Neurology

Charles P Denaro,* Thomas M Ferrier† * Director of Internal Medicine and Associate Professor, † Physician, Royal Brisbane Hospital, 9th Floor, Ned Hanlon Bldg, Butterfield Rd, Herston, QLD 4029. c.denaroATmedicine.uq.edu.au To the Editor: We comment on the report by Duffy and colleagues of a study of evidence-based care and outcomes of acute stroke.1 The Royal Brisbane Hospital contributed 300 patients to this study between September 1999 and May 2001. As our hospital’s geographically separate stroke unit did not open until February 2001, it is likely that most, and perhaps all, of these patients were cared for in the Department of Internal Medicine, a general medical service. The study compared 1664 patients treated in four types of unit — stroke, neurological, general medical or geriatric units — and found statistical differences between these units. The authors acknowledged that patients in the stroke units were younger than those in other types of unit and also that there “may be differences . . . in complexity and severity of cases that we did not assess . . .”. Our own experience at the Royal Brisbane Hospital may help readers to interpret this study. Our stroke unit has a defined number of beds and resources. While it tries to accommodate as many patients as possible, it often cannot serve all patients with stroke who come to the hospital. Patients of extreme age or with severe illness, caused by either the stroke or comorbidities, or those with adverse cognitive, social or residential status, are often not accepted into the stroke unit and remain in the general medical service. Thus, baseline characteristics differ markedly between patients in our general medical unit and the stroke unit. We are concerned that similar differences exist at the other institutions that provided data for this study. We see little point in publishing 20 separate χ2 tests that contrast differences between the four types of services looking after these patients, unless the baseline characteristics of the patients were very similar and statistically identical. In addition, one could also argue that with this number of statistical tests there would be a good chance of a type 1 error. There is no doubt that stroke units improve outcomes. This makes sense for any acute condition with likely long-term sequelae, as specialty units can provide more resources and a dedicated team of nurses and allied health professionals. However, in our opinion, this study does not provide convincing evidence for the superiority of stroke units over any other type of medical unit, as it is likely that the patients differed significantly between these units. Paddy A Phillips,* Brendan K Duffy,† Miriam E Vedadhaghi,‡ Stephen M Davis,§ Geoffrey A Donnan¶ * Head, † Cardiology Fellow, Department of Medicine, Flinders University of South Australia, Flinders Medical Centre, Bedford Park, SA 5042; ‡ Project Associate, Servier Laboratories, Hawthorn, VIC; § Director of Neurology, Royal Melbourne Hospital, Melbourne, VIC; ¶ Director, National Stroke Research Institute, Melbourne, VIC. paddy.phillipsATflinders.edu.au In reply: We agree with Denaro and Ferrier that there is selection pressure for admission of different types of patients to different units. This was clearly apparent in our study, with stroke units caring for significantly younger patients.1 We discussed in our report that, as this study was not a randomised controlled trial, differences in age and other undocumented factors have potential to bias the results. However, our primary aim was to determine whether current care of patients with stroke in major Australian hospitals accorded with evidence-based strategies. We showed major variations in the use of proven evidence-based strategies in different hospitals and by different specialty units in the real world of Australian healthcare. There were also major and significant variations in outcomes. We believe that all patients with stroke should be cared for in accord with the best evidence available, clinical expertise and their own values2 to produce the best possible outcomes.

Charles P Denaro · Thomas M Ferrier

Brendon J Smith Emergency Physician, Bankstown-Lidcombe Hospital, Locked Mail Bag 1600, Bankstown, NSW 2200. brendon.smithATswsahs.nsw.gov.au To the Editor: The recent article by Szoeke and colleagues on stroke management expressed the hope that thrombolytic therapy will be licensed for use by specialist units in Australia, based on the “proof” of its benefit demonstrated by the National Institute of Neurological Disorders and Stroke (NINDS) trial.1 The NINDS trial was a small, flawed study in which 312 patients received thrombolytic therapy with tissue plasminogen activator (tPA) for stroke.2 Higher scores for stroke severity in the placebo group could themselves explain the improved outcome attributed to thrombolysis. Further clarification has been thwarted by the investigators’ refusal to release the raw data and allow clarification of uncertainty surrounding the results whereby benefit appears confined to those treated at 0–90 minutes after onset, with no benefit in those treated at 90–180 minutes.2 Reports of the introduction of thrombolysis with tPA into clinical practice consistently document substantial protocol violations and worse outcomes than without thrombolysis. The study by Szoeke et al documents mortality attributed to thrombolysis given when protocol criteria were not met, as well as a 23% protocol violation rate in a presumed “best practice” setting. It should be highlighted that their finding in an audit of 30 patients that outcomes were “consistent with reported trial data” means they were also consistent with a worse outcome, although confidence intervals are not presented. Thrombolysis with tPA is not endorsed as a standard of care in stroke by the Canadian Association of Emergency Physicians, the American Academy of Emergency Medicine or the American College of Emergency Physicians; nor do any of these organisations advocate its introduction into practice outside research trials.3,4 In contrast, the American Heart Association upgraded its rating for thrombolysis in stroke from a class IIa to a class I recommendation in its 2000 guidelines without any additional data from randomised trials. Conflicts of interest are substantial and not widely disclosed.2 Genentech, the manufacturer of tissue plasminogen activator, has contributed US$11 million to the American Heart Association and paid for its national headquarters. Six of the nine panellists responsible for the guidelines had financial ties to Genentech, which were not disclosed.5 A dissenting panellist had his name removed from the list of contributors, despite previous assurances that his dissenting position would be published.5 There are not many areas where so much has been made of so little; it falls a long way short of proof. Geoffrey A Donnan,* Stephen M Davis,† Christopher R Levi‡ * Director, National Stroke Research Institute, Melbourne, VIC; † Director of Neurology, Royal Melbourne Hospital, Parkville, VIC 3050; ‡ Neurologist and Conjoint Senior Lecturer, John Hunter Hospital, Newcastle, NSW. stephen.davisATmh.org.au In reply: The comments of Smith may not reflect the consensus of his emergency medicine colleagues. The broad view of the place of tissue plasminogen activator (tPA) is best appreciated from overviews and meta-analysis of all trials of intravenous tPA in acute ischaemic stroke.1-3 Overall, tPA is one of the most powerful biological agents in medicine, with a number needed to treat of about eight to benefit one patient. The integrity of the investigators of the tPA trials is unquestionable. All results were published in journals of the highest repute (including the New England Journal of Medicine, the Lancet and the Journal of the American Medical Association). The National Institute of Neurological Disorders and Stroke (NINDS) trial4 was investigator-driven and funded by the US National Institutes of Health, the highest standard achievable in trial management.5 NINDS receives unrestricted grants from the pharmaceutical industry with appropriate ethical guidelines, as do many societies worldwide. To suggest a linkage is certainly extending conspiracy theory to its limits. Several trial-related issues mentioned by Smith deserve comment. In the NINDS trial, as in many randomised controlled trials, the analysis adjusted for minor baseline imbalances in stroke severity, with no significant impact on outcome. The Melbourne study of Szoeke et al was not a randomised controlled trial, but rather an audit of practice in an expert setting.6 The protocol violations were all relatively minor, and the rate of 23% is comparable with rates in other Phase IV studies.7 Although only a small proportion of stroke patients are eligible for tPA, it is one of the most important advances in stroke medicine. Emergency physicians must play a collaborative role with stroke physicians in delivering this benefit. Kent R Johnson Medical Director, Medical Technology Assessment Group (M-TAG), PO Box 5639, Chatswood West, NSW 2067. kjohnsonATm-tag.net To the Editor: Recent commentators have described the uncertainty surrounding the use of thrombolysis in acute ischaemic stroke.1,2 Recombinant tissue plasminogen activator (tPA) was first approved in 1996, yet its use in stroke still remains low. One explanation is feasibility, as treatment must begin within 3 hours of stroke onset. However, the evidence itself is being questioned.3,4 A recent Cochrane meta-analysis advises caution, noting particularly heterogeneity, and concludes that: “In the light of these considerations, some clinicians may wish to use thrombolytic therapy in highly selected patients; others who are concerned about the definite risks may choose not to use the treatment at all.”4 It is worth revisiting the two studies that supplied the preponderance of data for tPA approval — the two parts of the National Institute of Neurological Disorders and Stroke (NINDS) trial.5 Firstly, the results at face value cannot be considered particularly robust. The first part of the trial (291 patients) showed no difference in the primary endpoint, “early improvement” (resolution or improvement by at least four units on the 24-hour National Institutes of Health [NIH] Stroke Scale). The second part (333 patients) did show a difference in its primary endpoint, a 3-month global statistic6 that simultaneously assessed the Barthel Index, modified Rankin Scale, Glasgow Outcome Scale, and NIH Stroke Scale, with the odds ratio for a favourable outcome with tPA being 1.7 (95% CI, 1.2–2.6; P = 0.008). However, the two parts of this trial also showed substantial drug toxicity (a combined rate of symptomatic intracerebral haemorrhage of 6.4% with tPA versus 0.6% with placebo) with no improvement in mortality (17% with tPA versus 21% with placebo; P = 0.30). Few would describe these results as robust. Secondly, the design strategy added uncertainty to the interpretation. The two parts of the trial were sequential, so that the design of the second could profit from lessons learned from the first: an attractive and common strategy. The studies used identical entry criteria and dosing regimens but different primary endpoints and timepoints. Part 1 “test[ed] whether tPA had clinical activity”, using “early improvement” as the primary endpoint.5 It was then extended for 3 months, and those results were used by the Data Safety Monitoring Committee to design an efficient 3-month endpoint for Part 2. In effect, Part 2 was a test of both tPA therapy and of the new endpoint. This endpoint is then entirely conditional on Part 1; there was no prior trial experience with this endpoint. Consequently, the trial’s success is less generalisable than if a well-established endpoint had been used, and the two parts together carry less evidentiary weight than if they had been fully independent. Paul M Bailey Emergency Physician, Joondalup Health Campus, Shenton Ave, Joondalup, WA 6027. To the Editor: In their retrospective audit of stroke patients presenting to a Victorian hospital, Szoeke and colleagues present a one-sided view of the usefulness of thrombolysis with tissue plasminogen activator (tPA) in acute stroke.1 Proof of the efficacy of tPA in acute ischaemic stroke is far from settled. The National Institute of Neurological Disorders and Stroke (NINDS) trial, in which only 312 patients received thrombolytic therapy, remains the only trial demonstrating benefit from intravenous thrombolysis in a primary outcome measure.2 The study design of the NINDS trial required the enrolment of a disproportionate number of patients with very early stroke (within 0–90 minutes of onset). These patients are rarely encountered in everyday clinical practice. Patients in the 91–180 minute group who received placebo were sicker at baseline than those who received tPA, raising significant doubts as to the efficacy of tPA. After further analysis of the results, the NINDS investigators reported that the greatest positive effect of tPA was seen in the 0–90 minute group.3 The positive effect of tPA in the 91–180 minute group, while not specifically reported, can only have been very small. It is interesting that the median time to treatment in Szoeke et al’s study was 2 h 48 min, implying that 50% of patients were treated in the last 12 minutes of the 3-hour window — when benefits of treatment are at their smallest (should they exist at all), but all the risks of therapy remain. I am also astounded that in the setting of a dedicated stroke unit, with all patients attended to by a team comprising “a stroke neurologist, ‘stroke’ fellow, registrar and nurse”, and a requirement for specific approval for use of tPA to treat stroke in the hospital, that protocol violations occurred in 23% of patients (7/30). That is not the sort of performance that I would want to place in the public domain. Tiny retrospective “trials” are fraught with potential bias, as non-blinded treatments and outcome measures may reflect the enthusiasm of the authors. In addition, significant publication bias may exist — groups with bad results from thrombolysis may not publish. I await the publication of further well designed, randomised, placebo-controlled clinical trials, not linked to the manufacturers of tPA, that demonstrate an improvement in a primary outcome measure in patients treated with tPA before deciding that this treatment may have some use outside clinical trials. I will not hold my breath. Stephen M Davis,* Mark W Parsons,† Kenneth S Butcher,‡ Cassandra E I Szoeke§¶ * Director of Neurology, † Neurologist, ‡ Neurologist, § Registrar, Royal Melbourne Hospital, Parkville, VIC 3050. ¶ On behalf of the other authors.1 stephen.davisATmh.org.au In reply: Johnson correctly points out that the National Institute of Neurological Disorders and Stroke (NINDS) trial had two parts.2 Part 1 was designed to test whether tissue plasminogen activator (tPA) had early clinical activity at 24 hours, and Part 2 was designed to assess whether tPA conferred outcome benefits at 3 months. The results of Part 1 of the trial showed a non-significant improvement in neurological score at 24 hours. However, the finding in Part 2 that there was a significant difference in the primary endpoint (a global test statistic at 90 days) was also true for Part 1 and for a combined analysis of Parts 1 and 2.3 Although there was a substantial increase in symptomatic intracerebral haemorrhage in the thrombolysis group, there was no increase in mortality, and the adverse effects were outweighed by the highly significant benefits at outcome. Johnson’s comment on the choice of endpoints is also of interest. It should be emphasised that the efficacy of tPA in the NINDS trial applied to a range of standard outcome evaluations, including the NIH Stroke Scale, Glasgow Outcome Scale, modified Rankin Scale and Barthel Index, as well as the new global test statistic, which incorporates these scores.2 Many of the issues raised by Bailey have been covered by Donnan et al,4 but some additional comments are warranted. Based on the NINDS trial and meta-analyses of all the intravenous tPA data, this therapy has been licensed for stroke in the United States, Canada, Europe (including the United Kingdom) and many other parts of the world. It is being considered for licensing in Australia. The minor baseline disparities between the tPA and placebo groups have been subject to further rigorous analysis by an independent review committee commissioned by NINDS. This analysis confirmed the statistically significant benefit of tPA within 3 hours.5 The benefits of tPA are indeed time-linked, as shown by further analysis of the NINDS data, but are highly significant right up to the end of the 3-hour window.6 The odds ratio for favourable 3-month outcome with tPA was 2.11 (95% CI, 1.33–3.35) for treatment at 0–90 minutes and 1.69 (95% CI, 1.09–2.62) for treatment at 91–180 minutes. Furthermore, meta-analysis indicates benefit beyond the 3-hour window,7 but there is consensus that further trials are needed to extend the current window, and that tPA should not be used after 3 hours, except in clinical trials. We again emphasise that our audit was not a “trial” and that our protocol violations were generally minor and in line with other expert experience.1 We do not apologise for emphasising the importance of a well-resourced acute stroke team. This is integral to the expert setting required for tPA administration. In 2003, would anyone suggest that patients with acute myocardial infarction should be treated without optimal resources and expert care? Why should acute stroke patients, with high mortality and disability rates, be the poor relations?

Brendon J Smith

Objective: To determine the factors influencing survival among patients admitted to Western Australian hospitals for the first time with stroke or transient ischaemic attack (TIA).Design, setting and patients: Linked hospitalisation and death records of 7784 patients admitted to hospital for first-ever stroke or TIA between July 1995 and December 1998 were retrieved retrospectively to determine survival; effects of risk factors on death due to stroke were assessed using the Cox proportional hazards regression model.Main outcome measures: All-cause stroke survival; short- and long-term stroke survival probabilities.Results: Survival at 28 days was lowest for haemorrhagic stroke. However, following the first month after admission survival after haemorrhagic stroke was similar to, if not higher than, after ischaemic stroke. Among all patients, significant predictors of death were age (all subtypes of stroke), atrial fibrillation (intracerebral haemorrhage and ischaemic stroke), other cardiac conditions (ischaemic stroke and TIA), and sex and diabetes (TIA). Further predictors of death were residence in rural or remote areas (ischaemic stroke), and Aboriginality (TIA). Among 28-day survivors of ischaemic stroke, additional predictors of death were sex, diabetes and urinary incontinence still present 7 days after admission.Conclusion: Use of linked hospitalisation and death data allowed us to increase the scope and size of our study compared with previous studies of survival after stroke and TIA in WA. We confirmed the importance of type of stroke, age and comorbidities to this survival, and found that Aboriginality and place of residence are also important.

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

A palliative care approach has much to offer people in the advanced stages of neurodegenerative diseases, as well as elderly people dying from diseases other than cancer. Palliative care can be part of the treatment repertoire of any health worker, supported by intermittent consultation or referral to specialist palliative care services (eg, for management of neuropathic pain). A palliative care approach encourages a focus on pain and symptom management, and prompts more open communication about end-of-life issues. This approach recruits as necessary the expertise of specialists and multidisciplinary teams to encourage a flexible, responsive service. Home carers and healthcare providers require education to ensure a palliative approach that meets the physical, psychological, spiritual and social challenges facing patients and their families, and enhances dignity and quality of life.

Linda J Kristjanson PhD · Christine Toye PhD · Sky Dawson MSc

One of the most exciting possibilities in human therapeutics is that stem cells (embryonic or adult) may compensate for cell loss in disease, with functional recovery. This has received considerable publicity in the lay press. Much work remains to be done to turn stem cell therapy into a practical reality for major degenerative diseases, especially those affecting the nervous system. Medical scientists and journalists should work together in ensuring that the general public has a realistic understanding of the likely time frame in which benefits from stem cell therapies will be realised.

Edward Byrne MD, DSc · David W Howells PhD

The “new genetics” will require specialist physicians to deal with an increasing number of genetic issues. Huntington disease (HD) is a rare single gene adult-onset fatal neurodegenerative disorder. It provides a model to illustrate the role of the specialist physician in the new genetics. DNA testing options in HD include diagnostic DNA tests to confirm a provisional diagnosis, and predictive or presymptomatic DNA tests to determine whether disease will develop in an at-risk individual. The specialist physician is well positioned to interact with the genetics services by providing in-depth knowledge of the clinical implications. This will become particularly relevant as the more complex multifactorial disorders (eg, Alzheimer disease) are understood at the DNA level. For optimal use of the new genetics, a team approach is essential to ensure that all areas of expertise are covered.

Elizabeth A McCusker MB BS(Hons), FRACP

The recently released PREVENT trial provides some answers Venous thromboembolism (VTE) affects 1–2 people per 1000 in the general population each year.1 It most commonly manifests as deep vein thrombosis of the leg, or as pulmonary embolism. There are many acute provoking factors or triggers (eg, major trauma, recent surgery), and many chronic predisposing factors, both genetic (eg, factor V Leiden) and acquired (eg, cancer). Most patients with provoked VTE have a low risk of recurrence (0–4% per year without anticoagulation), presumably because most have no major predisposing factors for VTE.2 Treatment for provoked VTE is short term and consists of giving intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) for at least 5 days, followed by warfarin (target international normalised ratio [INR], 2.0–3.0) for 3 months.3 Further antithrombotic therapy is usually not required unless patients are re-exposed to known triggers for VTE. Standard-intensity therapy with warfarin remains the treatment of choice for the long-term prevention of recurrent VTE in patients who are at highest risk of recurrence Most patients with unprovoked VTE, however, have a higher risk of recurrence (≥ 5% per year without anticoagulation) over many years.4,5 This is because they are chronically exposed to one or more underlying genetic or acquired predisposing factors for VTE, which may be identifiable from the clinical history or through laboratory testing. Furthermore, the absence of a provoking factor or trigger for VTE is the most important predictor of recurrence in these patients. They require longer-term or indefinite treatment, which consists of giving intravenous unfractionated heparin or subcutaneous LMWH for at least 5 days, followed by warfarin (target INR 2.0–3.0).3 This is standard-intensity anticoagulation therapy, and is highly effective in preventing recurrent episodes of VTE for as long as it is continued. In trials in which patients were treated for a median of 4–6 months, it reduced the absolute risk by 7.6%, which is equivalent to preventing one event for every 13 patients treated (odds ratio [OR], 0.15; 95% CI, 0.10–0.23).6 In patients considered at highest risk of recurrent unprovoked VTE (eg, > 10% per year; see Box), warfarin therapy is continued indefinitely, whereas in most patients, it is discontinued after 6–12 months.3 This is because long-term anticoagulation is associated with a cumulative risk of bleeding, which is perceived to outweigh its benefits in preventing recurrent VTE. Standard-intensity therapy with warfarin causes minor "nuisance" bleeding in 5%–15%, major bleeding in 2%–3%, and fatal bleeding in 0.2%–0.6% of patients each year.7 A hitherto burning question for patients with unprovoked VTE is whether there are other anticoagulant treatment regimens with a more acceptable benefit-to-harm ratio, such as lower-intensity oral anticoagulation therapy. The recently reported Prevention of Recurrent Venous Thromboembolism (PREVENT) trial was initiated in July 1998 to test the hypothesis that long-term, low-intensity warfarin therapy (target INR, 1.5–2.0) might provide a safe and effective method of reducing the risk of recurrent VTE among patients who had a previous idiopathic (unprovoked) venous thrombosis.8 After completing at least 3 months of standard-intensity warfarin therapy (target INR, 2.0–3.0), 508 patients were randomly allocated to receive low-intensity warfarin therapy or placebo in a double-blinded fashion. The trial was terminated after a mean follow-up duration of 2.1 years because there was strong evidence of efficacy of warfarin. Of 253 patients assigned to placebo, 37 had recurrent venous thromboembolism (7.2 per 100 person-years), compared with 14 of 255 patients assigned to low-intensity warfarin therapy (2.6 per 100 person-years). This represents a relative risk reduction of 64% (hazard ratio [HR], 0.36; 95% CI, 0.19–0.67; P < 0.001), and an absolute risk reduction of 4.6%, equivalent to one event prevented for every 22 patients treated for 1 year. Bleeding episodes necessitating hospitalisation occurred in two patients in the placebo group (0.4 per 100 person-years), and five patients in the warfarin group (0.9 per 100 person-years); this difference was non-significant (P = 0.25).8 Although the PREVENT trial showed no significant excess of major bleeding with low-intensity warfarin therapy compared with placebo, event rates were low (5 v 2), and the 95% confidence intervals do not reliably exclude even a 13-fold increase in risk of major bleeding (HR, 2.53; 95% CI, 0.49–13.03). Yet, there is no doubt that low-intensity warfarin causes bleeding. In the PREVENT trial, "minor" bleeding was significantly increased in the warfarin group compared with the placebo group (12.8% v 6.7%; HR, 1.92; 95% CI, 1.26–2.93), with an increase in absolute risk of 6.1%, equivalent to one minor bleed caused for every 16 patients treated for 1 year. The results of the PREVENT trial indicate that low-intensity warfarin therapy is effective for long-term prevention of recurrent VTE. However, it was not shown to be sufficiently superior to placebo for low-intensity warfarin to be adopted for this indication. Standard-intensity warfarin is also superior to placebo when continued for up to 4 years after an initial thrombotic event.6,9-11 Indeed, it almost eliminates the risk of recurrent VTE in patients who continue the therapy, but is not routinely used because of the bleeding risks. Mini-dose warfarin therapy (fixed-dose, 1–2 mg daily) has never been shown to be effective for this indication, while low-intensity warfarin therapy is unlikely to offer any advantages over standard-intensity therapy in terms of convenience, and would only be a viable alternative if it were significantly safer. Indirect comparisons of the relative effectiveness and safety of low-intensity and standard-intensity therapy with warfarin, compared with placebo, are unreliable.8-11 For example, the apparently lower rates of bleeding in the PREVENT trial when indirectly compared with previous trials of warfarin might simply be explained by differences in patient selection. The PREVENT trial randomly allocated patients to treatment or placebo after they had completed a median of 6.5 months of warfarin treatment, and also included a 28-day run-in phase. It is thus likely that patients at increased risk of bleeding were excluded from the long-term phase of the study. By contrast, in most previous trials of long-term standard-intensity therapy with warfarin, patients were randomly allocated after no more than 3 months of treatment. This is as unreliable as comparing two sporting teams by their respective performances against another team rather than having them oppose each other directly. Indeed, the results of a recent direct head-to-head randomised comparison showed that low-intensity warfarin therapy was not only less effective than standard-intensity therapy for preventing recurrent VTE (absolute risk increase of 1.3% per patient year, equivalent to one event caused for every 77 patients treated for 1 year), but provided no advantage in terms of major bleeding (1.0% v 0.9% per patient-year; HR, 1.0; 95% CI, 0.4–2.7) or minor bleeding (4.9% v 3.6% per patient-year; HR, 1.3; 95% CI, 0.8–2.1).12 Taken together, these results indicate that standard-intensity therapy with warfarin is more effective for preventing recurrent VTE than low-intensity warfarin therapy, which, in turn, is more effective than placebo. However, because low-intensity warfarin therapy does not appear to be any safer in terms of bleeding and still requires close laboratory monitoring, it is difficult to justify this approach as an alternative to standard-intensity therapy for the long-term prevention of VTE, irrespective of a patient's baseline risk of recurrence or bleeding. The implications of these results for clinicians are that standard-intensity therapy with warfarin (target INR, 2.0–3.0) remains the treatment of choice for the long-term prevention of recurrent VTE in patients who are at highest risk of recurrence (eg, history of recurrent unprovoked VTE, major predisposing factor such as cancer; see Box) or with an initial life-threatening event (eg, major pulmonary embolism), and low risk of haemorrhagic complications. For patients with a first episode of unprovoked VTE or at increased risk of haemorrhagic complications, to decide about long-term treatment, doctors need to weigh the absolute risks of recurrent VTE and bleeding complications with and without warfarin treatment in each patient. In most cases, this is likely to result in the discontinuation of treatment after 6–12 months. The implications of these results for researchers are that more data are required to improve the reliability of clinical and laboratory predictors of recurrent VTE and haemorrhagic complications in individual patients, and that randomised controlled trials are required to evaluate the effectiveness and safety of alternative long-term antithrombotic therapies (eg, ximelagatran,13 antiplatelet agents) that are likely to be more convenient or have a more favourable benefit-to-risk profile than either standard-intensity or low-intensity warfarin therapy. Major determinants of the risk of recurrent venous thromboembolism Low risk (0–4% per year) Provoked event* Isolated distal deep vein thrombosis Intermediate risk (5%–10% per year) First unprovoked event Major predisposing factor(s)† Highest risk (> 10% per year) More than one unprovoked event First unprovoked event plus major predisposing factor(s)† Active cancer * Provoking factors include, in the last 3 months: hospitalisation, major surgery, trauma, leg fracture, plaster cast, puerperium. †Major predisposing factors include: prolonged immobility, neurological disease with paresis, homozygosity for factor V Leiden, combined (multiple) thrombophilic abnormalities, antiphospholipid antibody syndrome, inferior vena caval filter. Cancer is also a major predisposing factor but is mentioned separately because it is such a strong predisposing factor in its own right.

John W Eikelboom FRACP, FRCPA · Graeme J Hankey MD, FRACP

A 43-year-old woman taking warfarin for past venous thrombosis presented with 4 days of flu-like symptoms and deterioration in level of consciousness. Computed tomography suggested subarachnoid haemorrhage, and magnetic resonance imaging showed widespread cerebral infarcts. However, these seemed out of proportion to the amount of haemorrhage, and lumbar puncture revealed meningitis caused by Streptococcus pneumoniae. Computed tomography (CT) is a vital investigation in acute medicine, but CT appearances may occasionally be misleading, as illustrated here. Clinical recordPresentation (Day 0): A 43-year-old woman was admitted to the emergency department (ED) in June 2002 with deterioration in her level of consciousness. She had a 4-day history of non-specific flu-like symptoms. On the day of admission, her husband had noted her to be lucid at 09: 00 but found her semi-comatose when he returned home at 14: 30. She had a past history of venous thrombosis, thought to be secondary to the presence of anticardiolipin antibody and lupus inhibitor, for which she took warfarin. She used topical and parenteral corticosteroids to control severe eczema, was a non-smoker and did not take the oral contraceptive pill. On examination, her score on the Glasgow Coma Scale (GCS) was 7/15. Pupils were equal and reactive, and no definite signs of meningism could be elicited. Respiratory rate was 24 breaths/min, with oxygen saturation of 99% on supplemental oxygen, 15 L/min via a Hudson mask. Tympanic temperature was 40.8°C, blood pressure 168/92 mmHg and pulse rate 128 bpm in sinus rhythm. Serum blood glucose level was 7.8 mmol/L (reference range [RR], 3.6–5.8 mmol/L), white cell count was 18.6 x 109/L (RR, 4.2–11.0 x 109/L), with toxic changes on the blood film, and platelet count was 357 x 109/L (RR, 150–460 x 109/L). The international normalised ratio (INR) was 1.8 (RR, 0.8–1.3), with normal values for fibrinogen and fibrin cross degra-dation products, and activated partial thromboplastin time. C-reactive protein level was raised at 402 mg/L (RR, 0–10 mg/L). Other laboratory results, including renal function, were within the reference ranges. In the ED, the patient underwent tracheal intubation because of her low GCS score, and was subsequently sedated with morphine and midazolam. Blood was taken for culture, and intravenous ceftriaxone (2 g daily) was begun. Chest radiography showed segmental right upper-lobe consolidation. Non-contrast CT of the brain was performed during her transfer to the intensive care unit (ICU). This was reported as showing subarachnoid haemorrhage, with increased density in the subarachnoid space, particularly within the basal cisterns (Box A). A neurosurgeon was consulted, and subarachnoid haemorrhage with aspiration pneumonia was diagnosed. The differential diagnosis of meningitis was thought less likely because of the CT appearance. A nimodipine infusion was begun, and cerebral angiography was planned. Her high INR was normalised with 4 units of fresh frozen plasma. Day 1: At 06: 00 the next morning, the patient's pupils became unequal and non-reactive. This was thought secondary to either vasospasm or a re-bleed. Urgent repeat contrast CT at 07: 00 showed a parietal infarct, but no further bleeding or signs of raised intracranial pressure. The hyperdensity in the basal cisterns was less apparent, but there was subtle hyperdensity within the subarachnoid space, around the cerebral sulci near the vertex. On subsequent review, the amount of haemorrhage suggested by the cranial CT scans appeared insufficient to account for the patient's clinical condition. Diffusion-weighted magnetic resonance imaging (MRI) at 13: 30 showed multiple acute cerebral infarcts in the territories of the right middle and posterior cerebral arteries, as well as in the watershed zone between the middle and anterior cerebral arteries (Box B). There was no abnormal enhancement of the leptomeninges to suggest infectious meningitis, and, in particular, no basal leptomeningal enhancement to suggest granulomatous meningitis (Box B). In the absence of abnormal leptomeningeal enhancement, the presence of increased signal within the subarachnoid space was thought to be due to subarachnoid haemorrhage (Box B). Magnetic resonance angiogram and venogram showed no aneurysm or dural venous sinus thrombosis. Appearances were again thought most likely to represent primary subarachnoid haemorrhage, with acute cerebral infarction secondary to vasospasm. However, meningitis with secondary cerebral infarction was raised as a differential diagnosis, and lumbar puncture was recommended. Lumbar puncture was subsequently performed after correction of residual coagulopathy, and revealed an opening pressure > 35 cmH2O, a white blood cell count in cerebrospinal fluid (CSF) of 1510 x 106/L (all polymorphs), red blood cell count of 160 x 106/L (decreasing on subsequent tubes, with xanthochromia not detected), and protein level of 2291 mg/L (RR, 150–450 mg/L). Gram-positive diplococci were visible on Gram stain, and the CSF was positive for pneumococcal antigen. Blood taken on admission subsequently grew Streptococcus pneumoniae. After consultation with the infectious diseases team, we changed the antibiotic regimen to intravenous ceftriaxone (2 g) and vancomycin (1 g) twice daily. The diagnosis was revised to primary pneumococcal pneumonia with secondary pneumococcal meningitis. Course: After 11 days' treatment in the ICU, the patient was transferred to a ward. On Day 13, she developed a large pulmonary embolus confirmed by CT angiogram and was readmitted to the ICU for respiratory support. She recovered and subsequently resumed anticoagulation therapy with heparin and warfarin. She was discharged back to the ward on Day 18. At review a month later: She was undergoing rehabilitation, and was lucid and able to move with a frame, but remained blind in both eyes. DiscussionCranial CT scanning is a vital diagnostic tool in patients presenting with acute alteration in level of consciousness. Our case posed a diagnostic difficulty because of the unusual appearance on initial brain imaging. The initial CT scan showed increased density in the subarachnoid space, which is mostly caused by subarachnoid haemorrhage. Based on the imaging findings alone, the most likely diagnosis was therefore felt to be subarachnoid haemorrhage with secondary vasospasm causing cerebral infarction. However, there seemed to be a disparity between the amount of subarachnoid blood and the patient's clinical condition. This was reinforced by MRI, which showed extensive infarction in different vascular territories. This degree of infarction secondary to vasospasm would be unusual without widespread haemorrhage or thick focal clot, which were not seen. Additionally, vasospasm secondary to subarachnoid haemorrhage tends to peak 4–12 days later, while our patient showed signs of neurological deterioration less than 24 hours after admission. Cerebral infarction has been well reported in bacterial meningitis in both adults2,3 and children,4,5 and is thought to result from an intense inflammatory response in the cerebral vasculature. It is particularly noted in pneumococcal meningitis. Although pneumococcal meningitis was not diagnosed initially in our patient, broad spectrum antimicrobials, to which the organism was fully sensitive, were fortuitously begun on admission. The delay in ascertaining the correct diagnosis created a dilemma about subsequent anticoagulation, which probably could have been recommenced earlier. Increased density in the subarachnoid space on CT has been described in tuberculous meningitis.6-8 However, this was unlikely in our patient — the condition is still uncommon in the Western world, and contrast enhancement of the basal leptomeninges (a sign of granulomatous meningitis) was absent. Increased density in the subarachnoid space has also been reported in anoxic encephalopathy,9 but our patient had no history of hypoxia or prolonged ischaemia. In addition, although the acute infarcts were within regions of the brain susceptible to acute hypoxic injury, they were all within the right cerebral hemisphere. With a global insult such as hypoxia, bilateral lesions would be expected. To our knowledge, there has previously been only one English-language article describing a patient with acute purulent meningitis mimicking subarachnoid haemorrhage on CT scan.10 Presumably this appearance is caused by the high protein concentration of the purulent exudate in pyogenic meningitis, as noted in our case. Although this is uncommon, we present this case to alert both radiologists and clinicians to the presence of this atypical appearance on imaging and to highlight the need for careful evaluation of such patients. The case also illustrates that results of investigations should not be interpreted in isolation from the clinical picture. We suggest that lumbar puncture should be performed if the clinical presentation is atypical or not in keeping with the radiological findings. Brain imaging in a patient with pneumococcal meningitis A: Computed tomography (CT) on Day 0 Non-contrast CT scan, showing increased density within the basal cisterns (arrow A) and along the sylvian fissures bilaterally (arrow B), suggesting subarachnoid haemorrhage. B: Magnetic resonance imaging (MRI) on Day 1 Diffusion-weighted MRI scan showing multiple foci of increased signal intensity in the anterior part of the right thalamus, posterior right temporal lobe and right occipital lobe. Increased signal intensity was also seen in the right frontal and parietal lobes (not shown). This appearance was consistent with multiple acute infarcts in the territories of the right middle and posterior cerebral arteries. Not shown: Multiple small acute infarcts were also seen in the watershed zone in the centrum semi-ovale between the territories of the right middle and anterior cerebral arteries. Gadolinium-enhanced T1-weighted MRI scan showing no abnormal enhancement of the leptomeninges, including the basal leptomeninges. This suggests no evidence of a granulomatous meningitis. Not shown: Increased signal intensity was seen within the subarachnoid space overlying the cerebral sulci of both cerebral hemispheres on the FLAIR sequence (a T2-weighted sequence that nullifies the signal from cerebrospinal fluid [CSF], improving detection of lesions within the subarachnoid space and brain parenchyma1). This is a non-specific finding in a wide range of conditions, principally subarachnoid haemorrhage and meningitis. In our patient, the absence of leptomeningeal enhancement on the post-contrast images favoured a diagnosis of subarachnoid haemorrhage.

Taposh Chatterjee MB BS · John R Gowardman FRACP, FJFICM · Tony D Goh FRANZCR

Stroke care units are the key to improving outcomes Over the past 25 years there has been a quiet revolution in care of patients with stroke, with the introduction of effective interventions to minimise the impact of stroke after its onset. Although some potential secondary prevention strategies were used sporadically before the mid-1970s, none had been proven to be effective with what we now accept as Level 1 evidence. However, since then, a series of evidence-based strategies have been introduced — antiplatelet agents (initially aspirin in 1978,1 and most recently clopidogrel2), carotid endarterectomy in 1991,3 warfarin (for patients with atrial fibrillation) in 1993,4 and perindopril in 2001.5 In spite of the tenuous epidemiological association between cholesterol levels and ischaemic stroke, statins (eg, simvastatin) may also be effective in secondary prevention.6 Interventions for acute stroke have been more problematic. Despite the exciting advances in treatment of ischaemic heart disease, developments in stroke treatment were slow. Stroke care units were introduced in the mid-1970s — the first in Australia at the Austin Hospital, Melbourne, in 1978.7 However, not until 1993 did it become clear that management in a stroke care unit reduced morbidity and mortality compared with general ward management8 and, more recently, that patients treated in physically discrete units have better outcomes than those who are dispersed in different locations and rely on mobile stroke teams.9 Thrombolysis with tissue plasminogen activator (tPA) (given within three hours of stroke onset) was introduced in 199510 and with aspirin (given within 48 hours of onset) in 1997.11 Neuroprotection with agents such as glutamate antagonists, among others, is still being evaluated. In this issue of the Journal, four articles reflect on the enactment of these advances in Australia.12-15 Duffy and colleagues ((page 318) document the secondary prevention strategies administered in Australian hospitals and show their relatively poor uptake into clinical practice despite Level 1 evidence of their effectiveness.12 This highlights the difficulty of bridging the evidence–practice gap.16 The other three articles focus on the "sharp end" of stroke intervention — a report of the first Australian experience of thrombolysis with tPA (Szoeke et al; (page 324),13 another on the reasons for delay to admission for acute stroke management (geographical location of the patient at stroke onset was the only independent predictor) (Broadley and Thompson; (page 329),14 and finally the outcomes of combined acute and rehabilitation care in a stroke unit — probably the ideal model of care (Ang et al; (page 333).15 It is salutary to compare the effects on death and disability of the three proven strategies for stroke intervention — management in a stroke care unit, and aspirin and tPA administration (Box). Using broad assumptions about the current uptake of these strategies by Australian physicians, the absolute benefits of stroke care unit management clearly outweigh those of aspirin and tPA administration. If use of all three strategies was maximised to about 80% for stroke care unit management, 80% for aspirin administration within 48 hours of stroke onset, and 10% for tPA administration within three hours, the difference in potential absolute benefits would be even more marked —the benefits of stroke unit management would be more than double those of either tPA or aspirin. Perhaps even more importantly, when a stroke care unit is established the staff skill base increases, and protocols are put in place, increasing the likelihood of evidence-based practice for both acute intervention and secondary prevention strategies. These benefits highlight the need for the timely introduction of stroke care units in Australia. What then is being done? Progress has been lamentably slow. While there have been stroke care units in most tertiary hospitals in Victoria for the past 10–15 years, their introduction in other States has been tardy. However, this is changing. The New South Wales Minister for Health has taken a bold initiative which would be well emulated in other States and Territories. Based on advice from senior physicians, a plan was established for the current and future health needs of the almost five million people living in Sydney and surrounding areas. An increase in the number and quality of stroke care units was clearly a priority. More than $10 million of recurrent and $2 million of capital funding was allocated to upgrade facilities within the greater metropolitan area, which will lead to the establishment or improvement of 18 stroke care units. Moves are also afoot nationally. The National Health Priorities Action Committee has formed a Heart, Stroke and Vascular Disease group. One of its first tasks, in collaboration with the National Stroke Foundation, has been to help coordinate the introduction of stroke care units in Australia. However, improving "front-end" resources is only one issue. Stroke management is a continuum of care from entry into acute stroke care units through to access to rehabilitation and geriatric facilities, community involvement and, for some, nursing home placement. Resources are needed to avoid blockages at any points on this continuum. Too many stroke care units are unable to admit patients for acute intervention because beds are blocked by those awaiting nursing home placement.18 As with other major health problems, the peculiarly Australian phenomenon of acute health being a state responsibility, while nursing home bed numbers are under federal control, acts as a political and bureaucratic barrier to action. Benefits to stroke patients are being lost while state and federal bodies debate who is responsible for this lack of coordination. It is time for constructive action! Actual and potential benefits (avoidance of death or disability) of acute interventions for stroke in Australia Intervention Absolute risk reduction Number needed to treat Estimated proportion of stroke patients treated* Current absolute benefit† (number of cases) Potential proportion of stroke patients treated Potential absolute benefit† (number of cases) Stroke care unit 4%‡ 25‡ 23% 423 80% 1472 Aspirin§ 1.2%§ 83§ 70% 387 80% 443 Tissue plasminogen activator¶ 12.0%¶ 8¶ < 1% < 23 10% 575 * From the National Stroke Foundation survey of stroke care unit access, 1998.16 † Number of deaths or cases of disability avoided among 46 000 strokes in Australia per year. ‡ From the Stroke Unit Trialists' Collaboration.17 § From the International Stroke Trial.11 ¶ From the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator trial.10

Geoffrey A Donnan MD, FRACP · Stephen M Davis MD, FRACP · Christopher R Levi FRACP

The identification of specific causal genes and the development of animal models of MND offer realistic hope of new treatments Since Charcot's first description, motor neurone disease (or amyotrophic lateral sclerosis) has remained an enigma.1 Without a clear understanding of the pathogenesis, and with relatively little therapy to offer other than symptomatic and palliative intervention, clinicians have faced the difficult task of effectively managing patients with this relentlessly progressive disease. However, advances in understanding over the past decade have reignited research interest, renewing hope that a curative approach may be forthcoming. Motor neurone disease (MND) is characterised by progressive deterioration involving the corticospinal tract, brainstem and anterior horn cells of the spinal cord. Extraocular and sphincter muscles innervated by motor neurones not receiving direct projections from the motor cortex are characteristically spared. The term MND is used to encompass all forms of the disease, whatever the combination of upper and lower motor neurone involvement, while Americans still call it Lou Gehrig's disease, after the New York Yankees baseballer diagnosed with MND towards the end of his playing career. The aetiology of MND is unknown but appears heterogeneous. Environmental factors may trigger a genetic susceptibility — toxins, chemicals, metals, previous infections, and trauma have all been proposed. Uncertainty about the aetiology often creates added concern in MND patients with regard to heritability, as highlighted by the Personal Perspective article in this issue of the Journal (page 344).2 Most aetiologies have been linked to a cascade involving the glutamatergic neurotransmitter system, with excessive activation of glutamate receptors at the synaptic cleft (excitotoxicity) eventually triggering destruction of motor neurones. In the rarer, familial type of MND, the breakthrough finding of a mutation involving the copper/zinc superoxide dismutase-1 (SOD1) gene3 (encoded on chromosome 21q22.1) has provided an impetus for MND research and suggested new therapeutic strategies. Mutations have subsequently been documented in a fifth of the approximately 5% of patients with familial MND. However, while SOD1 mutation screening is now clinically available, genetic counselling is critical before predictive testing is undertaken. While MND is usually relentlessly progressive, with 50% of patients surviving fewer than three years from diagnosis, a smaller proportion of patients (about 20%) may survive between 5 and 10 years.4 Predominantly lower motor involvement tends to predict longer survival. In contrast, bulbar onset and respiratory compromise suggest a worse prognosis. How is MND diagnosed?There remains no pathognomonic test for the diagnosis of MND. Physicians continue to rely on clinical criteria for diagnosis, specifically the presence of both upper motor neurone (spasticity, weakness and hyperreflexia) and lower motor neurone (fasciculation, wasting, weakness and hyporeflexia) signs. Fasciculations, an almost inevitable feature of MND, reflect spontaneous nerve activity, probably generated through upregulation of persistent sodium channels in dying motor axons.5 Clinical features, in combination with neurophysiological investigation, can confirm the diagnosis. Nerve conduction studies and electromyography may also be used to identify alternative, but potentially treatable, lower motor neurone disorders confined to motor fibres, particularly immune-mediated demyelinating neuropathies and multifocal motor neuropathy.6 While research criteria exist for diagnosis,7 these are rigorous and still rely on clinical findings to stratify the likelihood of diagnosis, with most patients considered as "possibly" or "probably" having MND before the diagnosis becomes "definite" with time. Although newer imaging techniques have shown promise in aiding diagnosis, the primary role of imaging is to exclude other conditions. Despite this clinically oriented approach, the reliability of diagnosis is high, demonstrated to be 90% when compared with autopsy findings.8 Confirming the diagnosis is devastating for the patient and family members and must be handled sensitively. Patients often complain that the diagnosis was conveyed in a hurried and inappropriate manner, with some told off-handedly "to go home and write their will". A follow-up appointment a few weeks later may be beneficial to answer questions not addressed at the initial consultation, and to provide further information about support networks, particularly the Motor Neurone Disease Association. MND management and disease-modifying treatmentManagement needs to be multidisciplinary, involving physiotherapists (mobility and prevention of contractures), speech therapists (communication aids and swallowing assessment), occupational therapists (maintaining function), social workers (counselling and organising home support), and dietitians (particularly with percutaneous endoscopic gastrostomy feeding), all coordinated by the supervising neurologist or physician, with the aim of collectively maximising function and alleviating symptoms.9 Involvement of palliative care services should occur early, anticipating patient needs (eg, implementation of home services) well in advance of deterioration, and later assisting with disease-related symptoms and psychosocial issues. The role of ventilatory support remains controversial: non-invasive ventilation may improve symptoms related to respiratory insufficiency without extending survival, while invasive support may extend survival in MND patients with severe disability.10 Riluzole, an inhibitor of glutamate release, is the first medication found to increase survival in MND patients (by 3–6 months in two large randomised trials).11 Recent retrospective analyses suggest greater benefit, but these data have been confounded by general improvements in the care of MND patients. Although licensed worldwide, riluzole was only recently made available in Australia, and is currently being reconsidered for listing by the Pharmaceutical Benefits Advisory Committee. Many MND patients take a range of over-the-counter antioxidants, particularly vitamins C and E, based on promising experimental data, although there remains no sound clinical evidence concerning efficacy. Neurotrophic and immunomodulatory treatments likewise have shown little clinical benefit, while preliminary studies focusing on neuroprotective approaches (eg, with minocycline12) suggest promise. "Alternative" therapies, some offering unrealistic hope of cure, are universally unproven for MND, are often expensive, and carry the risk of potentially harmful effects. New preventive and restorative approaches are being intensively explored, including the role of stem cells as vehicles to regenerate functional connections in motor pathways. After a century of limited progress, the identification of specific causal genes and the development of animal MND models offer realistic hope that new treatments will emerge.

Matthew C Kiernan PhD, FRACP

Objectives: To assess the use of evidence-based investigations and treatments in patients with acute stroke in selected Australian hospitals and to compare management and outcomes between stroke and other types of hospital specialty unit.Design: Retrospective, multicentre audit of hospital case files.Setting: Eight metropolitan tertiary-care hospitals from five Australian States.Subjects: 300 consecutive patients from each hospital admitted between 17 September 1999 and 23 May 2001 and having a discharge diagnosis of stroke or transient ischaemic attack.Main outcome measures: Use of investigations and treatments supported by best available evidence; comparison of management and outcomes between stroke, neurology, general medical and geriatric units.Results: 2383 patients were audited (median age, 72.7 years; 52% men); 72% had ischaemic events, and 28% haemorrhagic events. Use of investigations and treatments varied between hospitals and types of unit. Stroke units or teams cared directly for 23% of patients (range across hospitals, 0–100%). Although 47% of patients with ischaemic events presented within 3 hours of symptom onset (when thrombolysis might provide benefit), only nine (2%) received thrombolysis. Angiotensin-converting enzyme (ACE) inhibitors were given to 28% of survivors at discharge (range, 14%–38%). Stroke units were more likely to use diagnostic tests, while neurology units were more likely to prescribe heparin acutely for patients with ischaemic stroke (not recommended for patients in general), and geriatric units were less likely to discharge patients with atrial fibrillation on anticoagulation therapy. Outcomes also varied significantly between types of unit. In-hospital survival rates were 90% (stroke units), 91% (neurological units), 82% (general medical units) and 79% (geriatric units) (P < 0.001). Stroke units and neurological units sent more patients home than the other units. Stroke units also sent fewer patients to rehabilitation and had longer mean length of stay.Conclusions: Acute stroke care varies between Australian tertiary-care hospitals and types of specialty unit, with suboptimal use of many evidence-based interventions.

Brendan K Duffy MD · Paddy A Phillips DPhil, FRACP, FACP · Stephen M Davis MD, FRACP · Geoffrey A Donnan MD, FRACP · Miriam E Vedadhaghi BSc, PGDipNutrDiet

Objective: To report initial experience with the use of intravenous tissue plasminogen activator (tPA) to treat acute ischaemic stroke at an Australian tertiary-care hospital.Design: Retrospective audit of computerised hospital stroke database.Participants and setting: All patients with acute ischaemic stroke treated with intravenous tPA between April 1999 and July 2002 at the Royal Melbourne Hospital, VIC.Main outcome measures: Times from stroke onset to arrival at the emergency department (ED) and treatment; rates of symptomatic intracerebral haemorrhage (ICH); clinical outcome at three months; and violations of treatment protocol.Results: Of 932 patients admitted with ischaemic stroke, 30 were treated with intravenous tPA. Median time from stroke onset to tPA treatment was 2 h 48 min, and median door-to-needle time was 1 h 49 min. Door-to-needle time improved in the last 12 months of the audit, with four of 15 patients achieving the recommended 60 min. Eleven patients (37%) had excellent clinical outcomes at three-month follow-up (modified Rankin score, 0–1), and 15 (50%) were functionally independent (score, 0–2). Mortality rate was 10%, similar to that of all ischaemic stroke patients during the audit period. Two patients (7%) had symptomatic ICH. Treatment deviated from protocol in seven patients (23%), five of whom received tPA over three hours after stroke onset.Conclusion: Rates of favourable outcomes and symptomatic ICH at our hospital were similar to those achieved in international phase III and IV trials in specialised centres.

Cassandra E I Szoeke MB BS · Mark W Parsons FRACP · Kenneth S Butcher MD, PhD, FRCP(C) · Tracey A Baird MRCP · Peter J Mitchell FRACR · Sonya E Fox RN · Stephen M Davis MD, FRACP

Objectives: To determine the time from symptom onset to hospital admission of patients with suspected acute stroke, final diagnoses and patient eligibility for thrombolytic therapy.Design: Hospital-based, prospective, observational study.Setting: Royal Adelaide Hospital Stroke Unit, South Australia.Patients: All patients admitted to the unit with suspected acute stroke over 11 months (11 April to 10 October 2000 and 20 August 2001 to 19 January 2002).Main outcome measures: Time from symptom onset to admission; final diagnosis.Results: Of 284 patients admitted, 39 (14%) had diagnoses other than stroke (including eight with transient ischaemic attacks), 42 (15%) had haemorrhagic stroke and 203 (71%) had ischaemic stroke. Median time to admission after symptom onset was 6 hours (range, 30 min to 13 days), with 100 patients admitted within 3 hours of symptom onset (35%), and 80 within 2 hours (28%). Thirty-seven patients (13%) could have been considered for thrombolysis (diagnosis of non-severe but disabling ischaemic stroke and admission time < 3 hours). Location at stroke onset was the only independent predictor of time to admission.Conclusions: Most patients with stroke do not present urgently to the emergency department, rendering them less likely to be considered for thrombolytic therapy.

Simon A Broadley PhD, MRCP · Philip D Thompson PhD, FRACP

Objectives: To compare hospital length of stay (LOS) and outcome after stroke between patients in a stroke unit offering combined acute and rehabilitation services and patients treated elsewhere in New South Wales.Design: Retrospective audit of two hospital databases (Diagnosis-Related Groups [DRG] database and Australian National Subacute Non-Acute Patient Classification System [AN-SNAP] database), with comparison with DRG and AN-SNAP data for NSW.Setting and participants: 242 episodes of acute stroke in patients admitted to the stroke unit of a metropolitan teaching hospital between July 1999 and November 2000, 113 of whom also underwent rehabilitation in the unit; 9777 episodes of acute stroke in the NSW DRG database, and 2350 in the NSW AN-SNAP database.Main outcome measures: Acute and rehabilitation LOS; mortality in acute care; FIM (Functional Independence Measure) score at discharge and change in FIM score; and discharge destination.Results: Patients in the combined stroke unit had shorter LOS and better functional outcome in all DRG and AN-SNAP groups, with both higher discharge FIM scores and greater gain in FIM scores than NSW patients. Acute stroke mortality of 12% and nursing home admission rate of 15.5% in the combined stroke unit were not significantly different from rates for NSW (15.7% and 11.2%, respectively).Conclusions: Combining acute and rehabilitation services in a stroke unit may reduce LOS and improve functional outcome of patients with acute stroke.

Yan H Ang MRCP · Daniel K Y Chan MD, FRACP · Qing Shen MB BS, MSc · Derrick M K Heng MB BS, MPhil

Clinical record A 65-year-old woman had recurrent generalised tonic–clonic seizures. She was being treated with peritoneal dialysis for chronic renal failure caused by a combination of agenesis of the left kidney and focal sclerosing glomerulonephritis. Other medical problems included mixed connective tissue disease, ischaemic heart disease, Raynaud's phenomenon, anaemia of chronic disease, asthma, hypertension and chronic bilateral serous otitis media (treated with tympanostomy tubes). Her regular medications included atorvastatin, alendronate, perindopril, aspirin, allopurinol, ranitidine, doxepin, controlled release morphine sulfate, ferrous sulfate, calcium carbonate, frusemide, prednisolone, and diltiazem. Intermittently she had been given erythropoietin (a seizure precipitant)1 for her anaemia. She developed a rash when taking cephalosporins, and had a sister who had primary generalised epilepsy. The seizures continued despite cessation of the erythropoietin therapy and administration of sodium valproate. Magnetic resonance imaging of the brain and electroencephalography gave normal results. Meticulous medication review eventually revealed the coincidence of seizures with the intermittent prescription of ciprofloxacin eardrops. Eight of the nine seizures occurred while taking Ciproxin HC Ear Drops (ciprofloxacin 2 mg, hydrocortisone 10 mg; Alcon Laboratories, Sydney) for otitis media (Box). The ciprofloxacin eardrops were neither recorded on admission nor listed by the patient on direct questioning about medications she was taking. She has had a seizure-free period of 9 months after cessation of the eardrops, despite tapering of the dose of sodium valproate. The ciprofloxacin eardrops are considered the probable cause of the seizures in this case, according to the Naranjo algorithm for estimating causality of an adverse drug reaction (score, 8).2 Polypharmacy in complex medical patients frequently causes adverse effects.3 Up to 26% of prescription drugs are not recorded at the time of hospital admission,4 and eardrops are a common omission from medication lists. Ciprofloxacin is a fluoroquinolone antibiotic that inhibits bacterial replication. It is thought to lower seizure threshold by reducing γ-aminobutyric acid (GABA) transmission. Ciprofloxacin is excreted renally and has a half-life of 2.9–4.3 hours, which doubles in end-stage renal failure. Dose reduction is advised when patients not receiving dialysis have a creatinine clearance of less than 30 mL/min.5 There are reports of seizures after enteral and intravenous administration of ciprofloxacin,6 but, to our knowledge, this is the first report of seizures with ciprofloxacin eardrops. The recurrent seizures were believed to be due to the combination of an epileptogenic predisposition, renal failure, and intermittent ciprofloxacin use, with absorption facilitated by the bilateral tympanostomy tubes. Topical medications can produce systemic effects and this should be considered, particularly when other factors favour systemic absorption. A thorough drug history is necessary in assessing patients with complex medical problems taking multiple medications. Lessons from practice Topical medications can produce systemic effects. Fluoroquinolones may trigger seizures by any route of administration. A thorough drug history is necessary in assessing patients with complex medical problems. Eardrops are a frequent omission from medication histories. Chronological sequence of seizures and medication The period during which the patient had seizures () related to receiving ciprofloxacin eardrops (dropper), erythropoietin (EPO) for anaemia in chronic renal failure, and increasing doses of sodium valproate. (We thank Heidi Cartwright for preparing the diagram.)

Carolyn F Orr MRCP · Dominic B Rowe PhD, FRACP

"Rod, are you sure it's MND?" It was James Lance, my former Professor of Neurology (now Professor Emeritus, University of New South Wales), on the telephone. He had just received the letter I sent to all my close friends and colleagues when the diagnosis was confirmed. Jim had always emphasised the importance of leaving no stone unturned before accepting a diagnosis of incurable disease, both in his book on headache — which inspired me to do neurology — and during my subsequent clinical training. However, I had to tell him there was no doubt. Four months previously, I had experienced the sudden dramatic onset of widespread muscle fasciculation, without definite weakness, and, after four weeks of rising anxiety, I took my concerns to a colleague. Although at that stage he reassured me that he had found no definite abnormality, I was concerned that during the examination I had not been able to support my weight on my left leg. I then entered a period of uncertainty, during which I could not discuss my fears with family or friends. Three weeks later my colleague found measurable muscle atrophy and hyperreflexia, and electromyography documented fasciculation and early muscle denervation. Magnetic resonance imaging and a second opinion finally confirmed the diagnosis of MND. When I went to see David Burke, my then Professor of Neurology (Institute of Neurological Sciences, Prince of Wales Medical Research Unit, Sydney, NSW), to tell him my news, he tried to focus his mind on practicalities. As a young registrar he had supervised my research for an MD thesis and now, as my Chief of Neurology, he would have to arrange my replacement as Visiting Medical Officer and Director of the Comprehensive Epilepsy Service at Prince of Wales Hospital. However, for some moments all he could say was, "Rod, we go back a long way . . . ". It is now 16 months since the onset and there has been significant progression of weakness and spasticity. I can look back on my experience of MND thus far and make some observations. DiagnosisThe final confirmation of the diagnosis came almost as a relief after the period of uncertainty and false hopes — certainly the worst four months of my life. Once the diagnosis was confirmed, it was as if a great weight had been lifted from my shoulders and I was able to face the challenges ahead. The hardest task was breaking the news to my wife and each of my four children, but then they were able to provide much-needed emotional support. I was also able to begin the complicated process of selling my practice and disengaging myself from all my medical commitments. A lot of friends and colleagues were surprised by the speed and completeness with which this was achieved and still ask me if I miss medicine. On looking back, I can honestly say I have no regrets about this course of action. Freeing myself from the day-to-day concerns of clinical practice has allowed me to make up for lost time, especially with my family, and to "smell the roses". It has also made easier the transition from doctor to patient. This experience has reinforced my long-held view that one must be completely frank with patients about the diagnosis and prognosis of terminal illness. The neurologist who has assessed the patient and confirmed the diagnosis of MND is in the best position to break the news, and then to discuss the myriad issues that will come up. These include a frank discussion of prognosis, the manner of progression, symptoms to be experienced, the role of exercise and drugs and the possible need for assisted breathing and feeding in the future. AetiologyAlthough most cases of MND are sporadic, up to 10% are familial and may be associated with a mutation on the superoxide dismutase gene.1 I was relieved to find that this test was negative in my case, reducing the chances of other family members being affected. MND patients have a higher than normal incidence of previous paralytic poliovirus infection. In 1951, when aged 5 years, I suffered a febrile illness which was associated with diplopia, recurrent seizures and coma and followed by three weeks of limb weakness. Although I made a complete recovery without ventilatory support being needed, this was thought to be poliovirus encephalomyelitis and I suspect that this illness may have played a role in my MND. Ongoing careThe general practitioner should, as always, coordinate care, but the possibility of this diagnosis should always lead to a referral to a neurologist. One or both of these practitioners might feel that one of the specialist MND clinics, now available at several of the teaching hospitals, is the best place for making the definitive diagnosis and providing the ongoing care. These clinics provide an expert diagnostic service, and they can monitor progress and arrange referral to a number of ancillary services. When necessary, they arrange provision of aids and can refer patients for advice on respiratory support and gastrostomy feeding at the appropriate time. My GP put me in touch with the MND Society of New South Wales, a registered charitable, not-for-profit organisation which provides information, outreach support and access to disability aids and equipment. I have had a home visit from my designated outreach worker to discuss the diagnosis and prognosis, and my current and future needs and those of my wife as future carer. I have since become a board member of the society to assist them in their admirable work. Role of exerciseAs a neurologist I had always advised my patients to exercise only to the onset of muscle pain or weakness and then to cease, as exercise beyond this point was thought to be unhelpful and possibly harmful. However, as a patient, I found that, if I continued to exercise despite these symptoms, over the next few days the muscle pain and stiffness resolved and the weakness improved, even though it did not recover to previous levels. I was able to maintain a program of exercise with weights, stair-climbing and walking for two to three hours a day for 12 months before increasing weakness and spasticity forced a gradual reduction and finally cessation of these activities. This program was so successful that it is spasticity rather than weakness that is now forcing me off my feet. Role of drugsThe American Academy of Neurology (AAN) Practice Parameters for ALS2 represent a significant advance in formulating evidence-based guidelines for the care of people with MND and should be consulted when treatment options are being considered. Riluzole is the only drug which has been shown to prolong survival in MND. Two large randomised trials3 suggest that it improves survival of MND patients by at least three months. I began taking the drug as soon as the diagnosis was confirmed and have had no side effects. It costs $700 per month on private script, but it is currently being considered for listing on the Pharmaceutical Benefits Scheme. Baclofen is essentially the only muscle relaxant available, as the alternative, dantrolene sodium, is associated with unacceptable side effects (asthenia and muscle weakness). I have been taking baclofen with only modest benefit, but no side effects. Oxandrolone is a synthetic anabolic steroid, and a pilot trial of this drug over 12 months involving 12 MND patients found that the most severely affected muscles underwent little or no further deterioration, while less affected muscles continued to deteriorate.4 I began taking this drug (cost, $1400 per month) three months ago, but unfortunately this has not prevented progression of weakness of my left leg, nor of other, less affected muscles. I have therefore ceased taking the drug. Minocycline, a semi-synthetic tetracycline derivative, has been found to improve survival in a mouse model of MND,5 and I have been taking it with no side effects. ProgressionIn MND, respiratory muscle strength is a strong predictor of survival, and death usually results from respiratory failure. Non-invasive ventilation improves quality of life and possibly survival.6 The AAN recommends commencing non-invasive ventilation when vital capacity is less than 50% predicted. Recent work7 suggests that measurement of sniff nasal inspiratory pressure is more predictive of benefit, and that non-invasive ventilation should begin when sniff nasal inspiratory pressure is less than 60% predicted. I am monitoring both vital capacity and sniff nasal inspiratory pressure and will make a decision about non-invasive ventilation, and the option of gastrostomy feeding, closer to the time these may be necessary. Meanwhile, I am content to take one day at a time. As someone said, "Every day you're breathing is a good day". Life issuesI now realise that the most important entities of my life are my family and friendships sustained over many years. Although my medical career defined my day-to-day existence and most others' perception of me, its significance pales in comparison. However, my knowledge of medical issues, such as those with which I am now personally faced, will hopefully help me cope with what lies ahead.

Roderick A Mackenzie MB BS, MD, FRACP

110 Puzzling cases of epilepsy. Dieter Schmidt, Steven C Schachter (editors). London: Martin Dunitz, 2002 (xxiv + 451pp). ISBN 1 85317 962 0. Epilepsy has been the great teacher of neuroscience. The study of the many and varied faces of epilepsy has allowed scientists to discover regional brain function. The editors of this book have asked over 100 epilepsy experts from around the world to contribute a case study of epilepsy that provided a clinical teaching message. Their collection gathers presentations of unusual causes and surprising clinical courses, as well as unforeseen problems and unexpected solutions. Those expecting carefully crafted biographical short stories in the style of Oliver Sacks will be disappointed, but the book is fun and easy to read. Many of the cases are fascinating, and titles like “A patient who would not leave his apartment for hours every three days” impart a sense of mystery to engage and challenge the reader. The cases are brief, and the messages clearly enunciated. Despite the numerous authors, the quality is relatively even. Although there is an index, this is not a volume that can be consulted easily when seeking the answer to a specific question related to epilepsy. However, the clinical case approach championed here does provide a counterpoint to cohort studies and multi-centre trials, in which subtleties of clinical diagnosis and patient-specific situations may be lost. Those with a clinical interest in epilepsy will enjoy and benefit from this book. It is clearly intended for those with at least a basic, if not a moderately advanced, knowledge of this important subject. Samuel F BerkovicDirector, Epilepsy Research Institute West Heidelberg, VIC

Samuel F Berkovic

To the Editor: We applaud the efforts of Wasiak et al to apply the principles of evidence-based medicine to answer clinical questions.1 However, it is important to understand the historical context of clinical trials reported in the literature, and, when necessary (eg, when conducting a meta-analysis or when the results of trials appear to conflict), to seek additional information from the authors. One of us (H K G) designed the randomised-controlled trial (RCT) reported by Corry et al.2 It was a pilot study and not a definitive clinical trial. The primary outcome measure was resonant frequency, an objective measure of muscle stiffness. This trial was conducted before the introduction of validated outcome measures for assessing upper limb function in children with cerebral palsy, and it was not possible to perform any sample size calculation for functional outcomes. At 12 weeks in the group receiving injections of botulinum toxin A, there was a significant difference in grasp and release but not in the ability to pick up coins. It is not surprising therefore that this study found significant decreases in muscle stiffness, but the functional results were inconclusive. The other RCT identified by Wasiak et al also involved one of us (D F).3 It was designed specifically to investigate functional outcomes, a sample size calculation was performed from pilot work, and a specific functional outcome measure (QUEST) was used. This study reported significant functional improvements after the use of botulinum toxin combined with occupational therapy. These two studies, when understood in their historical sequence, should therefore be considered complementary and not contradictory. It is important to assess the quality of randomised clinical trials as well as their conclusions (eg, using the Physiotherapy Evidence database PEDRO scale <http://ptwww.fhs.usyd.edu.au/pedro>).4,5 The smaller study by Corry et al2 had insufficient power and inadequate methodology to investigate functional outcomes. On the other hand, the conclusions of the study by Fehlings et al3 should be taken as the current level of evidence. We therefore submit that the conclusion drawn by Wasiak et al is incorrect. We support further research to evaluate and strengthen the evidence relating to botulinum toxin A and upper-extremity function.6

H Kerr Graham · Roslyn N Boyd · Darcy Fehlings

In reply: We thank Graham et al for their response to our article.1 It is important to understand that the clinician who posed the question regarding botulinum toxin A injection wished to find the "best available medical evidence". We were not asked to take account of the historical context of previously published articles, nor were we asked to exclude specific types of RCTs. If we were to exclude specific RCTs based on the preference of an author, then the strong methodological principles that surround the evidence-based practice movement would be open to extreme forms of bias. We also disagree that our conclusions were incorrect. Our reading of the article by Corry et al2 differed from that of Graham et al. We do not consider that their study showed that botulinum toxin injection significantly improved the function of the hemiplegic upper limb. Together with the results of the study by Fehlings et al,3 indicating a significant improvement in weight-bearing at four weeks (part of the QUEST assessment), our conclusion — that we could not support or refute the efficacy of botulinum toxin injections for improving upper-limb function in cerebral palsy because of differing opinions — remains unchanged.

Jason Wasiak · Brian J Hoare

Multiple sclerosis. Sharon Warren and Kenneth Warren. Geneva: World Health Organization, 2001 (ix + 123 pp). ISBN 92 4 156203 X. The last fifteen years have seen not only an exponential growth in published research on multiple sclerosis but also an abundance of books on the subject. Despite this abundance, this relatively small paperback fills a real void in the market. The book reviews, summarises and provides an objective and considered opinion on epidemiological research into multiple sclerosis. It covers issues relating to diagnosis as well as research methodology, case-ascertainment methods, prevalence and incidence rates, environmental risk factors, genetic susceptibility, other risk factors and prognostic factors. The authors are eminent Canadian multiple sclerosis researchers. They provide an overview of the subject and bring together research from around the world in order to answer some of the difficult questions that our patients often ask. They do this by discussing, in depth and detail, the methodological aspects and the results of these studies in simple language. A separate section deals with prognostic indicators and the last chapter addresses challenges for future research. Multiple sclerosis should appeal to a wide range of readers, but especially to those starting out in the field, such as clinicians or researchers. It is scientific in its prose, but relatively easy to read for a person with multiple sclerosis who wants to know what the current state of knowledge is without spending a lot of money. It is not a book for those readers looking for information on the scientific aspects of the genetic basis of the disease or its management. It does, however, include a very good section on the epidemiological research into genetic susceptibility. I think the authors should be congratulated on producing a small, easy-to-read, comprehensive and objective book. It lends itself to a wide range of readers and should be updated regularly. For those of us who try but can’t always manage to read all that we want to on multiple sclerosis, the book is a valuable and easily accessible reference source. Garry D PearceMedical Director Multiple Sclerosis Society, NSW

Garry D Pearce

Human neural stem cells (HNSCs) can be isolated from both the developing and adult central nervous system (CNS). HNSCs can be successfully grown in culture, are self-renewable, and can generate mature neuronal and glial progeny. Embryonic HNSCs can be induced to differentiate into specific neuronal phenotypes. HNSCs successfully integrate into the host environment after transplantation into the developing or adult CNS. HNSCs transplanted into animal models of Parkinson's disease and spinal cord injury have induced functional recovery. The risks associated with stem cell transplantation trials are difficult to assess, but have not become overtly apparent throughout preclinical investigations. Major hurdles remain to be overcome before human clinical trials can be embarked upon.

Kerry A Galvin BSc(Hons), PhD · D Gareth Jones MBBS, DSc

Surgery shows promise for patients with severe, poorly controlled motor fluctuations Parkinson's disease afflicts around 78 000 Australians. Mortality is almost twice that of age-matched controls1 and the mean disease duration is only 13 years.2 No treatment has yet been shown to slow disease progression. Fortunately, motor disability can be markedly improved with levodopa therapy. However, after 3–5 years, the duration for which each dose of levodopa is effective shortens and many patients begin to experience fluctuations in their motor function throughout the day. Involuntary movements appear, in particular painful posturing of the legs or arms, as the beneficial effect of levodopa wears off ("end of dose dystonia") and writhing choreoathetoid movements that accompany part or even all of the period when levodopa is working ("peak dose dyskinesia"). These problems can be ameliorated to some extent by the addition of dopamine agonists or catechol-o-methyltransferase (COMT) inhibitors. Unfortunately, problems that are not reversed by levodopa, such as worsening of balance and speech, cognitive decline and depression, can also supervene. Patients who never experience sustained benefit from levodopa are likely to have a different underlying pathology from idiopathic Parkinson's disease, such as vascular parkinsonism, progressive supranuclear palsy or multiple system atrophy. It is in patients with severe, poorly controlled motor fluctuations that surgical therapy has re-emerged as a treatment option. In this issue of the Journal (page 142), Iansek and colleagues report the results from 14 patients at their centre who underwent bilateral deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease.3 Motor function was improved with subthalamic nucleus stimulation for at least six months when patients were assessed both with and without levodopa treatment. Dyskinesias were also apparently reduced, and mean levodopa dose was reduced by 30% after surgery. The procedure was not without risk (one patient had a disabling intracerebral haemorrhage, another required relocation of the stimulators to the thalamus), but overall this is an exciting and encouraging development. Data were also collected from the first six patients in the reported series as part of an international multicentre trial, which included another Australian centre, St Vincent's Hospital, Sydney.4 Results from 96 patients who underwent bilateral subthalamic nucleus stimulation showed a median reduction of 49% in motor disability without medication using blinded videotape analysis, a mean increase from 27% to 74% of the day spent with good mobility without involuntary movements, a 58% improvement in dyskinesia scores, and a 37% reduction in mean daily levodopa dose. Similar, but less marked, improvement was seen in 38 patients treated with bilateral pallidal stimulation, although the dose of levodopa was not reduced after surgery in these patients. The incidence of intracranial haemorrhage was 2.5%, and infections requiring electrode removal occurred in less than 1%. These are benchmark figures by which the results of Australian centres offering these procedures can be compared. Surgical therapy for Parkinson's disease is not new, but there have been advances in our understanding of why it works. Loss of dopaminergic projections from the substantia nigra to the basal ganglia results in pathological overactivity of the subthalamic nucleus and globus pallidus. Patients undergoing deep brain stimulation have a wire implanted into the brain that is attached to a programmable battery implanted subcutaneously in the chest wall, much like a pacemaker. Deep brain stimulation mimics the effects of stereotactic lesioning, but has the added advantages of being reversible and allowing postoperative programming to optimise the site of stimulation. However, it is expensive and programming is time-consuming, sometimes requiring months before the optimal stimulating parameters can be established. Economic and geographical constraints limit access to therapy for many patients in whom surgery would otherwise be appropriate; such issues need to be addressed by healthcare providers. At present, there are a number of Australian centres performing subthalamic nucleus stimulation and pallidotomy (lesioning of the globus pallidus); experience in pallidal stimulation is as yet limited. The indications and choice of operation are still evolving. Nevertheless, some general guidelines may be suggested. Who should be offered surgery? Surgically fit patients with severe motor fluctuations or dopa-induced dyskinesia, or both, are the main candidates. Surgery does not significantly improve the patient's best response to levodopa (except by reducing dyskinesias). A good or excellent response to levodopa predicts the response to surgery, and is essential.5,6 The procedure, particularly subthalamic nucleus stimulation, may take hours, during which time the patient remains fully conscious, so a degree of stoicism on the part of the patient is required. For the rare patient with disabling parkinsonian tremor that is poorly suppressed by levodopa, without accompanying akinesia, thalamic surgery can be contemplated. Who should not be offered surgery? Patients who have never responded well to levodopa will not benefit from surgery. The presence of cognitive or psychiatric complications of Parkinson's disease (frequent hallucinations, psychosis, parkinsonian dementia, uncontrolled depression) is an absolute contraindication to surgery; significant cerebral atrophy on computed tomography or magnetic resonance imaging is also a contraindication. Levodopa-resistant symptoms such as impairment of balance or speech can worsen after surgery.7 Which procedure? Overall, subthalamic nucleus stimulation appears more promising than pallidal surgery. However, a randomised trial comparing the two has not been performed, and excellent and sustained improvement following both bilateral subthalamic nucleus stimulation and bilateral pallidotomy is seen.8 Physicians should be guided not only by theoretical considerations, but also by local experience and expertise. Objective evaluation of the results of surgery by a neurology team not involved in patient selection or the surgical procedure is an advantage, and this information should be available to patients and their treating neurologists to aid decisions about therapy.9 Where to refer? The process of optimising therapy for advanced Parkinson's disease, differentiating between idiopathic Parkinson's disease and related disorders, and choosing the appropriate operation, is not always straightforward. For this reason, we recommend that patients considering surgical treatment be referred to a unit with specialist expertise in movement disorders, and that surgery be offered in the setting of a multidisciplinary assessment by teams including a neurologist, neurosurgeon, neuropsychologist and Parkinson's disease nurse specialist.

Victor S C Fung PhD, FRACP Director, Movement Disorders Unit · John G L Morris DM, FRACP, FRCP · Malcolm F Pell MB BS, FRACS Visiting Medical Officer

Objective: To evaluate the effects of bilateral deep brain stimulation in the subthalamic nucleus for symptomatic relief of advanced idiopathic Parkinson's disease.Design: Prospective cohort study.Setting: Patients were assessed and received medical treatment at the Kingston Centre, Southern Health, Melbourne. Surgery took place at Melbourne Neuroscience Centre, The Royal Melbourne Hospital. Both are tertiary public institutions.Subjects: 14 patients with Parkinson's disease with intact cognition and difficult to manage motor symptoms who were referred to Kingston Centre between 1996 and 2000 and were eligible for surgical intervention.Interventions: All patients were assessed both after 12 hours' withdrawal from and while taking their levodopa medication on two occasions before surgery. Further assessments were carried out one, three, six and 12 months after surgery.Main outcome measures: The Unified Parkinson's Disease Rating Scale motor exam and gait parameters, such as stride length and velocity, were compared at six months after surgery with neither stimulation nor medication, with stimulation only, with medication only, and with stimulation and medication.Results: Stimulators were explanted in one patient after intracranial haemorrhage and relocated to the thalamus in a second. Extraneous factors prevented two patients from attending at six-month follow-up. Motor performance improved significantly with stimulation alone in the 10 remaining patients. Further significant gains were seen with stimulation and medication combined, with an apparent reduction in side-effects such as dyskinesia.Conclusions: Bilateral deep brain stimulation of the subthalamic nucleus significantly improves motor performance in advanced Parkinson's disease, despite a rather high complication rate.

Robert Iansek PhD, BMedSci, MB BS, FRACP · Jeffrey V Rosenfeld MB BS, MS(Melb), FRACS, FRCS(Ed), FACS, FACTM · Frances E Huxham DipPhysio, GradDip(HealthResMeth)

Case report A 63-year-old woman with hypertension and non-insulin-dependent diabetes underwent restudy coronary angiography for recurrent angina. She had had coronary angioplasty in 1991 and coronary arterial bypass surgery in 1998 with two saphenous vein grafts and a left internal mammary artery graft. Angiography of her native coronary arteries, both saphenous vein grafts, and a left ventriculogram were completed without difficulty. The left internal mammary artery was more difficult to engage selectively. The left vertebral artery, which was adjacent, was outlined by contrast. During this time the patient's blood pressure increased to 200/110 mmHg and she became nauseous and vomited. She complained that "everything has gone black". The study was terminated with a non-selective injection into the left subclavian artery, which showed an adequate left internal mammary artery graft. A total of 160 mL of non-ionic, low-osmolar contrast agent ("Ultravist") containing iopromide was used. During post-procedure monitoring she could not see light or objects and complained of headache. There was impaired alertness. Her blood pressure stabilised at 140/80–160/90 mmHg. Her pupils were equal and reactive to light. Extraocular muscle movements were normal. Funduscopy revealed "copper wiring" of hypertension without significant diabetic retinopathy. Cranial nerve, peripheral motor and sensory examinations were normal. Bilateral cortical blindness was diagnosed. Computed tomography (CT) brain scan was performed three hours after the completion of coronary angiography. No additional contrast was used. The CT brain scan (Box 1) showed marked bilateral contrast enhancement of the occipital lobes and no evidence of a cerebral haemorrhage. Intravenous heparin treatment was commenced. By the following day, she was able to see shapes and shadows but had persistent headache and nausea. A repeat CT brain scan did not show any residual abnormality. During the next 48 hours, her vision progressively returned. She described flashing lights in her right eye and had evidence of right homonymous hemianopia. Magnetic resonance imaging (MRI) showed increased signals in the grey matter of the medial aspect of the left occipital lobe, on a background of longstanding mild ischaemic changes consistent with her age and cardiac risk factors (Box 2A). Magnetic resonance angiography (MRA) showed patency of both posterior cerebral arteries, with dilatation of branches supplying the left occipital lobe (Box 2B). Heparin therapy was ceased, as there was no evidence of acute thromboembolism or acute infarction. She fully regained her vision five days after coronary angiography. Transient cortical blindness related to coronary angiography was first reported in 1970.1 Since then there have been fewer than two dozen cases recorded, some of which include angiography of coronary bypass grafts.2-5 This is a rare neurological complication given the widespread and frequent use of such investigations worldwide. The incidence of cerebrovascular complications in diagnostic cardiac catheterisations and coronary angiography is low. The National Institutes of Health in America reported a rate of 0.03%,6 and the British Cardiac Society report from 34 041 patients gave an incidence of 0.06%.7 This included cerebrovascular accidents, transient ischaemic attacks and amaurosis fugax. Neither study described transient cortical blindness. Usually neuro-ophthalmologic complications of cardiac catheterisation relate to embolic phenomena or migraine. Cortical blindness is better recognised as a complication of cerebral and vertebral angiography, with an incidence of 0.3%–1.0%,8 but as high as 4% when hyperosmolar iodinated contrast agents are used.3 However, it can occur with newer low-osmolar and non-ionic radiographic contrast media, and this potential complication is indicated in the product information. Review of clinical information available from English language reports of transient cortical blindness after coronary angiography showed 17 cases.2-5,8-12 Thirteen of these involved men, and only four involved women, but this reflects the greater number of men who have coronary artery investigations. The average age of the patients was 58 years, and more than half (10 patients) had known systemic hypertension. Eleven (65%) had angiography of internal mammary artery grafts. Another five had additional aortography or coronary angioplasty. The volume of contrast dye used ranged from 80–400 mL. The time taken to recover normal vision varied from 15 minutes to three weeks, with an average of three days. Selective vertebral angiography carries the highest risk of neurological complication.13-15 As the internal mammary artery used for coronary grafting is adjacent to the origin of the vertebral artery, it is likely that a direct injection into the vertebral artery occurs. The cerebral reaction is not patient-specific, as later rechallenge with contrast medium has produced no recurrence.3 Minimising the amount of dye used is also advisable.3 PathophysiologyThe mechanism of cerebral injury remains speculative. It is thought that contrast agents disrupt the blood–brain barrier in the occipital lobes and exert a neuronal toxic effect.13 The posterior cerebral circulation is known to be more susceptible to such injury and this may relate to differences in sympathetic innervation.14 There may be a relationship to hypertensive encephalopathy, a clinical syndrome which can include visual disturbances. Imaging in hypertensive encephalopathy, including eclampsia, has shown bilateral abnormalities in the occipital lobes, involving the subcortical white matter and often extending to the cortical surface.16 Reversible oedema, localised mainly to the occipital lobes, is a prominent feature. Our patient was known to be taking drugs for chronic hypertension and had a documented acute blood pressure rise during the procedure. More than half the patients in previous reports had chronic hypertension, although the details of pressure changes during angiography have not usually been reported. Hypertensive encephalopathy is thought to result from sudden elevation of systemic blood pressure exceeding the auto-regulatory capacity of the cerebral vessels, producing regions of vasodilatation and vasoconstriction with a breakdown of the blood–brain barrier and focal transudation of fluid.16 These mechanisms seem possible in our patient, and they were supported by the results of imaging studies. There were bilateral occipital lobe changes when she had clinical cortical blindness (Box 1), representing oedema and passage of contrast across the blood–brain barrier. Cortical blindness is synonymous with bilateral homonymous hemianopia from involvement of the occipital cortex.1 When our patient was recovering and exhibiting right homonymous hemianopia, there were MRI changes in the left occipital gyrus, and differences in the calibre of the vessels on the two sides (Box 2). PrognosisIt is devastating for the patient, the family and the person carrying out the procedure when cortical blindness complicates coronary angiography. Cerebral embolism and haemorrhage have to be excluded by CT scan or MRI studies. Fortunately, the condition is usually transient. Lessons from practice Transient cortical blindness is a rare but alarming complication of coronary angiography. It has to be differentiated from an embolic problem. Computed tomography or magnetic resonance imaging is necessary. Oedema secondary to disturbance of autoregulation of the posterior cerebral vessels is a possible mechanism. Vision is usually recovered fully within a few days. 1: Computed tomography scan of the patient's brain three hours after completion of coronary angiography, when she had cortical blindness No additional contrast was given. There is marked bilateral contrast enhancement of the medial aspect of both occipital lobes in a symmetric distribution (arrows). 2: Magnetic resonance imaging (MRI) of the patient's head 48 hours after coronary angiography, when she had right homonymous hemianopia A: MRI (FLAIR image) shows increased signals in the medial aspect of the left (compared with the right) occipital gyrus separated by a fissure (arrow). Scattered foci of longstanding ischaemic damage on the rim of the lateral ventricles and frontal horns are consistent with the patient's age and risk factors. B: A magnetic resonance angiogram (MRA) at the same time shows that both posterior cerebral arteries are patent. The peripheral branches on the left side are larger (arrow).

Kiam K Lim MB BS · Dorothy J Radford MD FRACP

An 88-year-old man was admitted to hospital with "collapse", manifested as hypotension and fever. It was noted that he had gaze palsies. He had been admitted for a three-day period, 12 days earlier, with a urinary tract infection, which was treated with intravenous, then oral, antibiotics. On this occasion he was again started on intravenous antibiotic therapy. He was seen by an ophthalmologist, and a cranial computed tomography (CT) scan was arranged. Later that evening, the ward nurses sought further medical review, as the patient remained hypotensive, with a systolic blood pressure of 80 mmHg. On examination he was observed to have a partial left third cranial nerve palsy and complete right third cranial nerve palsy (see Box, A). A presumptive diagnosis of pituitary apoplexy was made, and the patient was commenced immediately on intravenous fluids and hydrocortisone 100 mg, 12-hourly. The CT scan (Box, B) confirmed the diagnosis, showing a pituitary tumour measuring 12 mm in diameter. The salient feature is the variegated appearance, suggesting haemorrhage within the tumour. In patients presenting with the constellation of collapse and gaze palsies, a diagnosis of pituitary apoplexy should be considered. The mechanism of third-nerve palsy is illustrated in the Box (C). The condition is life-threatening, but responds well to appropriate treatment. After the patient had undergone hypophysectomy, the gaze palsies took about three months to resolve completely. The patient remains active on pituitary replacement therapy only. Cranial nerve palsy caused by pituitary tumour This picture of the patient's eyes 12 hours after commencing hydrocortisone (A) shows partial left third cranial nerve palsy and complete right third cranial nerve palsy. A computed tomographic image (B) shows a 12 mm diameter pituitary tumour with haemorrhage (arrow). The mechanism of third cranial nerve palsy is illustrated in C: as the tumour expands, it involves the optic chiasm anteriorly and displaces the carotid siphon laterally. The third cranial nerve is vulnerable to lateral displacement. (Adapted from Patten J. Neurological differential diagnosis. New York: Springer Verlag, 1982.) A: Patient's eyes B: Computed tomography scan C: Mechanism of third cranial nerve palsy

Dan Harmelin BSc DipEd MB BS FRACP