischaemic stroke (page 386).5-7 A single dose of aspirin provides benefit to about 15 times as many stroke patients as does tPA,1 at far less risk. This is true even assuming tPA benefits one in every eight patients treated, which is based on a point estimate taken from the National Institute of Neurological Diseases and Stroke (NINDS) trial,8 the only randomised controlled trial which found a benefit for its primary endpoint. This does not take into account the wide confidence intervals in the NINDS trial, the negative results of multiple other randomised controlled trials,9,10 and the far worse results in non-expert hands. Even under a “maximum benefit” scenario, with further assumptions that overestimate the impact of tPA (including that it could be given safely and effectively to 10% of acute stroke patients, rather than the 1%–3% non-protocol-violation treatments in typical community studies),11,12 tPA would have only minimally greater impact than aspirin. Ultimately, regardless of who is correct about the available evidence, the overall impact of tPA in acute ischaemic stroke is at most marginal, which makes it difficult to understand why “so much has been made of so little”.7 Perhaps it has to do with enthusiasm for what is frequently called the “first treatment for stroke”, although, as noted, there are far more important (but far less dramatic) treatments available. Readers will have to decide for themselves whether it also has something to do with money,3 or if this is truly “extending conspiracy theory to its limits”, as Donnan and colleagues claim (page 388).13 Previous critiques of the use of tPA in ischaemic stroke have raised the following issues: There is a paucity of positive evidence; all but one small randomised controlled trial failed to find benefit in the primary outcome, or found substantial harm.14,15 Even in the NINDS trial, the benefit was primarily in patients treated less than 90 minutes after symptom onset16 (almost no such patients exist in actual community practice), so the number needed to treat in the 91–180-minute group is surely far higher than the “eight patients needed to treat” widely quoted. “Effectiveness” in a community setting is far different from “efficacy” as reported in the NINDS trial (even if NINDS is taken at face value).15,16 Let me add the following observations. Most supporters of tPA claim that three trials involving streptokinase are irrelevant (including one done in Australia, with very negative results10). However, in the absence of studies directly comparing them, there is no reason to believe that tPA should be better than streptokinase for treating ischaemic stroke. In head-to-head cardiac megatrials (ISIS III, GISSI II, and GUSTO I), tPA consistently caused more intracerebral haemorrhage than streptokinase, which is likely to be even more important in patients with stroke. Furthermore, the GUSTO I trial, which provided the only remotely credible (albeit controversial) evidence suggesting tPA might be a bit more effective than streptokinase in coronary patients, was explicitly based on the notion that adjunctive intravenous heparin must be given with tPA — an approach contraindicated in stroke. Excluding streptokinase trials from the analysis of thrombolytics in stroke because they happened to be negative is simply inappropriate. Although Szoeke et al’s report is not strictly an “efficacy” study, neither is it a community practice “effectiveness” study, as treatment was by experts in a tertiary care facility. Thus, in no case should the results be extrapolated to other practice environments. Furthermore, it is critical to note the report’s limitations: Most obviously, there were no randomised controls, and outcomes were measured unblinded to the use of tPA, creating enormous potential for measurement bias. The study failed to meet most of the methodological criteria considered critical for chart reviews17 (eg, use of trained abstractors [ideally other than the authors], standardised abstraction forms and multiple independent reviewers for at least some of the charts, with some measure of agreement between reviewers; use of explicit criteria for coding of outcomes and explicit definitions for interpreting absent or inconsistent data). Outcomes among 30 patients receiving tPA may have been “consistent with” the NINDS result, but, given the small numbers and extremely wide confidence intervals, were also consistent with virtually any result. The report may well represent publication bias. Indeed, the most positive “effectiveness” study reported results from 57 of 83 centres that participated in a proprietary randomised controlled trial18 — what happened to the other 26? The only two reports that included all patients receiving tPA in a given community each documented unacceptable outcomes.11,12 Finally, there is the problem of interpretation bias. Szoeke et al classified one of the deaths after tPA therapy as a protocol violation, which will allow advocates to claim the results “would have been even better if . . .”. But this was based on an exclusion criterion that was not part of the NINDS protocol (ie, “early signs on computed tomography [CT] suggesting infarct of more than a third of the territory of the middle cerebral artery”), and despite the fact that the study’s expert CT readers did not agree whether this patient even met that criterion! This example (out of many) should provide insight into the way the “spin” of enthusiastic authors can lead to conclusions that are rosier than results actually justify. Many of us believe that thrombolytic therapy in stroke remains far from proven, so that its use should be restricted to further randomised controlled trials. This would not only enable us to determine whether this therapy produces more good than harm, or vice versa, but might also allow identification of subgroups in whom it is, or is not, indicated. We could then avoid giving a potentially fatal drug to a patient in whom it increases risk unacceptably, while also allowing current sceptics to use it in a different patient likely to benefit — assuming such patients, in either category, could be identified. If tPA use becomes more widespread, a very small number of patients may receive great personal benefit, while a very few others may be subjected to great personal harm. However, the broader implications of this debate are substantial. Modern health policy traditionally rests on the “precautionary principle”, which requires that no new practice be widely introduced until it is shown to be safe. This principle is under fierce attack in postmodern society by advocates of the contrary “Kehoe principle”, which asserts that if something may have value it should be accepted unless it’s proven dangerous.19 It is, of course, almost impossible to prove such danger, and, once approval is given, it may take many years — and a great deal of harm — before the decision can be reversed. Such was the case with leaded gasoline, which was termed “a gift of God” by its discoverer, Robert Kehoe, after whom this dangerous principle is named,19 and which was used ubiquitously for over 60 years, despite widespread understanding of its terrible public health impact. Whether or not the medical community insists on real evidence that tPA will do more good than harm in acute ischaemic stroke will also reflect how we feel about the introduction of all manner of potentially beneficial, but also potentially dangerous, new treatments.

Jerome R Hoffman MA, MD