Neurology

Effective dementia care depends on early and accurate diagnosis It is predicted that over the next 40 years there will be a fourfold increase in the prevalence of dementia in Australia, as well as considerably more people with milder forms of cognitive impairment.1 To date, despite extensive research, no effective treatment for established dementia is available. As a result, taskforce policymakers conclude that there is insufficient evidence at present to warrant routine screening for dementia syndromes.2,3 However, emerging evidence shows that early non-pharmacological intervention can improve cognitive outcomes for patients with milder forms of cognitive impairment and those at risk of cognitive decline.4 Early diagnosis also enables patients to plan, with their caregivers, for the future, and deal with matters such as enduring power of attorney authorisation, before they lose the capacity to do so. Over two-thirds of people who notice symptoms of cognitive decline consult a physician for evaluation.5 However, up to 90% of mild cases are missed at the initial primary care assessment.6,7 So how can we improve early detection of cognitive impairment, and what evidence base do we have for dementia screening in Australia? A diagnosis of dementia relies on a full mental status assessment, with comprehensive history taking and physical examination. Presently, detailed neuropsychological testing is the gold-standard tool for objectively evaluating the magnitude and pattern of cognitive decline. However, neuropsychological evaluation is costly, time-consuming and not generally available as only specialist psychologists can do it. Consequently, general practitioners and specialist physicians, who evaluate most patients presenting with cognitive complaints, administer brief screening instruments such as the mini-mental state examination (MMSE) to assess cognition. In Australia, the use of such instruments has been propagated by guidelines for prescribing acetylcholinesterase inhibitors. The MMSE has many documented and widely appreciated shortcomings. It lacks diagnostic specificity and is insensitive to patient variables such as extreme levels of education, premorbid ability and poor command of English.8 It has also been criticised for its unsystematic and atheoretical construction, and its poor ability to detect milder forms of cognitive impairment.8,9 The idea that any brief screening tool would have sufficient sensitivity and specificity to diagnose dementia is unrealistic. However, when used as an adjunct to a good clinical history, a more accurate instrument, particularly one that can be serially administered, would potentially increase the reliability of diagnosis. A recent review of screening instruments available for mild cognitive impairment concluded that there are more useful screening tools than the MMSE.10 Some are in use in Australia, including the Addenbrooke’s Cognitive Examination – Revised (ACE-R); the Alzheimer’s Disease Assessment Scale — cognitive subscale (ADAS-cog); and the Montreal Cognitive Assessment battery. In addition, there are other screening instruments specifically validated for use in Australia, such as the General Practitioner assessment of Cognition (GPCog) and Rowland Universal Dementia Assessment Scale (RUDAS). Recently, the ACE-R was validated for use in an Australian population.11 The ACE-R, which incorporates the MMSE, has been shown to have more diagnostic sophistication, with improved sensitivity and specificity values, than the MMSE alone. This is not to say that the ACE-R is without limitations. For instance, it cannot fully assess some aspects of cognitive function (eg, non-verbal skills). Furthermore, the ACE-R takes on average 16 minutes to administer and is therefore unlikely to see much uptake by busy GPs; however, it could be used by nurses working in general practices. As with all screening tools, clinicians using the ACE-R in the primary care setting need to be trained to correctly score and interpret patients’ ACE-R performances. Development of effective dementia treatments depends on earlier and more accurate identification of disease. Cognitive screening tests will continue to evolve, and may in time be replaced with screening for disease-related biomarkers. However, such diagnostic biomarkers have yet to be discovered. With the number of people with dementia growing each year, the lack of adequately validated diagnostic tools is a serious concern. Empirical investigations to further evaluate and validate screening instruments for cognitive impairment are necessary as we strive to develop effective treatments for all forms of this debilitating disorder.

Zoe Terpening BPsych(Hons), MSc, DClinNeuropsych · John R Hodges MD, FRCP, FMedSci · Nicholas J Cordato MB BS, PhD, FRACP

Overcoming multiple sclerosis. An evidence-based guide to recovery. George Jelinek. Sydney: Allen & Unwin, 2010 (375 pp). ISBN 9781742371795. MULTIPLE SCLEROSIS (MS) is a chronic disabling disease that predominantly affects young women, with onset commonly at the age of 30–35 years. Its prevalence in Australia and elsewhere is steadily increasing. Many treatments have been tried over the years without success but, over the past decade, immunotherapy with beta-interferons and glatiramer has been demonstrated by many clinical trials to reduce the number of relapses and the rate of progression of disability. More recently, natazilumab has proven to be very effective. Unfortunately, all these drugs have side effects and none has yet been able to completely stop, let alone reverse, the progression of the disease. George Jelinek is an Australian academic emergency physician with MS and a family history of the condition. In this book, he reviews the possible causes and treatments for, and effects of, the disease, with particular emphasis on dietary treatment and lifestyle changes. He advocates a low saturated fat diet, exposure to 10–15 minutes of sunlight 3–5 times weekly, correction of vitamin deficiencies, regular exercise, avoidance of stress, and daily meditation, as well as one of the approved drug therapy regimens. The evidence for dietary measures and other non-pharmacological forms of treatment for MS is not very convincing, but they are not harmful and may improve general health. The book is well written. Each chapter has helpful summaries of the main points in language readily understandable by lay readers. It provides important, up-to-date information about the disease, positive support, encouragement and guidance for those with MS.

James McLeod

To the Editor: Significant morbidity and mortality are associated with excessive alcohol use, which, for Aboriginal Australians, generally occurs within a context of disadvantage. During 2007–2009, we assessed cognitive and psychological factors (using CogState1 and Strong Souls2 [CogState Ltd, Melbourne, Vic]) of 21 men and 11 women on admission to a 2-month Aboriginal residential treatment program in the Northern Territory. Participants’ mean age was 32 years (SD, 8.7 years) and the mean length of time for which they had used alcohol was 13.3 years (SD, 7.7 years). To determine the effect of age, number of years of drinking and other factors on continued alcohol use, we reinterviewed and reassessed participants in their home community with the same cognitive and psychological measures used at the initial assessment after a mean period of 11 months (SD, 4.4 months). At both baseline and follow-up, the number of participants for whom data were available varied for some characteristics. The Human Research Ethics Committee of the Northern Territory Department of Health and Community Services and Menzies School of Health Research (including the Aboriginal Ethics Sub Committee) approved the study. At baseline, 14 of 23 alcohol users reported drinking every day or most days, and 26 of 31 drank more than 10 standard drinks on each occasion. At follow-up in the community, 23 had resumed drinking at the same level, and nine had reduced their use (six had stopped using alcohol, and three had resumed drinking at lower levels). Compared with users who reduced their alcohol intake, users who did not showed poorer paired associate learning at the time of admission for treatment, and poorer performance at follow-up in visual attention, learning and executive function, visual learning and recall, and paired associate learning tasks (Box). This suggests that while subtle cognitive impairment may be a risk factor for continued heavy alcohol use after treatment, heavy alcohol use is also a likely cause of additional cognitive deficits.3 While reduced alcohol use may be associated with improvements in cognitive function, continued use may lead to further cognitive decline. Alcohol users who resumed drinking at the same level were significantly more likely to experience the psychological symptom “worry” after treatment (4/6; Fisher exact test, P < 0.05) than were users who reduced their alcohol use (0/6), which suggests that alcohol may have been used for self-medication or that excessive alcohol use may mask underlying psychological problems. Interestingly, a greater proportion of alcohol users who resumed drinking at the same level (10/16) were also using cannabis at follow-up, compared with those who reduced their use (1/9; Fisher exact test, P < 0.05). Cannabis use has been independently associated with psychological symptoms in other Australian studies, but with no impact on cognition.2,4 Our data indicate that there is a need to treat mental health problems concurrently with alcohol misuse problems among alcohol users undergoing treatment. Alcohol users who resumed drinking at the same level were less likely to return to remote communities with restricted alcohol availability (11/23), compared with those who reduced their alcohol use (9/9; Fisher exact test, P < 0.01), lending some support to the effectiveness of alcohol restrictions. Overall, our data show that cognitive problems and alcohol availability may be underlying factors in ongoing alcohol misuse by Aboriginal Australians. Charactersitics of alcohol users who resumed drinking at the same level and those who reduced their alcohol use after a 2-month residential treatment program, at baseline and at follow-up (n = 32) Characteristic Unchanged alcohol use, median Reduced alcohol use, median Z Significance No. of alcohol users 23 9 Age at baseline, years 31.3 29.0 − 0.15 ns Years of drinking, at baseline 13.0 11.6 − 0.59 ns Visual attention, speed (log transformed)* Baseline 2.81 2.76 − 1.67 ns Follow-up 2.79 2.71 − 2.10 P = 0.04 Working memory, accuracy (arcsine transformed)† Baseline 0.70 0.70 − 0.19 ns Follow-up 0.80 0.74 − 0.53 ns Psychomotor speed, moves per second† Baseline 0.77 0.95 − 0.35 ns Follow-up 1.17 1.37 − 0.75 ns Learning and executive function, moves per second† Baseline 0.44 0.47 − 0.39 ns Follow-up 0.58 0.76 − 2.32 P = 0.02 Visual learning and recall, moves per second† Baseline 0.48 0.46 − 0.21 ns Follow-up 0.73 0.84 − 2.20 P = 0.03 Paired associate learning, duration (seconds)* Baseline 307.81 214.11 − 2.52 P = 0.01 Follow-up 286.51 168.48 − 2.67 P = 0.008 ns = not significant; P > 0.07. * Higher values indicate poorer performance. † Higher values indicate better performance.

Kylie M Dingwall · Paul Maruff · Sheree Cairney

Clinical record A 78-year-old woman who was previously very active and in good health presented to hospital feeling unwell and with an extensive rash, involving both upper limbs (C3–T1 dermatomes), consistent with herpes zoster. Three weeks later, extensive diffuse left upper limb neuropathic pain developed over her C5–C7 dermatomes. The following week, her condition worsened to include progressive severe paresis of the left upper limb; weakness in the right hand; bilateral lower limb weakness; patchy areas of paraesthesia affecting many areas of the upper limbs, trunk and proximal lower limbs; severe constipation; and urinary retention, which required insertion of an indwelling catheter. She was bedbound and needed assistance with all self-care activities. About 10 days after the onset of weakness, a neurologist diagnosed a cervical myelopathy and recommended magnetic resonance imaging of the spine. This revealed an area of inflammation at C2–C4 involving the full thickness of the spinal cord at that level, consistent with transverse myelitis (Figure). She was diagnosed with herpes zoster myelitis. Sagittal T2-weighted magnetic resonance image with gadolinium enhancement showing an ovoid hyperintense lesion in the upper cervical spinal cord (arrow). About 6 weeks after her initial presentation, the patient was transferred to another acute hospital for further assessment. Detailed examination revealed asymmetric tetraparesis; upper limbs (left greater than right) were affected more than the lower limbs. On manual muscle testing she had muscle strength in her limbs as follows: 0/5 in the proximal and 1/5 in the distal left upper extremity, 4/5 in the right upper extremity and 2/5 in both lower limbs, with partial loss of sensation from her C4 to L3 dermatomes. Laboratory findings for full blood cell count, urea and electrolytes were unremarkable except for mild hyponatraemia and mild derangement of liver enzymes. Because of the severity of the herpes zoster infection, the patient was tested for underlying immunocompromise. She was found to have a κ monoclonal gammopathy of undetermined significance (12.0 g/L IgG; reference range [RR], 7.0–16.0 g/L) and borderline low values of immunoglobulins IgA (0.40 g/L; RR, 0.7–4.0 g/L) and IgM (0.31 g/L; RR, 0.4–3.0 g/L). It was thought that all of these immune abnormalities were of questionable significance. Treatment was initiated with intravenous methylprednisolone (1 g/day for 6 days) and intravenous (300 mg three times a day for 6 days) then oral (800 mg five times a day for 2 weeks) aciclovir. During the course of this treatment, gradual improvement in power of all four limbs became evident. She was subsequently admitted to a spinal rehabilitation unit and discharged 8 weeks later with evidence of ongoing neurological and functional improvement. Her hospital stay was complicated by severe postherpetic neuralgia, which was eventually controlled with gabapentin (400 mg three times a day). She recovered bladder function but needed aperients to achieve controlled faecal continence. At discharge, neurological examination revealed persisting asymmetric tetraparesis. She had 4/5 upper extremity muscle strength in C7–T1 myotomes on the left, 4/5 in L2 and L3 myotomes in both lower limbs and her remaining myotomes were of normal power. She was able to walk with a four-wheel frame or a single-point stick for 10–20 m and was independent for many activities of daily living. At follow-up 9 months after her initial presentation, her condition was still improving gradually. She had weaned off the gabapentin with no residual postherpetic neuralgia. She was able to walk short distances unaided and had regained full independence with most of her self-care using aids. Herpes zoster is associated with several neurological complications, including postherpetic neuralgia, aseptic meningitis, meningoencephalitis, transverse myelitis, peripheral nerve palsies, cranial nerve palsies and granulomatous cerebral angiitis.1 These complications are particularly prevalent among older people and patients with immunodeficiency. A causative relationship with herpes zoster in many of these syndromes is probably more common than suspected owing to difficulties in diagnosis and lack of awareness among clinicians. However, to our knowledge, there are no published reports of any known association between the neurological complications of herpes zoster, including myelitis, and postherpetic neuralgia. Transverse myelitis is a focal inflammatory disorder of the spinal cord. It results in sensory, motor and autonomic dysfunction 2 Onset may be acute, developing over a few hours or several days, or subacute, developing over 1 to 2 weeks. The critical factor is an abnormal immune response to infection, rather than the direct effect of an infectious agent.3 Transverse myelitis may be an isolated entity or may occur with a background of viral diseases, vaccinations, systemic lupus erythematosus, vasculitis, multiple sclerosis, heroin misuse or trauma.3 About 25%–40% of cases of transverse myelitis are caused by viral infections with herpes viruses or poliovirus.2 A recent publication provides useful additional information about transverse myelitis.4 Lessons from practice Herpes zoster myelitis is rare in the context of normal immunity; it is more common among patients with immunocompromise. Clinicians should be aware of the close temporal relationship between skin rash and the onset of myelitis so that appropriate investigations and treatment can be instigated. Magnetic resonance imaging of the spine should be performed to aid diagnosis. Although early treatment of herpes zoster myelitis is preferable, delayed treatment may also be worthwhile. Transverse myelitis following herpes zoster or herpes zoster myelitis (HZM) is rare, and typically occurs in hosts who are immunocompromised. Its onset is usually acute, occurring shortly after the appearance of the rash, with the development of sensory, motor and autonomic dysfunction.5 No diagnostic test is completely accurate, as the virus cannot usually be isolated from blood or cerebrospinal fluid in HZM.5 In most cases, diagnosis of HZM is clinical and based on detection of typical vesicular lesions in dermatomal distribution in association with clinical features of transverse myelitis. Suggested treatment involves high doses of corticosteroids and aciclovir.5 The prognosis ranges from spontaneous recovery to ascending neurological progression and death.6 The frequency of transverse myelitis during or after varicella infection is reported to be 0.3%.7 Devinsky and colleagues analysed their findings in 13 immunocompromised patients with HZM.8 The pathogenesis of HZM is unclear, but it may be due to direct viral invasion, which was demonstrated in one autopsy case.9 Diagnosing HZM can be challenging. The importance of a careful clinical assessment to establish the likelihood of this diagnosis and the level of the spinal cord damage, in combination with confirmatory magnetic resonance imaging (MRI)7cannot be overstated. MRI not only provides information about the site but also the extent of spinal cord involvement, and excludes other possible diagnoses. In our patient, HZM was diagnosed based on the temporal relationship of myelopathy to the rash and MRI findings. Although the area of the spinal cord that was involved on the MRI scan was less extensive than that affected by the herpetic rash, we do not see this as clinically inconsistent. There are no proven treatment regimens for HZM, but there is anecdotal evidence for treatment of HZM with high doses of aciclovir and corticosteroids.5,10 It appears that antiviral treatment was not provided early to our patient because it was not initially recognised that the rash was due to herpes zoster. Once HZM was diagnosed, this treatment was provided. Despite the delay of 3 weeks following the onset of rash, improvement appeared consistent with a clinical response to this therapy. Although early treatment of herpes zoster with antivirals is crucial to prevent the development of postherpetic neuralgia, there is little evidence that such treatment reduces the risk of HZM. To date, no evidence has emerged regarding the protective efficacy of the new live, attenuated herpes zoster vaccine (Zostavax) against HZM. Trials assessing the impact of antivirals or the herpes zoster vaccine on risk of HZM would require very large numbers of participants, given the rarity of this complication. Nevertheless, the vaccine has proven to be efficacious in reducing the incidence of and morbidity associated with herpes zoster and postherpetic neuralgia in older adults.11 It has been noted in a previous case report that, following the diagnosis of HZM, even delayed treatment with oral antivirals may prevent neurological progression.12 Our case provides support for this assertion.

Olivia L W Ong MB BS, BMedSci · Andrew C Churchyard PhD, MB BS, FRACP · Peter W New MB BS, MClinEpi, FAFRM(RACP)

To the Editor: We report a case of ischaemic stroke in a 34-year-old man with severe vitamin C deficiency caused by poor nutrition. The patient was a lifelong non-smoker with no history of hypertension or hypercholesterolaemia, and no family history of stroke, although he had recently been diagnosed with type 2 diabetes mellitus. At presentation, neurological examination showed profound left-sided hemiparesis, with normal sensory examination and visual fields. Cardiovascular examination was normal, and there were no carotid bruits. The patient’s body mass index was 25.5 kg/m2. Magnetic resonance imaging of of his brain showed acute infarction in the right posterior corona radiata (Box, A). Coagulation and lipid profiles were normal. Glycosylated haemoglobin was 7.1%. Comprehensive testing for underlying thrombophilia, vasculitides and Fabry disease all returned negative results. Computed tomography angiography and carotid ultrasonography confirmed normal carotid and vertebral arteries. Transoesophageal echocardiography showed a structurally normal heart without a source of embolus. The patient had poor dentition, with calculus deposition, scorbutic gums and gingival inflammation (Box, B), and reported easy bruising in recent months. Suspecting a diagnosis of scurvy, we conducted a nutritional assessment of the patient. His diet consisted mainly of fast food, with negligible vegetable and fruit intake, and no vitamin supplementation. For the week before admission, we determined that his average vitamin C intake was 4 mg/day. This corresponded to a > 99% probability of inadequate intake when compared with the estimated average requirement of 30 mg/day for adults1 (z = − 4.33; P = 0.0015). Laboratory testing confirmed the presence of severe vitamin C deficiency (< 5 μmol/L; reference range, 40–100 µmol/L). The patient was admitted to a stroke unit, commenced on aspirin, ramipril and atorvastatin, and received dietary counselling. Vitamin C 1000 mg daily was prescribed for one month. Subsequent testing confirmed normalisation of his plasma vitamin C. Following inpatient rehabilitation, he regained motor function and returned to independent living. There is growing evidence that vitamin C deficiency is an important, but largely unrecognised, risk factor for modification in patients with cerebrovascular disease.2 Vitamin C is a water-soluble antioxidant that inhibits oxidation of low-density lipoprotein and protects against endothelial dysfunction. Primate models have confirmed that cerebral infarct size is inversely related to cerebral vitamin C content.3 Although scurvy is now relatively rare, subclinical vitamin C deficiency is not uncommon, being present in about 10% of the general population.4 Alcoholics, institutionalised and elderly people are particularly at risk. In this case, we hypothesise that an unhealthy diet resulted in deficiencies in antioxidants (including vitamin C), and that this contributed to stroke pathogenesis. The marked prematurity of disease onset may have resulted from effect modification of antioxidant deficiency on conventional atherosclerotic risk factors (such as diabetes). A cohort study previously observed the modifying effect of vitamin C deficiency on the association between stroke and hypertension.5 However, it is unlikely that a direct causal link will ever be established. Since malnutrition and unhealthy eating practices continue to be serious public health problems, we suggest attention to nutritional status should be incorporated into the new standard of stroke care. Perhaps a new adage should be considered: an orange a day keeps stroke away? A: Diffusion-weighted magnetic resonance image of the patient’s brain showing an acute infarction in the posterior limb of the right corona radiata. B: The patient’s mouth showing scorbutic gums consistent with scurvy.

Emily Y-J He · Louis W Wang · Matthew C Kiernan

Providing world-class stroke care in Australia Cerebrovascular disease is the third leading cause of disease burden in developed nations, and is predicted to be the fourth ranked disease burden worldwide by 2030 after unipolar depressive disorders, ischaemic heart disease and trauma.1 All of these conditions are characterised by sudden and unpredictable demands requiring an immediately accessible, systemised and multidisciplinary approach to care. The complexities of acute ischaemic stroke in Australia have been addressed by detailed clinical guidelines.2 An emergency care bundle for stroke and transient ischaemic attack has recently been offered by the National Institute of Clinical Studies of the National Health and Medical Research Council.3 When administered to appropriate patients within 3 hours of stroke symptom onset, the benefits of recombinant tissue plasminogen activator (rt-PA) are significant, with treated patients 30% more likely to be in the excellent outcome grade — an absolute increase of 13%4 — and improvements in modified Rankin scores for some other patients with higher modified Rankin scores. The number of patients needed to treat for benefit may be as low as three.5 The associated risk of an intracerebral haematoma causing deterioration is about one in 30.5 The third European Cooperative Acute Stroke Study (ECASS3), a randomised trial of intravenous rt-PA in the 3–4.5 hour window, demonstrated a smaller but statistically significant benefit with no increase in haematoma rate.6 A recent Cochrane review of 26 thrombolysis trials of rt-PA, streptokinase, desmoteplase, urokinase and pro-urokinase, which included 7125 patients, found a significant net benefit in terms of death and dependency.7 The clinical applicability of new therapies may be exaggerated by the Hawthorne effect of clinical trials. The European Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST) registry — a mandated requirement of European drug licensing authorities — was established to monitor thrombolysis in day-to-day clinical practice.8 It included centres not experienced with thrombolysis and demonstrated the feasibility and safety of thrombolytic therapy across Europe. The cover of the issue of The Lancet in which the registry outcomes were published declared that rt-PA is “safe and effective in routine clinical use”. The rate of symptomatic intracerebral haemorrhage (ICH), as defined by the National Institute of Neurological Disorders and Stroke (NINDS), was 7.3% in SITS-MOST for both experienced and new thrombolysis centres, with a calculated mortality rate from ICH at 3 months of 1.9%.8 Early deterioration due to ICH in the SITS-MOST registry occurred in 1.7% of cases. In this issue of the Journal, Simpson and colleagues report the Australian contribution to the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register (SITS-ISTR),9 reflecting the local experience of treating acute stroke 15 years on from the NINDS trial.4 Participation in the Australian component of the SITS-ISTR was voluntary. Many centres undertaking thrombolysis did not participate, and this may weaken the generalisability of this new data. Nevertheless, over 500 patients were enrolled and outcomes did not differ from those of the larger international database. The important safety data were reassuring, with a symptomatic ICH rate of 8.3% by the definition used in the NINDS randomised controlled trial, and 1.3% by the SITS-MOST definition. The 3-month ICH mortality rate was 2.2%. A British subset of SITS has been reported recently, with outcomes also comparable to those for the rest of Europe.10 In the SITS-MOST registry, new and experienced centres did not differ in terms of their haemorrhagic complication rates.8 While the Australian report by Simpson et al does not detail information regarding the types of centres involved, implementation of thrombolysis in Australia beyond the centres that participated in the thrombolysis trials is already well established. Audits by the National Stroke Foundation have found that 33 hospitals were regularly treating with rt-PA in 2007,11 and that this increased to 50 by 2009.12 New metropolitan and rural centres can adopt thrombolysis with executive support and leadership from medical and nursing “stroke champions”. This nearly always results in the establishment of a stroke unit and the adoption of a local thrombolysis protocol with coordination of the prehospital emergency services. Mentorships with established metropolitan centres are worthwhile in the early stages. Some direct links using telemedicine for the treatment of the first cases have been employed in Victoria (Associate Professor Bernard Yan, Neurologist and Neurointerventionist, Royal Melbourne Hospital, personal communication). Early recognition and intervention for stroke requires a tightly coordinated interdisciplinary approach and rates of intravenous thrombolysis administration can be used as a clinical quality indicator for stroke care.13 Ongoing participation in the SITS-ISTR and the Australian Stroke Clinical Registry is crucial for monitoring the progress of this important therapy. A coordinated system of care for stroke and transient ischaemic attack in Australia has been stalled by the lack of a concerted effort to adopt thrombolysis. Australian registry data provide reassurance that Australian stroke physicians, emergency physicians and systems that support thrombolysis can achieve similar results to those recorded in Europe. We can now move beyond discussing the efficacy and feasibility of implementing this therapy and work toward a more coordinated system of applying the evidence.

Mark Fitzgerald MB BS, FACEM · Richard P Gerraty MD, FRACP

Carotid artery stenting has a place in managing symptomatic stenosis, but only sometimes Carotid stenosis remains one of the most readily treatable causes of ischaemic stroke. Its treatment has undergone many changes in recent years, with the advent of endovascular techniques seeming to offer great promise of a much less invasive procedure. In the late 1990s, the Australian Association of Neurologists published guidelines for the use of carotid balloon angioplasty alone (ie, without stenting) as a treatment for carotid stenosis, recommending cautious use in the absence of data from randomised controlled trials (RCTs).1 However, advances in vascular stent technology have resulted in a greatly increased use of carotid artery stenting (stenting), often with specialised filter devices deployed distal to the carotid stenosis to catch embolic debris that may arise from catheter or stent manipulation. Recent evidence from RCTs has cast doubt on the safety of widespread use of stenting for the treatment of patients with symptomatic or asymptomatic carotid stenosis. The overall results from these RCTs indicate that carotid endarterectomy (endarterectomy) is still the preferred treatment option for symptomatic carotid stenosis. The results of three major European studies into the treatment of symptomatic stenosis — Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S); Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE); International Carotid Stenting Study (ICSS) — showed that stenting was more hazardous than endarterectomy for the outcomes of stroke and death during the periprocedural period (30 days), and on longer-term follow-up.2-4 Perhaps in contrast, the recent North American Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) demonstrated equivalent (non-significant) rates of stroke, myocardial infarction and death in its stenting and endarterectomy groups in the periprocedural period, and at 4 years.5 However, in CREST there was a significantly reduced rate of stroke and death in the endarterectomy group, but this was offset by an increased risk of myocardial infarction, in part due to the definition of myocardial infarction used, and a greater number of study patients with comorbid ischaemic heart disease.5 Use of cerebral protection devices during stenting was mandated in CREST but not in the European studies. The value of these devices is in question, with evidence indicating that they were no more effective in reducing the clinical risk of stroke than unprotected stenting.6,7 Moreover, data from a magnetic resonance imaging substudy undertaken as part of the ICSS indicated that, compared with endarterectomy, there was a threefold increase in silent brain infarctions in stenting with use of cerebral protection devices (adjusted odds ratio, 3.28 [95% CI, 1.5–7.2]).7 A meta-analysis of 11 RCTs (including EVA-3S, SPACE and ICSS, but not CREST) showed that endarterectomy was superior to stenting in short-term but possibly not longer-term outcomes, a difference largely driven by non-disabling stroke.8 The Australasian guidelines9,10 have now been upgraded following additional published data from CREST5 and a meta-analysis of the three large European trials (EVA-3S, SPACE, ICSS)11 indicating that stenting is at least as safe as endarterectomy in patients under 70 years of age, while it presents a greater risk of stroke for those older than 70 years (Box). The RCTs indicate that there is currently no clear evidence to support either endarterectomy or stenting as a treatment for asymptomatic carotid stenosis. Indeed, current medical therapies have reduced the risk of stroke in asymptomatic stenosis to as low as 0.5% per year.12 Ongoing RCTs continue to address this question (eg, the Asymptomatic Carotid Surgery Trial 2, comparing stenting and endarterectomy in the treatment of asymptomatic carotid stenosis).13 Until recently, in Australia and New Zealand, there were no specific published guidelines for carotid artery stenting. To redress this, an intercollegiate working group was formed — the Carotid Stenting Guidelines Committee — comprising expert representatives of the Royal Australasian College of Physicians, the Royal Australasian College of Surgeons, and the Royal Australian and New Zealand College of Radiologists. Consensus for guideline parameters was reached using the modified Delphi consensus method of iterative consultation. The committee’s guidelines recommend clinical selection criteria for carotid artery stenting, as well as cognitive and technical requirements that clinicians should meet before performing stenting.9,10 The guidelines do not deal with training criteria and procedural accreditation as these are determined by the Conjoint Committee for Recognition of Training in Peripheral Endovascular Therapy of the abovementioned colleges. On current evidence, the guidelines recommend that carotid artery stenting may be considered a treatment option in specific, high-risk patients with symptomatic severe stenosis who are considered unsuitable for endarterectomy (Box).10 It is important to note that these are relative contraindications to endarterectomy as there is no evidence to support stenting in these patients (indeed, they are often excluded from clinical trials). Finally, it is important that all patients being considered for a carotid intervention have preprocedural neuroimaging and independent neurological assessment before and after the procedure. This allows for an audit comparison with the results of RCTs where neurological evaluation of all patients is routine, and serves as a benchmark for best clinical practice. In summary, the evidence from RCTs indicates that, at present, a cautious approach should be taken to recommending carotid artery stenting — festina lente (hasten slowly). Stenting should not be performed in most patients with symptomatic severe carotid stenosis, and there is currently no evidence to support stenting as a treatment for asymptomatic carotid stenosis. Stenting warrants consideration in younger patients (< 70 years of age) and those with symptomatic severe carotid stenosis unsuitable for endarterectomy. These standards should apply in all health care settings, public and private. Advances in endovascular technologies, and evidence from future RCTs and meta-analyses, will guide revisions of the guidelines. Carotid Stenting Guidelines Committee: recommended indications and contraindications for carotid artery stenting (CAS)10 Indications Symptomatic carotid disease in the following conditions may be assessed at high surgical risk for carotid endarterectomy (CEA) by an appropriate clinician experienced in the management of carotid stenosis: post-radiation therapy block dissection of the neck in-situ tracheostomy recurrent stenosis following previous CEA severe cervical spine arthritis surgically inaccessible carotid stenosis (eg, obesity, high carotid bifurcation) contralateral recurrent laryngeal nerve injury contralateral internal carotid artery occlusion Symptomatic severe carotid stenosis* in patients under 70 years of age, where carotid revascularisation is considered appropriate Symptomatic or asymptomatic carotid stenosis where carotid revascularisation is considered appropriate, and the patient is randomised to CAS in a clinical trial Contraindications Absolute Carotid stenosis in a patient with significant contraindications to angiography Carotid stenosis with angiographically visible intraluminal thrombus Carotid occlusion Relative Carotid stenosis associated with an intracranial vascular malformation Contraindications related to vascular anatomy and atherosclerosis (eg, type 2–3 arch; bovine arch; severe aortic arch or ipsilateral common carotid atherosclerosis; severe proximal common carotid artery tortuosity; severe distal internal carotid artery tortuosity (possibly compromising embolic protection devices); sharply angulated internal carotid artery; carotid string sign; circumferential calcification of carotid plaque; loose thrombus associated with carotid plaque) * Severe carotoid stenosis is defined as ≥ 70% using North American Symptomatic Cartoid Endarterectomy Trial criteria.5

on behalf of the Carotid Stenting Guidelines Committee (Australia and New Zealand)

Objective: To report Australian outcomes from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register (SITS-ISTR).Design: Observational study using data collected prospectively from December 2002 to December 2008.Setting: Centres administering thrombolysis for acute stroke in Australia and worldwide.Patients: All patients treated with recombinant tissue plasminogen activator for acute stroke in participating centres, regardless of stroke severity, time of treatment and other clinical factors.Intervention: Thrombolysis for acute stroke, administered according to local protocol.Main outcome measures: Functional outcome as 3-month modified Rankin score (mRS), and frequency of symptomatic intracerebral haemorrhage (ICH).Results: During the study period, a total of 32 countries participated, and confirmed baseline data were available for 581 Australian patients and 20 953 patients in the rest of the world. Australian patients were older (median age, 73 v 69 years; P < 0.001), were less independent before stroke (premorbid mRS of 0–1, 87.5% v 91.2%; P < 0.005), and had more comorbidities and more severe strokes. Comparing the Australian cohort with the rest of the world, the odds ratio of 3-month mRS of 0–2 was 0.98 (95% CI, 0.88–1.08; P = 0.63), the odds ratio of symptomatic ICH was 0.98 (95% CI, 0.83–1.16; P = 0.85 [by the definition used by the National Institute of Neurological Disorders]) and the odds ratio of death was 1.04 (95% CI, 0.91–1.19; P = 0.54). Good outcome in the Australian cohort was predicted by younger age, presence of hyperlipidaemia, lower premorbid mRS, absence of infarct on early brain imaging, less severe stroke, and lower baseline blood glucose level.Conclusion: Clinical outcomes after thrombolysis in Australia were similar to those worldwide.

Marion A Simpson BSc, MB ChB(Hons), MRCP · Helen M Dewey PhD, FRACP, FAFRM(RACP) · Leonid Churilov PhD · Niaz Ahmed MD, PhD · Christopher F Bladin MB BS, MD, FRACP · David Schultz BM BS, FRACP · Romesh Markus MB ChB(Hons), PhD, FRACP · Jonathan W Sturm MB ChB, PhD · Christopher R Levi BMedSci, MB BS, FRACP · David J Blacker MB BS, FRACP · Jim Jannes BM BS, FRACP, PhD · Richard I Lindley MD, FRCP, FRACP · Mark W Parsons PhD, FRACP

The take-home message is not only early intervention but education and teamwork I was due to fly out to the United States the next morning. I was bending down to clean the floor of my car when it happened. First my right hand wouldn’t respond and I fumbled picking up a spoon from the floor, then my right leg wouldn’t support my weight. I tried to call out to my wife but only grunts came out, except of course the f-word when I knew what had happened. I crawled to the front door of the house, my intensivist wife called 000 and the ambulance was there in 3 minutes! The paramedics ignored my pleas to go to the closer private hospital ... “no you’re off to the Stroke Unit at The Alfred” ... and wasted no time — scoop and run. I was in the resuscitation bay of the emergency department (ED) in 20 minutes and, despite it being late on a Friday night, I was assessed, I had my computed tomography (CT) scan to exclude an intracranial haemorrhage, and the intravenous thrombolytic therapy was running within 60 minutes. The next day a repeat CT scan and a magnetic resonance imaging scan confirmed multiple small infarcts in the insula consistent with an embolic stroke. A patent foramen ovale (PFO) showed up on the transoesophageal echocardiogram on Day 3 and the PFO was occluded, percutaneously, on Day 7. I was home the next day and back at work 3 weeks later, with no significant residual deficit. Bending over in the car may have been the trigger, with a Valsalva that opened up the PFO and caused the clot to flip up my left middle cerebral artery (MCA) into the insular cortex. It is pleasing when published data justifies one’s own teaching; it is even more encouraging when it justifies treatment that affects one’s own life and health. Every 10 minutes, up to 20 million neurones will die in a typical infarct in the MCA territory, if not recanalised.1 A recent updated pooled analysis of eight trials using multivariate logistic regression has been used to assess the relationship of onset-to-treatment time with 3-month morbidity, brain haemorrhage and mortality.2 When selected by symptoms and CT findings, the critical time from onset of symptoms to the intravenous infusion of recombinant tissue plasminogen activator (rt-PA) seems to be 3 hours, though that window of opportunity can be increased to 4.5 hours, after which risk may outweigh benefit. After 4.5 hours, the risk, particularly of reduced recovery of brain function, brain haemorrhage and death, increases. However, not all patients benefit. It was shown that about five patients need to be treated within 0–90 minutes of symptom onset, nine patients within 91–180 minutes or 15 patients within 181–270 minutes for one of them to have an excellent outcome attributed to treatment. Clearly rt-PA is not a panacea, and other interventions need to be analysed for the ultimate objective of reperfusion of 100% of patients rather than 40%. Other modalities need to be investigated, particularly the therapeutic combinations of thrombolytics, neuroprotectives and antithrombotics in addition to ultrasound and endovascular mechanical clot manipulation.1 My experience with swift prehospital assessment and efficient ED intervention with intravenous rt-PA, after sustaining an acute ischaemic stroke, with full recovery, emphasises that time is critical.1 However, the take-home message here is not only early intervention but education and teamwork, similar to the model in trauma care — the “golden hour” and a well trained trauma team.3 For stroke management, this means the development of stroke centres, training of prehospital and emergency staff, prioritisation of patients to achieve door-to-needle times of less than 60 minutes and public education programs on acting early with the onset of symptoms.1,4 For me, it may have been luck: stroking out at home and not in the air; having a medico wife who recognised the signs; a paramedic crew trained to scoop and run and to take me to an ED with a stroke unit, not just passing by the end of my street when they got the call; ED staff who wasted no time; a neurology registrar who started the rt-PA immediately, though pointing out to me and my wife the risks of intracranial haemorrhage; and having a well trained team of health professionals in the Stroke Unit. Some cynics might say I got red carpet treatment because I am a professor of surgery. I disagree. I believe it was not just a stroke of luck but that I benefited from the ideal model of care of stroke management that should be available to all Australians.

Bruce P Waxman FRACS, FACS, MRACMA

Introducing an innovative, evidence-based resource for use in the emergency department In early 2008, the National Institute of Clinical Studies (NICS) Stroke Clinical Reference Group was formed to develop an acute stroke care resource for use in emergency departments (EDs) in Australian hospitals. The NICS reference group used a care bundle approach to develop a guideline implementation tool based on specific recommendations from the 2007 National Stroke Foundation (NSF) Clinical guidelines for acute stroke management relevant for ED care.1 Although these guidelines were already available, there are well known barriers to guideline implementation in the ED. These include increasing demand and acuity, and the broad diversity of clinical presentations. Clinical information provided for ED clinicians needs to be concise and relevant to the emergency care context. The nine-member NICS reference group represented a collaboration between stroke and ED specialists, prehospital providers and managers of state-based stroke networks, with additional guidance from the NSF. Over the following 12 months, a consultative process took place, with a combination of face-to-face and teleconference meetings and email exchanges. The reference group used a Delphi process to reach consensus. In December 2009, the NICS released two documents — the Emergency department stroke and TIA care bundle: information and implementation package and the accompanying Summary for clinicians. These are available on the National Health and Medical Research Council (NHMRC) website (http://www.nhmrc.gov.au/nics/programs/emergency/stroke_tia.htm). This editorial presents a précis of the care bundle. Care bundles have already been shown to improve guideline compliance and lead to improved patient outcomes in several settings, including the ED.2-6 A care bundle is made up of a small number of best-practice recommendation components, is not as comprehensive as a guideline, and aims to identify critical recommendations relating to areas in which there is a significant practice gap or to act as a trigger to other best practice.7 The NICS care bundle needed to bring together several components to help clinicians provide quality care to adult patients who present to the ED with suspected stroke or transient ischaemic attack (TIA) by reducing morbidity and mortality and optimising patient outcomes (Box 1). The criteria for a component’s inclusion in the care bundle were determined by the model developed by the Institute for Healthcare Improvement in the United States:7 each component must be based on sound evidence; the delivery of each component must need improvement; the delivery of each component must be achievable in terms of universally available resources; no component should be a major source of controversy; and the delivery of each component must be measurable. Two components — stroke unit care and thrombolysis — are not included in the care bundle. We acknowledge the importance of stroke unit care — and thrombolysis for patients who meet the criteria for its use — when appropriate resources are available. The NSF recommendations, along with similar international guidelines, state that thrombolysis should only be given under the authority of a specialist team with expert knowledge of stroke management and with pathways and protocols in place to guide the acute phase.1,8-10 Although there is level I evidence that thrombolysis and stroke unit care are effective early interventions for stroke,2 currently thrombolysis is only offered in 28% of acute hospitals that manage stroke patients, and stroke unit care is only available in a third of hospitals across Australia.8 The reference group considered all of these factors and decided, by consensus, not to include thrombolysis and stroke unit care in the care bundle, as the necessary resources to support these are not universally available. However, the reference group believes that an emphasis on the first component of the bundle — a rapid initial stroke screen — could lead to earlier referral to stroke specialists and rapid access to computed tomography or magnetic resonance imaging to confirm the diagnosis and develop a management plan that would consider thrombolysis if clinically appropriate.11 This illustrates how the components of the care bundle may trigger additional best-practice recommendations as a natural consequence and establish joint clinical decision making with other disciplines to improve patient care (Box 2). The NICS clinical reference group is planning to collaborate with key stakeholders in 2010 to evaluate the effectiveness of the care bundle, both as a format for providing specific guideline recommendations to a target audience and in terms of the impact on stroke care in the ED. An implementation plan and auditing tool have also been developed to assist in the uptake of the recommendations. The NICS care bundle is based on the 2007 NSF clinical guidelines,1 and its recommendations are consistent with the current draft of the 2010 NSF guidelines. It is intended that the care bundle will evolve to ensure that recommendations relevant to the ED remain current. 1 Components of the NICS care bundle Rapid initial stroke screen (grade C; level II)* ABCD2 assessment† for suspected TIA (grade B; level II) Urgent‡ CT or MRI (grade A; level I) Nil by mouth until bedside swallow screen (within 24 hours) for stroke (grade C; level I) Aspirin as soon as possible,§ if haemorrhage excluded (grade A; level I): 150–300 mg one-time loading unless contraindicated Physiological monitoring and treatment Neurological status (grade C; levels II and III-2): regular monitoring to establish baseline and identify change Blood glucose (grade B; level II): cautious treatment of markedly elevated blood glucose levels; early, intensive maintenance of euglycaemia is not recommended. Avoid hypoglycaemia Blood pressure (consensus¶): cautious lowering by no more than 10%–20% if extremely high (≥ 220/120 mmHg); monitor for neurological deterioration Hydration status (grade B; level II): maintain euvolemia NICS = National Institute of Clinical Studies. TIA = transient ischaemic attack. CT = computed tomography. MRI = magnetic resonance imaging. * Evidence-based grades and levels as per 2007 National Stroke Foundation clinical guidelines.1 † A seven-point score calculated from age, blood pressure, clinical features, duration of symptoms, and diabetes status. ‡ “Urgent” means as soon as possible, but certainly within 24 hours.1 § “As soon as possible” means within 48 hours.1 ¶ Recommended best practice based on clinical experience and expert opinion. 2 Application of the NICS care bundle* Case study 1: a 68-year-old man presents to a hospital emergency department (ED), having woken with marked weakness of his left arm. Enquiry establishes that he was fine when he went to bed 7 hours earlier. The patient’s blood pressure (BP) at triage is 186/99 mmHg. The triage nurse is concerned that the patient is having a stroke. Case study 2: a 74-year-old woman with a history of type 2 diabetes mellitus and hypertension presents to a metropolitan tertiary hospital ED. She is unable to speak and has no strength in her right arm or right leg. Her friend states that the symptoms started only 2 hours ago. The patient’s BP is 170/95 mmHg; her heart rate is 80 beats/min and the heart is in sinus rhythm; and her blood glucose level is 9 mmol/L. The following care is provided for these patients, consistent with the use of the care bundle: as part of the patient’s assessment, and based on clinical findings, conduct a rapid initial stroke screen using a validated stroke screening tool to determine whether the patient is likely to have had a stroke. If a stroke is suspected, promptly refer the patient for expert stroke management — this may include referral to a stroke unit, or thrombolytic treatment (which is likely for the patient in case study 2); order an urgent computed tomography (CT) scan of the brain; ensure no oral intake until the patient undergoes a swallow screen for dysphagia; maintain hydration via intravenous or nasogastric fluids; administer aspirin (150 mg) within 48 hours if the brain CT scan excludes haemorrhage (if the patient in case study 2 proceeds to thrombolysis, delay aspirin treatment until 24 hours after thrombolysis); monitor the patient’s neurological status, blood glucose level, BP and hydration status to prevent further deterioration. NICS = National Institute of Clinical Studies. * The NICS care bundle was written for the care of stroke patients while in the ED. If the patient is transferred out of the ED early in his or her care, it is anticipated that the remaining components of the bundle will still be provided in the new setting.

Jayantha I Weeraratne MB BS, FACEM · Annette J Lenstra BSc, GradDip(Gov) · Andrew W Lee MB BS, MPH, FRACP · Kelvin M Hill BAppSci(Physio), GradDip(BusComm) · Susan D Huckson BAppSci, RN, ICU(Cert) · Jodie L Clydesdale BNurs, GradDip(ClinNurs)

From 1967, the Australian Human Pituitary Hormone Program offered treatment for short stature and infertility using human cadaver-acquired pituitary hormones (human growth hormone [hGH] and human pituitary gonadotrophin [hPG]). The program was suspended in 1985 when a growth-hormone recipient in the United States developed Creutzfeldt–Jakob disease (CJD), an incurable and rapidly progressive neurodegenerative disorder. Since this time, recipients have lived with the significant anxiety that they have an elevated risk of developing CJD. Furthermore, additional CJD infection control measures are required when recipients undergo some types of surgery. As it is 20 years since the last Australian pituitary hormone recipient developed CJD, we evaluated the risk for Australian recipients of developing iatrogenic CJD, and compared Australian data with data from New Zealand and selected other countries who had pituitary hormone programs. Our evaluation indicates that pituitary hormone recipients in Australia have the lowest risk of developing iatrogenic CJD, and that Australia is the only country not to have experienced ongoing CJD-related deaths. Thus, we believe that: in the Australian hGH recipient cohort, the risk of developing CJD is sufficiently low for this cohort to no longer require additional infection control measures in the health care setting; and in the Australian hPG recipient cohort, if another 5 years elapses with no further occurrence of CJD in this group, the hPG recipient cohort could also be considered as not requiring additional infection control measures in the health care setting. These recommendations should not be misunderstood as implying that there is no ongoing risk, but that the risk is acceptably low and generally in keeping with guidelines that stratify the risk.

Alison Boyd DipAppSci(Nursing), GradDipGenCoun · Genevieve M J A Klug BSc(Hons), PostGradDipEpiBioStat · Lawrence B Schonberger MD, MPH · Amelia McGlade BSc · Jean-Philippe Brandel MD · Colin L Masters MD · Steven J Collins MD

To the Editor: The recent review by Hayes and colleagues1 does not sufficiently emphasise practical approaches to managing the later stages of Parkinson disease (PD). Nazem and colleagues2 reported active suicidal or death ideation in 30% of patients with PD of mild-to-moderate severity, and an overall rate of major depression of 27.6%. They found that psychiatric symptoms and disorders, especially major depression, rather than PD-related variables, predicted suicidal or death ideation. Only half of the depressed patients were being treated with an antidepressant. Screening for psychiatric disorders should occur on assessment. Skilled counselling is required, and carers need to be well supported, particularly if the patient has intermittent suicidal ideation and a strong wish for the end of life. Clozapine is the only antipsychotic shown to be effective for treating psychosis in patients with PD.3 If the psychosis is schizophrenia-like, with persistent bizarre delusions and florid hallucinations causing agitation, clozapine can be prescribed in Australia by a registered psychiatrist and the patient can be registered with the clozapine monitoring service. If the patient is started on a very low dose (6.25 mg daily) that is only very gradually increased, side effects can be minimised. Successful use of clozapine enables remission of the psychosis and optimal treatment of motor symptoms. Mild hallucinations may be tolerated without specific treatment while the patient retains insight. In an open-label study of patients with mild hallucinations comparing no treatment with quetiapine therapy (or clozapine therapy in a minority of cases),4 the rate of progression to hallucinations without insight, or delusional psychosis, was significantly slowed. Hely and colleagues5 have argued that pathological processes in addition to Lewy body disease may have a role in the appearance of dementia, as age is a better correlate than PD duration. If it is clear that the dementia is a PD dementia, or dementia with Lewy bodies, a cholinesterase inhibitor such as rivastigmine could be prescribed. As rivastigmine is not subsidised on the Pharmaceutical Benefits Scheme in Australia for this indication, a private prescription could be provided in the first instance, and if there was a likelihood of significant Alzheimer disease associated with PD, an authority prescription would be justified. Hely and colleagues pointed out that, in the later disease stages of PD (at 20 years), less than 50% of patients still see their neurologist. However, the quality of life for PD patients in nursing-home care could still be significantly improved by specialist review by members of a multidisciplinary team on an inpatient, outpatient or outreach basis.

David S Tofler

Clinical record We report anoxic convulsions occurring in two medical students competing in a breath-hold dive competition in shallow water. The seizure-like activity occurred during a competition called the “Dolphin Dive”, which was part of a university medical school swimming function. The goal set for the competitors was to swim as far as possible underwater in a swimming pool without taking a breath. Three students participated in the event and two students had convulsions. In both cases, the students hyperventilated before the dive. Student 1 A 27-year-old man, with a past medical history of asthma, had been involved in underwater hockey and spear fishing, and was previously able to underwater breath-hold for 2 minutes while keeping still. During the competition, he swam about 60 metres and spent 40 seconds underwater. After the dive, he stood up in the water, lost consciousness and was witnessed to have multifocal myoclonic jerks lasting about 1 minute. He recalled some jerking of the limbs when asked afterward. Student 2 A 27-year-old man, with no significant past medical history, had previously swum at national championship level and had worked as a surf lifesaver. He reported swimming about 85 metres for the competition and spending 90 seconds underwater. At the end of his dive, he became unconscious, floated to the surface of the pool and had multifocal myoclonic jerks lasting less than 1 minute. He had no recollection of the convulsive movements. Many people were observing the race and so the students were rapidly retrieved from the pool; they regained consciousness and did not experience any long-term consequences. The seizure-like activity that occurred in the two university students was probably convulsions secondary to cerebral hypoxia induced by breath-holding. Anoxic convulsions result from interruption of the oxygen supply to metabolically active neurones, particularly in the cerebral cortex.1 They may be regarded as a brainstem-release phenomenon in which primitive movements can occur, particularly multifocal arrhythmic myoclonic jerks.1,2 They can result from voluntary breath-holding, such as cyanotic breath-holding of early childhood.1 Swimmers often hyperventilate before breath-holding to reduce the urge to breathe from hypercapnia. This may result in prolonged breath-holds with consequent hypoxaemia. Loss of consciousness may ensue without forewarning because the respiratory stimulus from hypoxaemia is weak and easily overridden.3 Vigorous exercise, such as underwater swimming, may exacerbate hypoxia by increasing oxygen consumption. These factors are likely to result in syncope occurring late in the dive, as in our two cases. Hyperventilation-induced hypocapnia is known to constrict cerebral vasculature and may contribute to syncope.2 In addition, the Valsalva manoeuvre can cause syncope during the early stages of a breath-hold dive,4 probably by reducing cerebral blood perfusion further as a result of decreased cardiac output from reduced thoracic venous return. This may be a cause of early syncope before hypoxia and hypercapnia have occurred, but the Valsalva effects may still be operative late in the dive. When Student 1 stood up at the end of his dive, the change in posture would have impaired venous return even more, and may have triggered the anoxic convulsions. Breath-hold practitioners are often skilled male swimmers who are not closely watched by lifeguards. Loss of consciousness underwater can lead to drowning. A report of 58 cases of syncope during underwater swimming and diving found that all victims were known to be good swimmers or divers and the victims were almost exclusively men (56 cases).5 Victims were often involved in a competition in which they wanted to “beat” someone else’s or their own underwater distance record. The number of fatalities in that particular medical case series was high (23 cases). Anecdotal observations suggest that underwater breath-holding is a relatively common practice in Australia. The practice is particularly dangerous if coupled with prior hyperventilation. This report provides further evidence that hyperventilating before breath-holding should be discouraged. Swimming pool authorities should be made aware of the potentially dangerous consequences, as should, arguably, children and adults undergoing basic swimming training. Lessons from practice Syncope can manifest as seizure-like activity. Hypercapnic respiratory drive is important in breath-hold diving and swimming. Hyperventilation before breath-hold diving reduces hypercapnic respiratory drive and can result in anoxic loss of consciousness. Hyperventilation is the main causative factor in the development of hypoxia and syncope in underwater breath-holding. Loss of consciousness underwater can lead to drowning — the danger of underwater breath-holding is an important public health and safety issue that warrants increased awareness among the general public.

Kishore R Kumar MB BS, FRACP · Karl Ng MB BS(Hons I), FRACP

Decisions regarding the use of triple therapy should take into account the balance between thromboembolism and bleeding risk in individual patients The combined use of warfarin and dual antiplatelet therapy (aspirin plus clopidogrel) — so-called triple therapy — is a challenging management problem in patients with a coronary stent who also have an indication for oral anticoagulation. One of the most common clinical scenarios is a patient with atrial fibrillation (AF) who undergoes percutaneous coronary intervention with stenting. Guidelines for antithrombotic therapy recommend that patients with AF who are at high risk of stroke (ie, prior history of stroke or more than one of: age ≥ 75 years, hypertension, diabetes, and congestive cardiac failure) receive warfarin;1 and guidelines for percutaneous coronary intervention management recommend dual antiplatelet therapy in all stent patients to prevent stent thrombosis.2 Both warfarin and clopidogrel increase the risk of bleeding in patients treated with aspirin, and combining all three drugs can be expected to further increase bleeding risk. However, the efficacy and safety of triple therapy have not been evaluated in randomised controlled trials. What is the evidence concerning the efficacy of anticoagulation or antiplatelet therapy in patients with AF who have recently received a coronary artery stent? In patients with AF who are at risk of stroke, warfarin compared with placebo or no treatment reduces the risk of stroke by about two-thirds, whereas aspirin reduces the risk by about one-fifth.3 Adding clopidogrel to aspirin improves the effectiveness of antiplatelet therapy for stroke prevention,4 but warfarin is substantially more effective than dual antiplatelet therapy.5 In patients with a recent coronary artery stent, dual antiplatelet therapy compared with the combination of aspirin and warfarin reduces death or myocardial infarction by half.6 Premature discontinuation of clopidogrel (less than 3 months of treatment for sirolimus-eluting stents; less than 6 months for paclitaxel-eluting stents) is the single most important risk factor for stent thrombosis.7 The efficacy and safety of triple therapy have been examined in multiple observational studies. Meta-analysis of 10 observational studies involving 1349 patients with AF who received triple therapy after stent insertion revealed a weighted mean incidence of major bleeding at 30 days of 2.2% (95% CI, 0.7%–3.7%).8 Increasing the duration of triple therapy to longer than 6 months doubles the risk of major bleeding compared with 1 month of treatment.9 The guidelines recommend at least 4 weeks of dual antiplatelet therapy for patients who receive a bare metal stent and at least 1 year for those who receive a drug-eluting stent.2 What is the optimum antithrombotic management of patients with AF who undergo coronary stent insertion? Decisions regarding the use of triple therapy should take into account the balance between thromboembolism and bleeding risk in individual patients. Dual antiplatelet therapy alone is likely to be adequate for stent patients with AF if they are at low or moderate risk of stroke (CHADS2 stroke risk score [congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; previous stroke or transient ischaemic attack, 2 points10], 0–1), or if they are at high risk of stroke (CHADS2 stroke risk score, > 1) and deemed to be at unacceptably high risk of bleeding with triple therapy. The most important risk factors for bleeding are older age (eg, > 75 years), severe renal dysfunction (eg, creatinine clearance < 30 mL/min), recent gastrointestinal bleeding (eg, within 6 months), previous stroke, and uncontrolled hypertension (eg, systolic blood pressure > 160 mmHg, diastolic blood pressure > 110 mmHg).11 All other patients with AF who are at high risk of stroke (CHADS2 stroke risk score, > 1) and have recently undergone coronary artery stenting should probably receive warfarin in addition to dual antiplatelet therapy (Box).8 Cardiologists and primary care physicians should communicate closely to optimise antithrombotic therapy and minimise the risk of bleeding in patients who may be candidates for triple therapy. Firstly, the duration of exposure to triple therapy should be limited where possible by selecting a bare metal stent, which requires a shorter duration of antiplatelet therapy than a drug-eluting stent.2 Secondly, aspirin should be used at the lowest proven effective dose of 50–100 mg/day to minimise the risk of gastrointestinal bleeding.12 Thirdly, in patients at high risk of gastrointestinal bleeding, consideration should be given to the use of acid-suppressive therapy, either with a histamine H2-receptor antagonist (eg, ranitidine) or a proton-pump inhibitor.13 Retrospective analyses of administrative databases have suggested that the concomitant use of a proton-pump inhibitor (particularly omeprazole) reduced the efficacy of clopidogrel,14,15 but subsequent analyses of data from randomised controlled trials indicated no loss of benefit of clopidogrel when the two were used in combination.16 If a proton-pump inhibitor is used, it may be reasonable to avoid the use of omeprazole. Finally, warfarin therapy should, ideally, be monitored by an expert anticoagulation clinic to optimise the quality of international normalised ratio (INR) control (target INR, 2–3).11 What are the unresolved issues? Our recommendations for the use of triple antithrombotic therapy in patients with AF and a stent are based on observational studies8 and extrapolations of evidence from randomised controlled trials of antithrombotic therapy for prevention of stent thrombosis and thromboembolism in patients with AF. Dedicated randomised studies are urgently needed to obtain more reliable estimates of the risks and benefits of triple antithrombotic therapy in patients with a coronary artery stent who have AF, as well as in stent patients with other indications for warfarin therapy, such as mechanical heart valves or recent venous thromboembolism. Treatment decision algorithm for patients with atrial fibrillation and a coronary artery stent8 * CHADS2 stroke risk score (congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; previous stroke or transient ischaemic attack, 2 points).10

Jeremy S Paikin MD · Shamir R Mehta MD, MSc, FRCPC · John W Eikelboom MB BS, MSc

Clinical recordA 24-year-old woman presented to hospital in May 2009 after two generalised seizures with focal motor onset involving the right arm and leg. She had a 2-month history of intermittent frontal headaches and twitching of the right hand that did not interfere with usual activities. Her family had noticed she had lost weight. The patient was originally from the Eastern Equatoria province in southern Sudan and spent 12 years in a Ugandan refugee camp before migrating to Australia in 2007 with her family. Her only significant past medical history was malaria. Her family were in good health. On admission, the patient was hypothermic (temperature, 35.7°C), with a Glasgow Coma Scale score of 6, and gaze deviation to the left. Initial investigations showed hypochromic, microcytic anaemia (haemoglobin concentration, 100 g/L, reference range [RR], 115–160 g/L; mean cell volume, 65 fL, RR, 78–101 fL; and mean cell haemoglobin, 20 pg/cell, RR, 25–35 pg/cell), hyponatraemia (132 mmol/L; RR, 135–147 mmol/L), and raised serum protein level (109 g/L; RR, 60–84 g/L). Results of computed axial tomography of the brain with contrast and chest x-ray were unremarkable. Cerebrospinal fluid (CSF) contained polymorphonuclear leukocytes (45 × 106/L), mononuclear cells (168 × 106/L), red blood cells (23 × 106/L), protein (0.88 g/L) and glucose (2.5 mmol/L). No organisms were seen on Gram stain. Persistent status epilepticus necessitated treatment with loading doses of phenytoin, sedation and intubation. Magnetic resonance imaging (MRI) of the brain showed extensive areas of uniform high signal intensity within the supratentorial white matter and mild meningeal enhancement (Box 1). Meningoencephalitis was diagnosed, and the patient was treated with ceftriaxone and aciclovir. Based on history, presentation and cerebrospinal fluid findings, she was also given isoniazid, rifampicin, ethambutol, pyrazinamide, pyridoxine and dexamethasone for suspected tuberculous meningoencephalitis. Multiple investigations for bacterial, viral and fungal pathogens, including serological tests for HIV, and polymerase chain reaction (PCR) tests and culture for Mycobacterium tuberculosis, gave negative results (Box 2). The patient was extubated on Day 4, and her condition improved, with no further seizures, although periods of fluctuating drowsiness and confusion were noted. Electroencephalography showed generalised slowing consistent with diffuse cerebral dysfunction. To clarify the diagnosis, lumbar puncture was repeated; CSF showed polymorphonuclear leukocytes, 0 × 106/L; mononuclear cells, 141 × 106/L; protein, 0.52 g/L; and glucose, 2.0 mmol/L; but was again Gram stain-negative. Investigations for autoimmune and malignant disease, as well as mitochondrial disorders and metabolic leukodystrophies gave negative results (Box 2). Cervical lymphadenopathy was identified in the posterior cervical triangle, and examination of a fine needle aspirate suggested reactive lymphadenitis. A subsequent biopsy showed relatively preserved nodal architecture with reactive follicles, and no evidence of granulomas or malignancy. PCR testing of the biopsy specimen for M. tuberculosis and culture gave negative results. In view of the apparent clinical response to treatment, tuberculous meningoencephalitis was considered the most likely diagnosis, despite the negative results on investigation and brain MRI. The patient was discharged on Day 36, with continuing treatment with the anticonvulsant levetiracetam, antituberculous therapy and dexamethasone (4 mg tapering by 1 mg weekly). The patient re-presented 2 weeks later with increasing confusion, somnolence, gait unsteadiness and worsening bilateral tremor, and was re-admitted. Repeat MRI of the brain with gadolinium contrast showed progression of the diffuse subcortical and deep white matter abnormalities observed on previous MRI, with extension into the midbrain and pons. Treatment was begun with methylprednisolone (4 mg daily), and antituberculous therapy was discontinued. A diagnosis of West African trypanosomiasis was considered, but peripheral blood and lymph node tissue were negative for trypanosomes; lumbar puncture was not performed because of concern about increased intracranial pressure. Because of a rapid deterioration in the patient’s condition and the continuing uncertainty over the diagnosis, a stereotactic brain biopsy was performed. Histological examination of the biopsy specimen showed meningoencephalitis with Mott (morula) cells (Box 3A), suggesting human African trypanosomiasis (HAT). Review of the previous CSF cytology specimens also revealed Mott cells (Box 3B), which had not been recognised initially. Indirect haemagglutination tests of serum for HAT-specific antibodies gave positive results, with a titre of 1:4096. Treatment with intravenous pentamidine (200 mg daily) was begun 2 months after the patient’s first presentation and was continued for 4 days pending the arrival of eflornithine provided by the World Health Organization. The patient regained consciousness after pentamidine treatment began, and her condition improved dramatically with a 14-day course of intravenous eflornithine (5 g four times daily). Corticosteroid therapy was tapered and ceased. She was discharged to a rehabilitation unit, able to walk independently and undertake basic activities of daily living, but requiring ongoing help with executive functioning. After discharge, she returned to her family and community life. She had a residual hand tremor but continued to show steady improvement in level of functioning, mentation and social interactions. At 3-month follow-up, she remained well, but repeat lumbar puncture revealed persisting CSF lymphocytosis. 1 Magnetic resonance image of the brain 17 days after presentation An axial T2-weighted magnetic resonance image at the level of the basal ganglia showed symmetrical high signal intensity in the white matter, particularly in the centrum semi-ovale (subcortical white matter) (arrowed). 2 Summary of investigations undertaken with negative results* Infectious diseases screen Viruses. Cytomegalovirus (IgM, IgG); Epstein–Barr virus (IgM, IgG, PCR), herpes simplex virus and human herpes virus 6 (PCR), adenovirus, influenza A and B viruses, parainfluenza virus, and respiratory syncytial virus (DIF), and hepatitis A, B and C and HIV (serology). Bacteria. Brucella abortus (serum agglutination titre), meningococcus (PCR), mycobacterium (PCR, culture), mycoplasma (PCR), syphilis (serology), streptococcal antigen, rapid screen for bacterial antigens, and blood, urine, cerebrospinal fluid, sputum and stool cultures. Parasites. Blood parasite screen (including malaria), cryptococcal antigen, schistosomiasis (IgG) and toxoplasma (IgM, IgG). Toxicology screen: Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, ethanol, methadone, opiates. Metabolic screen: Cerebrospinal fluid pyruvate, lysosomal enzymes and very long chain fatty acids. Immune screen: Anticardiolipin antibody, anti-double stranded DNA, antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antigen antibodies, anti-Purkinje cell antibody, antineuronal antibody, anti-neuromyelitis optica antibody, complement levels, cryoglobulins, lupus anticoagulant, ß2-glycoprotein, ß2-microglobulin, thyroglobulin antibody, thyroperoxidase antibody and oligoclonal bands. Oncology screen: a-Fetoprotein, tumour markers Ca 125 and Ca 19-9, flow cytometry for cell markers, and serum electrophoretogram/immunoelectrophoretogram. Other tests: Serum cortisol, ß-human choriogonadotropin, iron studies, thyroid function, vitamin D level and vitamin B12 and folate studies. PCR = polymerase chain reaction. DIF = direct immunofluorescence. * Tests are categorised for easy reference but were not necessarily performed in the order shown, rather on different occasions as clinically indicated. For example, investigations for toxoplasma and cryptococcus were performed shortly after the patient was first admitted, but those for schistosomiasis not until her second admission, almost concurrently with trypanosomiasis testing. 3 Mott cells in the patient’s brain and cerebrospinal fluid A. White matter from a brain biopsy specimen taken during the patient’s second admission showed perivascular inflammatory infiltrates composed of lymphocytes and plasma cells, including Mott (morula) cells (arrows). The cytoplasm of Mott cells contained brightly staining eosinophilic immunoglobulins (high-power magnification, haematoxylin and eosin stain). B. Review of the CSF specimens taken at presentation showed Mott (morula) cells with large Russell body inclusions (blue-staining globules), representing immunoglobulins (original magnification, × 400; Papanicalou stain). Human African trypanosomiasis (HAT or sleeping sickness) is a significant cause of morbidity and mortality in parts of Africa but is rarely seen in Australia. Lack of awareness of this disease among Australian physicians means it may be easily misdiagnosed, delaying timely treatment and resulting in inadvertent adverse outcomes. HAT is caused by the flagellated protozoan Trypanosoma brucei. Two subspecies cause human disease: T. brucei rhodesiense, which is found only in east Africa and causes an acute, fulminant illness lasting weeks to months (East African HAT); and T. brucei gambiense, which is found in western, central and parts of east Africa, and causes an indolent, chronic infection that may last many months to years (West African HAT).1 The fulminant course of T. b. rhodesiense illness means it is the form more frequently diagnosed outside Africa, in returned travellers. Infection occurs through injection of saliva containing trypanosomes from the bite of the tsetse fly, and a local skin reaction or chancre may follow. The infection follows two stages. The early (haemolymphatic) stage results from proliferation of parasites in the blood and lymph and presents with headache, fever, malaise, anorexia, anaemia and lymphadenopathy. The late (meningoencephalitis) stage occurs when trypanosomes invade the central nervous system (CNS), causing a range of neurological manifestations including psychiatric changes. Inversion of the sleep–wake cycle is common, resulting in daytime somnolence and nocturnal insomnia. Without treatment, CNS disease eventually results in coma and death. Our patient probably became infected in Uganda, where both subspecies of trypanosome are known to circulate.2 In retrospect, the initial improvement in her condition was most likely a response to corticosteroid treatment, and the subsequent regression coincided with a reduction in the corticosteroid dose. Cervical lymphadenopathy in the posterior triangle was noted at initial presentation but was recognised only during her second admission as a classic feature of T. b. gambiense disease (the Winterbottom sign3). Detection of trypanosomes in the CSF, blood or lymph tissue remains the diagnostic “gold standard”. However, methods of parasite detection vary in sensitivity, and the cyclical nature of parasitaemia means parasites are seldom detected in blood, especially in T. b. gambiense disease,4 although detected more often in CSF.5 We were not able to demonstrate trypanosomes in whole blood, lymph node tissue or CSF. In the absence of demonstrable parasites, and where there is clinical suspicion, serological testing is crucial in diagnosis of T. b. gambiense disease. The sensitivity and specificity of currently available serological tests vary from 71% to 100% and 95% to 99%, respectively. In our patient, the high antibody titre supported a diagnosis of active trypanosomal infestation, although titres are known to remain high several years after treatment.6 MRI findings in trypanosomiasis are non-specific, ranging from meningeal enhancement in earlier CNS disease to bilateral confluent hyperintense T2 signals in the subcortical white matter in late disease, as seen in our patient.7 Although not diagnostic, MRI is a useful adjunct in supporting the diagnosis as relatively few conditions cause this distinct MRI appearance, including acute disseminated encephalomyelitis, cerebral gliomatosis, the leukodystrophies and lymphoma, all of which were considered in our patient. Non-specific CNS findings are meningoencephalitis, comprising leptomeningitis and encephalitis with diffuse perivascular white matter infiltration, microglial nodules and reactive astrocytosis.8 The presence of Mott cells in the CNS and CSF is characteristic of HAT, but these cells are easily overlooked.9 They are morula forms of plasma cells containing prominent eosinophilic cytoplasmic inclusions (Russell bodies) that stain positively with periodic acid-Schiff stain and are composed of immunoglobulin M. Although Mott cells can be found in myeloproliferative disorders, they are considered virtually pathognomonic of HAT in patients with appropriate clinical findings and exposure history.10 Early stage T. b. gambiense disease is treated with pentamidine. Eflornithine, an ornithine decarboxylase inhibitor that interferes with cell division, is the recommended first-line treatment for CNS disease.11 Side effects include seizures, gastrointestinal upset and reversible myelosuppression. As it requires intravenous infusions four times daily over 2 weeks, it is not ideal in resource-constrained settings; recent studies suggest a combination of eflornithine and oral nifurtimox to be as effective but superior in ease of administration and duration of treatment (requiring eflornithine to be given only twice daily for 7 days).12 From May 2009, the WHO has included combination therapy in its essential list of medicines for treatment of West African trypanosomiasis, but was unable to provide nifurtimox for our patient, as its use was approved at that time only for Chagas disease. To our knowledge, our patient represents the fourth case of HAT identified in Australia. A case of meningoencephalitis thought to be due to T. b. gambiense was diagnosed in Perth in 2008 in an immigrant from Sudan and is also reported in this issue of the Journal13 (page 417). A case due to T. b. rhodesiense was diagnosed at our institution in 1998 in a returned traveller with acute illness after visiting a Tanzanian game park.14 The first case in Australia is said to have occurred after World War II.15 Our patient illustrates the need for clinicians to be aware of HAT as a potential cause of meningoencephalitis, particularly in African immigrants, for months or years after they move to Australia.16 Had this possibility been recognised at presentation and specifically investigated, prompt treatment could have been given, and brain biopsy avoided. Lessons from practice Human African trypanosomiasis (HAT) or sleeping sickness is rarely encountered in Australia; physicians should be aware of its possibility in individuals who present with meningoencephalitis and have lived in or visited endemic areas. Definitive diagnosis relies on parasite detection; in its absence, serological testing is the next most appropriate investigation, particularly for disease cased by Trypanosoma brucei gambiense. Corticosteroid therapy can mask symptoms of disease and falsely suggest an improvement, confounding the diagnosis. We recommend that individuals from endemic areas with clinically suspected HAT be screened serologically. This would prevent a potentially fatal delay in diagnosis and permit further monitoring and investigation to confirm and treat disease earlier.

Adam P Liu MB BS, BMedSc(Hons) · Shaun Chou MB BS, BSc(Med) · Lavier Gomes BDS, BSc(Hons), FRANZCR · Thomas Ng FRCPA, FRCPATH · Elizabeth L Salisbury FRCPA, FIAC, FFOP · Grant L Walker MB BS(Hons), FRACP · Donald R Packham FRACP

A 19-year-old Sudanese woman, who had lived for about a decade in Ugandan refugee camps, was referred for investigation of a 12-month history of a generalised rash. Two months later, her condition had deteriorated to include cachexia and drowsiness. Despite initial negative findings on investigation, human African trypanosomiasis (HAT) was suspected, and parasites were found in a double-centrifuged sample of cerebrospinal fluid. Eflornithine, the appropriate drug for treatment of late-stage disease, was obtained through the World Health Organization. This case highlights the diagnostic and therapeutic difficulties in managing late-stage HAT in a non-endemic country. Clinical recordIn January 2008, a 19-year-old Sudanese woman was referred from the community to a tertiary hospital for investigation of a 12-month history of generalised pruritus. There were no obvious precipitants or triggers for the itch. She was born in southern Sudan, but had lived in refugee camps in north-western Uganda for about a decade before migrating to Australia in November 2006. Her past medical history was non-contributory. Initial examination showed generalised hyperpigmented papules and nodules with excoriations. Prurigo was diagnosed, and treatment with topical corticosteroids was trialled. By March 2008, her condition had deteriorated, and she experienced lethargy, apathy, fevers, night sweats, weight loss, reduced rousability, abulia (impairment or loss of willpower) and seizures. The pruritus was pervasive and the scratching automatic. A past family history of human African trypanosomiasis (HAT) in her mother, which was diagnosed and treated in Uganda, was elicited. On examination, she had cachexia, and was drowsy, but rousable, and oriented to person, but not place or time. She had generalised itch with hyperpigmented, lichenified papules and excoriated nodules (Figure 1). Neurological examination showed symmetrical brisk reflexes, bilateral upper-limb cogwheeling, and myoclonic jerks involving her limbs, mouth and periocular muscles. She had palpable posterior cervical lymph nodes of less than 1 cm in diameter. Late-stage HAT was suspected, and she was admitted to hospital for further investigation. Differential diagnoses included other infective encephalitides (tuberculous and viral), vascular events and malignancies (lymphoma). Investigations showed that the patient had microcytic anaemia (haemoglobin concentration, 96 g/L; reference range [RR], 115–145 g/L), which was attributed to a known α-thalassemia trait: her renal function and hepatic function were normal. Her erythrocyte sedimentation rate was 42 mm/h (RR, < 20 mm/h). Elevated concentrations of total serum protein (104 g/L; RR, 60–80 g/L), gammaglobulin (32 g/L; RR, 8–16 g/L), IgG (24.3 g/L; RR, 5.8–13.7 g/L) and IgM (7.8 g/L; RR, 0.3–1.7 g/L) were detected. A skin biopsy suggested lichen simplex chronicus. Initial peripheral blood smears, lymph node and bone marrow aspirates all tested negative for parasites. Examination of the cerebrospinal fluid (CSF) revealed a mononuclear pleocytosis of 100 × 106 cells/L (RR, < 5 × 106 cells/L), an elevated protein level (0.9 g/L; RR, 0.15–0.45 g/L), markedly elevated level of IgM (0.36 g/L; RR, undetectable) and a low level of glucose (2.1 mmol/L; RR, 2.4–4.6 mmol/L); micro-organisms were not seen on examination of the centrifuged deposit. Gadolinium-enhanced magnetic resonance imaging (MRI) showed bilateral, symmetrical, widespread high-signal white matter change on T2-weighted imaging (Figure 2). Simultaneous T2-weighted images demonstrated high signal changes in the splenium, the brainstem and the cerebellar white matter (images not shown), and post-gadolinium images showed minimal leptomeningeal enhancement (images not shown). An electroencephalogram (EEG) showed diffuse delta-wave slowing consistent with a metabolic encephalopathy, with no evidence of ictal activity. Despite initial negative results on CSF testing, HAT was suspected on clinical grounds. Thus, repeat large-volume CSF examination was performed. Direct examination of CSF was again negative, but double-centrifuged CSF microscopy showed trypanomastigotes (Figure 3), confirming the diagnosis of late-stage HAT. Both subspecies of Trypanosoma brucei can be acquired in Uganda.1 We considered Trypanosoma brucei gambiense infection to be more likely in this patient as it is hyper-endemic in north-western Uganda and because of the subacute clinical presentation. However, as Trypanosoma brucei rhodesiense infection remained plausible, given the patient’s past travel to southern Uganda, subspecies testing was indicated. Lacking an Australian medical reference laboratory for this, we referred specimens to the Institute of Tropical Medicine (Antwerp, Belgium) for serological testing, and to a local reference laboratory for nucleic acid amplification testing.2 While awaiting results, the patient became uncommunicative, bed-bound and increasingly cachectic, making empiric trypanocidal therapy imperative. Treatment for late stage T. b. gambiense infection was commenced 19 days after admission, with intravenous eflornithine (obtained through the World Health Organization [WHO]) at a dose of 100 mg/kg every 6 hours for 2 weeks. This was tolerated without significant toxicity. At discharge on Day 39, the patient was orientated, communicative and walking independently despite persistence of slight limb hypertonia. Subsequently, subspecies serology showed elevated titres to T. b. gambiense on a serum immunofluorescent antibody test (IFAT; titre, 1:1600; RR, negative) and a card agglutination antibody test (CAAT; titre, 1:32; RR, negative). The CSF IFAT titre to T. b. gambiense was 1: 8 (RR, negative). The local nucleic acid amplification test suggested T. b. rhodesiense (data not shown), but this was felt to be clinically discordant. Three months after discharge, the patient was lucid, conversant in both English and her native tongue, neurologically intact and free from itch. Examination of her CSF showed improving pleocytosis with normal biochemical findings. MRI verified improvement; the post-contrast enhancement had resolved, but mild, diffuse cerebral atrophy was evident. She has resumed her studies and normal social activities and was relapse free at 16-month follow-up. DiscussionHuman African trypanosomiasis or sleeping sickness is caused by two subspecies of the haemoflagellate parasite Trypanosoma brucei — T. b. rhodesiense (east-African HAT) and T. b. gambiense (west-African HAT).1,3 The parasite is transmitted by the bite of tsetse flies (Glossina spp.).1 HAT is endemic only in sub-Saharan Africa, where the WHO estimates that between 300 000–500 000 people are currently infected, with 100 000 deaths directly attributed to this disease annually.3 Uganda is currently the only country where infection with both subspecies occurs. While the two foci of trypanosomiasis within Uganda appear separate, as a result of civil unrest, population displacement and the northward spread of wild and domestic animals from central and south-east Uganda, it is likely that these foci will soon converge.4-6 HAT is rarely diagnosed outside Africa. When T. b. gambiense infection is diagnosed, it is usually in the late (secondary) stage.1,7 To our knowledge, this is the first case of T. b. gambiense infection diagnosed in Australia. HAT is a biphasic disease. Early-stage disease (Stage I) denotes the post-inoculation period followed by haemo-lymphatic spread.1 An inflammatory nodule or ulcer (chancriform) may be seen at the site of inoculation, more commonly with T. b. rhodesiense infection.1 Lymphatic spread results in lymphadenopathy, with posterior cervical lymphadenopathy (Winterbottom’s sign) typical in T. b. gambiense disease.1,3 Haematogenous spread produces fluctuating fevers, hepatosplenomegaly, serositis and myocarditis, which occur in both forms of the infection, but are more common in T. b. rhodesiense disease.1 In late-stage disease (Stage II), the parasite passes through the blood–brain barrier into the central nervous system, resulting in meningoencephalitis, which is invariably fatal if not treated.1,3 Headache, ataxia, itching, speech disturbance, behavioural change, extrapyramidal signs and mental state changes may manifest.1,3 Pineal and thalamic invasion leads to hypersomnolence and circadian rhythm disruption.3 The natural history of the diseases caused by the two subspecies varies significantly; T. b. gambiense infection is insidious (over months to years), whereas T. b. rhodesiense infection usually progresses over days to weeks.1 Dermatological manifestations of HAT are non-specific. Pruritus is a pervasive symptom, present in over 50% of cases, and is a feature of disease chronicity.8 Pruritus generally correlates with greater CSF pleocytosis.8 Parasternal and generalised pruritus are common, as is peripheral oedema. Transient urticarial and macular eruptions have also been described.1,9 In very chronic disease (of more than 24 months’ duration), pruritus may decrease, heralding a pre-terminal phase of illness.8 Definitive diagnosis of HAT requires direct visualisation of the parasites in blood, CSF or tissue. Detection of trypanosomes in the CSF confirms late-stage disease. False negative results are common because of the low number of parasites in T. b. gambiense infection.1 As in the case we present here, concentration techniques such as double-centrifugation of CSF increase the sensitivity of microscopy.10 Non-diagnostic CSF changes include: lymphocyte counts of > 5/μL, increased CSF protein and IgM concentrations, and morula (Mott) cells.9,11 Identifying the subspecies of trypanosomes is difficult because both subspecies are morphologically identical. The serological tests CAAT and IFAT are available for the detection of T. b. gambiense antibodies, and this is useful in screening high-prevalence populations.9 The use of nucleic acid tests for the subspeciation of T. b. rhodesiense and T. b. gambiense is an emerging technique, and has been used successfully in the research setting.5,6,9 However, these assays are not widely available.9 Obtaining a detailed travel history from patients and recording the timing of symptoms and signs over the course of the illness remain important for differentiating the two forms of the disease. Treatment of HAT depends on the subspecies of infecting trypanosome and disease stage. Patients with early-stage disease should have CSF examination to exclude subclinical neurological involvement.9 In Australia, treatment is challenging because we have limited access to targeted therapies for HAT. The necessary drugs are accessible through the WHO. Treatments for early-stage HAT infections are parenteral pentamidine for T. b. gambiense disease and suramin for T. b. rhodesiense disease.1,6 For late-stage HAT, melarsoprol was formerly the treatment of choice.1 However, 3%–10% of patients treated with melarsoprol develop encephalopathy, which is fatal in 10%–70% of cases. Survivors of encephalopathy frequently have residual brain damage.12,13 Eflornithine is equally efficacious and less toxic than melarsoprol12,13 for late-stage T. b. gambiense infection, with lower treatment-related mortality (about 0.8%).13 Adverse effects of eflornithine include seizures, gastrointestinal upset and neutropenia, but treatment interruption is generally not required.1 Recently, one week of combination therapy with nifurtimox and eflornithine was shown to be equally effective, less toxic and easier to administer than eflornithine monotherapy for late-stage T. b. gambiense infection,14 and is now considered the treatment of choice for this infection.15 Recommended follow-up after treatment for late-stage HAT includes 3–6-monthly CSF examinations for 2 years.4 This case highlights the diagnostic and therapeutic difficulties in managing late-stage HAT in a non-endemic country. Clinicians need to be aware of infections that are non-endemic to Australia that can occur in recently arrived travellers and migrants. Appropriate treatment of HAT is life-saving and associated with good clinical outcomes. Figure 1 The patient’s rash on presentation in March 2008, showing hyperpigmented, lichenified papules and nodules with excoriation involving the trunk. Figure 2 Axial T2-weighted magnetic resonance image showing high signal in both basal ganglia (white arrow) and symmetrical high signal in the white matter, including the internal and external capsules (black arrows). Figure 3 Double centrifuged sample of the patient’s cerebrospinal fluid shown on direct microscopy showing a trypanomastigote typical of Trypanosoma brucei, the pathogen of human African trypanosomiasis (Giemsa stain; original magnification, × 800).

Paul Cherian MB BS · Ralph K Junckerstorff MB BS · David Rosen MB BS, FRACP, PhD · Prasad Kumarasinghe MD, FACD · Alan Morling BSc · Philip Tuch MB ChB, FRACP · Sonja Raven MB ChB, FRANCR · Ronan J Murray MB BS, FRACP, FRCPA · Christopher H Heath MB BS, FRACP, FRCPA

We use vertebroplasty for patients with the most severe pain caused by osteoporotic vertebral fractures less than 6 weeks old, and have observed dramatic pain relief in this acute setting. A recent editorial in the Journal, written by the authors of two recent vertebroplasty trials, suggested that vertebroplasty is not an effective therapy for acute osteoporotic vertebral fractures. The trials described in the editorial sampled a very different patient cohort to the one that we treat with vertebroplasty. Our clinical experience and most of the published literature relating to the benefits of vertebroplasty are in striking contrast to the opinions presented in that editorial.

William A Clark MB BS, FRANZCR · Terrence H Diamond MB BS, MB BCh, FRACP · H Patrick McNeil MB BS, FRACP, PhD · Peter N Gonski MB BS, BMedSci, FRACP · Glen P Schlaphoff MB Bch, FCRad(SA), FRANZCR · John C Rouse MB ChB, FRANZCR

Assessment of medical fitness to drive can be a sensitive and difficult task, particularly when it involves a condition such as epilepsy, where impairment is intermittent. The patient, their doctor and the driver licensing authority (DLA) each have responsibilities, both to the patient and to the wider community of road users. DLAs in Australia have shifted most of the responsibility for determining fitness to drive to the treating doctor. This creates a conflict of interest and may lead to unsafe decisions, damage to the doctor–patient relationship, interference with medical management and legal vulnerability for the doctor. Australian neurologists have argued for a system in which the treating doctor provides objective information about the patient’s condition, rather than an opinion on fitness to drive, and the DLA uses that information to determine fitness. This must be supported by an expert review process. Although drivers are legally obliged to notify the DLA when they become unfit, most people are unaware of this law. However, passing this responsibility to doctors in the form of mandatory reporting is counterproductive to road safety.

Ernest R Somerville MB BS, FRACP, FRCP · Andrew B Black BMedSc, MB BS, FRACP · John W Dunne MB BS, FRACP

To the Editor: We present this case to highlight the differential diagnosis of afebrile seizures in patients from many asset-poor nations. A 3-year-old Congolese girl presented with sustained loss of consciousness after a prolonged generalised seizure. She had migrated, with her family, 12 months previously after a long period in a Zambian refugee camp. She was intubated briefly and given intravenous benzodiazepines. She made an uneventful recovery; she was discharged from hospital after 2 days. This was her first seizure and there was no history of fever, trauma or poisoning. The parents declined long-term anticonvulsants. Apart from mild malaria, she had been previously well and showed normal development. HIV serology and results of blood films for malarial parasites were negative; other blood tests, including an eosinophil count, were normal. Cerebral magnetic resonance imaging (MRI), performed because the diagnosis was unclear and the patient had had a prolonged seizure, revealed a single 8 mm cyst, with an enhancing wall and surrounding oedema, in the left frontal lobe. The cyst contained a scolex, pathognomonic of neurocysticercosis (Box). There were multiple foci throughout the brain, indicating active and resolving cysts. Serology results for Taenia solium were negative at presentation and 3 months later. The child was treated with 8 days of albendazole and 3 days of dexamethasone. Repeat MRI 2 months after presentation showed significant improvement, with a residual 3 mm calcified focus. The child has remained seizure-free for 18 months. Neurocysticercosis is caused by larvae of the pork tapeworm T. solium, which may encyst in the brain, eye or spinal cord, after ingestion of ova-contaminated food or water.1 In contrast, ingestion of encysted larvae (cysticerci) in undercooked meat results in intestinal infection with the adult tapeworm.1 Neurocysticercosis is common in many asset-poor countries, including those in Asia and sub-Saharan Africa from where many people in humanitarian refugee programs originate.2 In areas where it is endemic, T. solium is a leading cause of epilepsy in children and adults.3 The diagnosis of neurocysticercosis is difficult and the diagnostic differential is broad. Cerebral imaging showing typical lesions containing a scolex is diagnostic. T. solium serology is insensitive, especially in children with few cysts. Anticercal antibodies or cysticercal antigens in the cerebral spinal fluid are helpful, but these investigations are not widely available (they are available from the Centers for Disease Control and Prevention, Atlanta, United States). Treatment with anthelmintics is controversial; parasites may die spontaneously and treatment may cause local inflammation (reduced by steroids), which potentially exacerbates seizures or causes local tissue damage.4 Ocular cysticercosis should be excluded before anthelmintic treatment as the resultant inflammation may compromise sight; surgical excision should be considered if ocular cysticercosis is present.4 Empirical anthelmintics, often given before departure or following resettlement to people at risk, may potentially precipitate seizures.5 We treated this child with albendazole as there were multiple lesions likely to contain live parasites, and because anticonvulsants were declined. This case highlights that neurocysticercosis is a possible treatable cause of afebrile seizures in patients migrating from, or with a history of visiting, endemic areas, including resettled refugees. Clinicians in affluent countries are often unfamiliar with the disease, yet are managing increasing numbers of people at risk. Misdiagnosis is of particular concern because brain imaging is not routinely performed in children presenting with their first afebrile seizure. Magnetic resonance image of brain of 3-year-old girl showing cysticercus Encysted scolex of Taenia solium, surrounded by enhancing wall and significant oedema, in left frontal cerebral lobe.

Juliette M Lucey · James McCarthy · David P Burgner

A 29-year-old woman presented with a 19-day history of blurred vision and intolerance to bright light after a presumed viral illness (a sore throat and fever resolved 4 days before the onset of other symptoms). At presentation, she reported a dry mouth, mild constipation, abdominal bloating and hesitancy of micturition. Results of a clinical examination were normal apart from dilated, slightly asymmetric pupils (Figure, A), non-reactive to light and accommodation. The patient’s condition gradually improved over the subsequent 6 months. Tests of heart rate and blood pressure showed normal cardiovascular autonomic function. Thermoregulatory sweat testing was undertaken by applying a starch and iodine paste to the skin; this changes colour to purple in the presence of sweat. Results showed an absence of sweating in the patient’s arms and legs (Figure, B and C) compared with an age-matched control volunteer (Figure, D and E). These findings support a diagnosis of a subacute cholinergic neuropathy causing parasympathetic failure, which, in the clinical context, is likely to represent an uncommon variant of Guillain–Barré syndrome.1 Figure

Robert D Henderson · Jeyaraj D Pandian · Kaye M Dalton · John M Bradfield

Parkinson disease (PD) is a multisystem neurodegenerative disorder that affects about 1% of the population over the age of 55 years and has mean age of onset of about 60 years. The Braak hypothesis proposes that the earliest pathological evidence of PD is found in the enteric nervous system, medulla and olfactory bulb, and only subsequently progresses (over years) to the substantia nigra and cortex. Non-motor symptoms, such as constipation, hyposmia and sleep disorders, may precede typical motor features of PD by several years. No treatment has been convincingly shown to slow PD progression (ie, a neuroprotective drug remains elusive). Symptomatic benefit from dopaminergic therapy is usually maintained throughout the course of the disease. The decision as to whether to commence treatment with either levodopa or a dopamine agonist needs to be individually tailored, but long-term outcomes appear to be equivalent. Advanced PD is complicated by the loss of non-dopaminergic neurones, resulting in symptoms that are largely unresponsive to dopaminergic therapy. Treatment with apomorphine, Duodopa or deep-brain stimulation surgery may be beneficial for selected patients with advanced PD. Non-motor symptoms, such as mood disorders, cognitive impairment, autonomic dysfunction and sleep disorders, are responsible for significant morbidity. Management often requires a multidisciplinary approach.

Michael W Hayes MB BS, MSc, FRACP · Victor S Fung MB BS(Hons), PhD, FRACP · Thomas E Kimber MB BS(Hons), PhD, FRACP · John D O’Sullivan MB BS, MD, FRACP

Objective: To assess the feasibility of using a rapid access neurology clinic to assess and manage patients considered safe to discharge home from the emergency department (ED), yet requiring specialist neurology review.Design, setting and participants: The ED Rapid Access Neurology (ED RAN) clinic was trialled at Royal Prince Alfred Hospital, a major tertiary teaching hospital in Sydney, over a 12-month period (23 March 2008 – 22 March 2009). The service uses a new clinic and referral system to offer suitable patients specialist neurology outpatient review within 5 working days of their discharge from the ED.Main outcome measures: Quality of patient care, patient satisfaction, estimated service impact on the hospital system.Results: During the 12-month trial period, 311 patients were referred to the ED RAN clinic. Of these referrals, 222 patients (71%) attended the clinic, where a number of serious neurological diagnoses were made, and eight patients required admission after specialist review. All patients attending the clinic found the visit helpful. Consultant ED physicians believed that the clinic prevented 83 unnecessary admissions and 188 out-of-hours neurology registrar consultations, and saved an estimated 809 hours of ED bed time.Conclusions: The ED RAN clinic provides a viable model for improving the quality of patient care, with high levels of patient satisfaction. This model of care may allow significant cost savings and help to relieve the major access block in Australian EDs.

Rebekah M Ahmed MB BS(Hons) · Timothy Green MB BS(Hons), FACEM · Gabor M Halmagyi MD, FRACP · Simon J G Lewis MB BCh, FRACP, MD

The yipping tiger and other tales from the neuropsychiatric clinic. Perminder Sachdev. Sydney: UNSW Press, 2009 (x + 289 pp). ISBN 978 1742 230849. With the opening phrase “The golf swing is an act of grace and supreme poise,” I felt I was about to read another Harvey Pennick (teaching golf pro) publication. Rather, this is a compilation of case studies the author gathered over 20 years. Perminder Sachdev, Professor of Neuropsychiatry at the University of New South Wales and Director of the Neuropsychiatric Institute at Sydney’s Prince of Wales Hospital, considers 10 disorders and their underlying brain mechanisms. “The yipping tiger” examines golfer’s cramps, “Shaking hands with Dr Strangelove”, the alien hand syndrome, and “Swearing like a Spanish sailor”, coprolalia in Tourette syndrome. Other chapters cover brain enhancement, anorexia nervosa, frontal lobe dysfunction, major depression, obsessive compulsive disorder, phantom limb and mild cognitive impairment. The inclusion of depression and obsessive compulsive disorder as topics was a little surprising — knowing the immense range of material referred to neuropsychiatrists I was expecting to find other topics (such as Lewy body dementia, Huntington disease, stroke and depression, epilepsy and psychosis and demyelinating disease) selected for discussion of the overlapping neurological and psychological/psychiatric aspects of brain disease. While well referenced with good notes accompanying each chapter, Sachdev might have shortened each chapter by a few pages in order to include other examples of neuropsychiatric disorders. Books of this format demand the difficult balancing of clinical vignettes with more detailed discussion of underlying systems and constructs (as demonstrated by Oliver Sacks and Harold Klawans). Some of Sachdev’s detours and digressions are distracting to the reader, particularly if this book is intended for the lay audience rather than the medical fraternity. Yet this book is interesting and informative, with the audience lying midway between the interested layperson and the professional. It is very reasonably priced.

John H Lloyd

Australian autism handbook. The essential resource guide for autism spectrum disorders. Benison O’Reilly, Seana Smith. Sydney: Jane Curry Publishing, 2008 (xv + 399 pp). ISBN 978 0 9804758 1 4. Autism is not as rare as we once thought. Recent Australian research indicates autism occurs in one child in 160, and half a million Australians are living in a family that has a child or adult with autism. The annual cost of autism spectrum disorders (ASDs) to the community is estimated at between $4.5 and $7 billion. It is an expensive disability for both the government and for families. For example, the cost of intensive applied behavioural analysis for a family is around $40 000 per annum, with a program in the preschool years lasting 2 to 4 years. While most of the literature on autism, especially for parents, is published in the United States or the United Kingdom and refers to American or British services, we now at last have an Australian guidebook for families. The authors are parents of children with ASD, and the book is primarily written for families of a newly diagnosed child. However, the Australian autism handbook will be invaluable for clinicians as a resource when talking to families and providing advice on services and resources. The text often refers to Australian research, and we need to recognise the degree and depth of Australian expertise and research on ASD. This book provides current information on services in each state or territory, the latest Medicare initiatives, and research areas of Australian specialists and academics. Clinicians will be interested in the perspectives and experiences of families (such as the susceptibility of parents of a child with autism to develop signs of depression), and to learn more about the latest treatments that parents have heard about and may request for their son or daughter with autism.

Tony Attwood

Younger onset dementia. A practical guide. John R Hodges, Carol Gregory, Colleen McKinnon, et al. Sydney: Alzheimer’s Australia, 2009 (38 pp). Alzheimer’s Australia has been producing the Quality Dementia Care series of useful fact sheets and booklets for people with dementia and their carers but, until recently, had neglected the area of dementia with early onset. This booklet, together with a few others released during the past couple of years, helps rectify the situation. John Hodges, one of the world’s leading authorities on younger onset dementia, gathered a competent group of collaborators to produce this document, which can be freely downloaded from: http://www.alzheimers.org.au/content.cfm?infopageid=5484. The booklet is divided into five sections covering key features of the clinical presentation of younger people with dementia, practical approaches to manage cognitive deficits and behavioural disturbances, issues that are of relevance to carers, preparing for the future (including legal issues), and further resources. The document has a smart layout that will make it easy for readers to find the information they are after; and although information has been maintained at a basic level (basic, but up to date), carers will certainly appreciate the helpful hints on issues related to management, services and how to access other relevant resources. If you work with people with dementia, I would encourage you to keep a few copies of this booklet at hand in your office. I certainly will.

Osvaldo P Almeida