Neurology

Objective: To understand the current organisation of services for people with transient ischaemic attack (TIA) and the processes of assessment and management across Australian hospitals.Design and setting: Cross-sectional survey in 2008 of 134 Australian hospitals, mostly urban centres that treat large numbers of stroke patients.Main outcome measures: Survey questions covered assessment, early management and follow-up practices, as well as organisation of services for TIA.Results: Seventy-four hospitals (55%) responded: 47 (64%) reported access to a stroke unit, and 19 (26%) to a specialist clinic for TIA. Initial assessment included blood tests, electrocardiogram and brain computed tomography at most sites (92%–94%), and carotid imaging at more than half (65%), but magnetic resonance imaging at only 3% of sites. A tool to stratify the risk of subsequent stroke was used at 38 sites (51%), more commonly in hospitals with a stroke unit than in those without such a unit (64% v 30%; P = 0.005). Treatment was initiated at the initial assessment at 42 sites (58%), more commonly at stroke unit than non-stroke unit sites (68% v 37%; P = 0.007). Formalised policies for management of TIA patients were used at 38 sites (54%), with clear differences between sites with a stroke unit and those without (70% v 25%; P < 0.001).Conclusion: Access to rapid assessment and management services for TIA varies considerably between Australian hospitals. The presence of organised stroke care at a hospital leads to improved processes of care for patients presenting with TIA.

Christopher J Price BSc, BSW · David J Blacker MB BS, FRACP · Rohan S Grimley MB BS, BScMed, FRACP · Helen M Dewey PhD, FRACP, FAFRM(RACP) · Richard P Gerraty MD, FRACP · Simon A Koblar BM BS, FRACP, PhD · Sonia M Denisenko BPhys, MPH · Catherine E Storey MB BS, MSc, FRACP · Christopher F Bladin MB BS, MD, FRACP · Kelvin M Hill BApplSci(Physiotherapy), GradDipBusComm

Objective: To identify and quantify current deficiencies in primary and secondary stroke prevention, as well as potential gains from optimal employment of thrombolysis.Design, participants and setting: Observational study of 259 consecutive patients admitted to a tertiary hospital stroke unit from 24 January 2006 to 10 January 2007, with retrospective assessment of prestroke risk factors and therapies to determine stroke preventability, based on relative risk reductions from published meta-analyses of preventive therapies.Main outcome measures: Numbers of strokes preventable by optimal risk factor modification and numbers of strokes with preventable disability through optimal thrombolysis; characteristics of patients with preventable strokes; contributions of each risk factor to stroke preventability.Results: 183 patients had a disabling or fatal stroke; 135 patients had at least one suboptimally managed risk factor. On the basis of prespecified stroke preventability weightings, 70 strokes were preventable. The younger the patient, the more likely that the stroke was potentially preventable (relative risk [RR] for age < 60: ≥ 80 years, 3.10; 95% CI, 1.96–4.92). Smoking, inadequate control of hypertension and suboptimal anticoagulation accounted for nearly 90% of preventable strokes. Patients with target systolic blood pressures of 130 mmHg or lower were more likely to have inadequately controlled hypertension (RR, 4.27; 95% CI, 2.58–7.05). By comparison, disability could have been prevented in four strokes through optimal thrombolysis.Conclusions: A significant proportion of stroke remains preventable, especially in younger patients, by optimal modification of risk factors, particularly smoking, blood pressure and anticoagulation. Only a small proportion of patients will benefit from best-practice thrombolysis.

Timothy J Kleinig MB BS(Hons), FRACP, BA · Thomas E Kimber MB BS, PhD, FRACP · Philip D Thompson MB BS, PhD, FRACP

To the Editor: We report a case of proximal myopathy attributed to varenicline therapy to assist with smoking cessation. A previously fit and well 27-year-old man presented to the emergency department with a 1-week history of lethargy, myalgia and limb weakness. The pain and progressive weakness incapacitated the patient to the extent of him requiring assistance to move from bed to chair. The patient’s only medication on admission was varenicline (Champix [Pfizer]), which he had started taking about 6 weeks previously to assist with smoking cessation. He denied drinking excessive alcohol or using illicit drugs. There were no symptoms of recent infection. On examination, a proximal myopathy with weakness of grade 2/5 for both upper and lower limbs was noted. The patient’s muscles were mildly tender, reflexes were preserved, and both cranial nerves and sensory examinations were normal. Respiratory function was not impaired and there was no evidence of fatigability. The clinical impression was of proximal myopathy of uncertain cause. An adverse drug reaction to varenicline was considered and the medication ceased. Appropriate blood investigations and clinical neurophysiological studies were requested. A full blood count, thyroid function tests and autoimmune screen were all normal, as were levels of electrolytes, calcium, phosphate and magnesium. The erythrocyte sedimentation rate was 15 mm/h (reference range [RR], 1–15 mm/h), the C-reactive protein level was 20 mg/L (RR, < 5 mg/L), and the creatine kinase level was 1100 U/L (RR, 30–190 U/L). Cushing disease was excluded. Two days after cessation of varenicline, the muscle weakness had improved and the creatine kinase level had normalised. The patient declined neurophysiological studies and was discharged home. On review 1 week later, he had made a full recovery. Varenicline is a recently marketed smoking cessation drug treatment that has been shown to be more effective than placebo and bupropion treatment.1 Varenicline acts as a partial agonist at nicotinic acetylcholine receptors in the brain.2 The agonist activity at these receptor sites reduces the symptoms of nicotine withdrawal and craving, while the antagonist activity blocks the reinforcing and rewarding properties of nicotine binding. Recognised adverse effects include nausea, headache, insomnia and abnormal dreams. Musculoskeletal effects are uncommon and limited to joint stiffness and muscle spasms.2 Potential mechanisms for myopathy include muscle cell degeneration induced by excess acetylcholine activity at the neuromuscular junction3 or possibly by varenicline’s affinity for the serotonin receptor.4 Enquiries to the Australian Adverse Drug Reactions Advisory Committee (ADRAC) and searches of the Canadian adverse drug reaction database and PubMed database failed to identify any reports of myopathy associated with varenicline. Thus we believe this to be the first reported case of proximal myopathy due to varenicline, and have reported the case to ADRAC accordingly.

Shelley E Wood · P Gerry Fegan

Incorrect name of author: In the Notable Case “Clinical, electrophysiological and genetic features of a large Australian family with paramyotonia congenita” in the 16 March 2009 issue of the Journal (Med J Aust 2009; 190: 334-336), an incorrect author name was printed. The fourth author’s name was given as Thyagarajan E Dominic. It should have been Dominic E Thyagarajan.

Sharavanan Parasivam · Malgorzata Krupa · Mark Slee · Dominic E Thyagarajan

A 32-year-old woman with a 4-year history of multiple sclerosis presented with persistent clawing of the right hand. History revealed that she and five family members had lifelong symptoms of paradoxical myotonia (impaired relaxation of muscles following muscle contraction), exacerbated by cold. The family was diagnosed with paramyotonia congenita, based on neurophysiological and genetic studies. To our knowledge, this is the first report of an Australian family with paramyotonia congenita. Clinical record A 32-year-old woman of European ancestry was referred to a movement disorder clinic for evaluation of mild persistent clawing of the right hand (Figure, A), which had developed over the past year. She had no weakness of the hand or other neurological signs. The patient had been diagnosed with relapsing remitting multiple sclerosis 4 years earlier, based on clinical features (typical exacerbations), characteristic white matter changes on magnetic resonance imaging scans, and oligoclonal bands restricted to the cerebrospinal fluid. Her condition was managed in a multiple sclerosis clinic. Before her referral, she was in good health between exacerbations of multiple sclerosis. Since early childhood, the patient had experienced persistent cramping of her hands after their use, particularly in cold conditions. She had difficulty releasing tightly gripped objects, and cramping usually worsened, rather than improved, with ongoing exertion, such as when using clippers to groom a dog (ie, there was no “warm-up” phenomenon). She found it difficult to talk after ingesting cold food or drink, and difficult to open her eyes after jumping into a cold pool. In extremely cold conditions, she experienced widespread cramping of her muscles with clawing of her hands, and a tendency for her toes to curl inwards. These symptoms would typically improve over several hours as her body warmed. As the cramping improved, there was notable weakness of affected muscles. A diagnosis of paramyotonia congenita was suspected after referral to the clinic. On questioning, the patient reported that other members of her family had similar symptoms. Five were interviewed; their symptoms began in early childhood, and included muscle cramping induced by exposure to cold or exertion (both in most cases). Face and hand muscles were predominantly affected. These family members also described generalised cramping and weakness in response to severe cold, but none had a permanent deformity similar to the patient’s clawing of the right hand. Physical examination of the patient and five affected family members revealed that all had paradoxical myotonia of the orbicularis oculi muscles and the hands, and percussion myotonia over the thenar eminence. None had weakness or muscle hypertrophy. Owing to the unusual coincidence of white matter disease and suspected paramyotonia congenita in the patient, magnetic resonance imaging of the proband’s affected brother (Figure, B; V-4) was performed. A small area of gliosis in the left caudate nucleus was identified but no white matter abnormalities were present. A family pedigree was constructed (Figure, B). This revealed that the paradoxical myotonia was inherited in an autosomal dominant pattern, spanning at least six generations. Further investigations of the patient revealed a slightly elevated creatine kinase level, myotonic discharges on electromyography and evidence of cold paralysis on nerve conduction studies. DNA sequencing revealed that the patient had a sodium channel gene mutation (Box). The five affected family members were subsequently identified as being heterozygous for the same mutation, and an unaffected family member was shown to lack this mutation (Box). Paramyotonia congenita was diagnosed, and acetazolamide therapy was begun, which led to moderate amelioration of symptoms. Her multiple sclerosis remained well controlled on glatiramer acetate. A: Permanent deformity of the patient’s right hand. B: Pedigree of the patient’s family, demonstrating that the paramyotonia congenita is inherited in an autosomal dominant pattern (patient [proband] = V-1). * Individuals IV-3 and V-1 each appear twice in the pedigree, as indicated by the dashed lines. To our knowledge, this is the first report of an Australian family with paramyotonia congenita. Paramyotonia congenita is a rare autosomal dominant condition characterised by paradoxical myotonia — impaired relaxation of muscles following muscle contraction, which worsens with repetitive muscle activity.1 It is distinct from other forms of myotonia, which typically improve with repetitive activity (the warm-up phenomenon).4 Paramyotonia is typically exacerbated by exposure to cold, and can be associated with cold-induced paralysis.1 Mutations in the skeletal muscle voltage-gated sodium channel gene SCN4A cause paramyotonia congenita,5 and can also cause hyperkalaemic periodic paralysis, potassium-aggravated myotonia, and a small proportion of hypokalaemic periodic paralysis cases.6 Patients carrying an SCN4A mutation may have manifestations of more than one of these allelic disorders. Our patient’s neurophysiology findings and the clinical features of her affected family members are typical for paramyotonia congenita associated with cold paralysis, and similar to those described in the largest reported case series for this condition.7 In this case series, age of onset was typically during early childhood, and clinical myotonia was evident in 100% of the 56 patients studied. Cold was identified as a precipitant in 91% of patients, and exercise was identified as a precipitant in 46%. Electromyographic evidence for myotonia was seen in 100% of the patients, and 92% had a reduction in compound muscle action potential in response to cold (objective cold paralysis). Forty-nine of the patients (88%) had a mutation of the SCN4A gene. The electromyographic changes evident with cooling in our patient were typical for paramyotonia congenita — cooling initially resulted in abolition of the myotonic discharges, and electrical silence was recorded at lower temperatures.1 The T1313M mutation was identified in our patient and the five affected family members, but not an unaffected family member. This is one of the more common mutations that causes paramyotonia congenita,4,8,9 and has been reported to exclusively cause paramyotonia with the cold-paralysis phenotype.9-13 The hands and face are predominantly affected in patients who carry the T1313M mutation.9-13 A report of French families with paramyotonia congenita noted significant clinical variability in patients carrying the T1313M mutation — in both severity of myotonia and its permanence — and myotonia permanens was evident in six of eight of these patients.9 In our patient, the clawing of the right hand is also likely to reflect myotonia permanens, rather than an interaction between the paramyotonia and multiple sclerosis. The T1313M mutation has been predominantly described in families with French ancestry, and to a lesser extent in families of English and Japanese background. 5,9,11 One de-novo mutation has been identified in the literature, which occurred in a Japanese man.12 All individuals from the six generations of the family we studied were born in Australia and lived in Australia, but the ancestral origins of the family are unknown. Present knowledge of SCN4A channel physiology provides insight into the clinical manifestations seen in our patient and the affected members of her family. Voltage-gated sodium channels are heteromultimeric, integral membrane proteins; they are composed of a single large pore-forming α subunit, and 1 or 2 smaller β units.6 There are nine subtypes of α subunit, one of which is expressed in skeletal muscle — SCN4A.6 The α subunit is composed of four structurally homologous domains (D1–D4), with six membrane spanning segments (S1–S6) within each domain.6 The sodium channel is important for generating and propagating action potentials and switches through three functional states: activation (the open-channel state), inactivation, and recovery from inactivation.6 The consequences of the T1313M mutation have been studied by patch-clamp studies using various cell lines. 10,14-17 Overall, the mutation has been shown to slow the rate of channel inactivation, diminish the voltage dependence of inactivation, and increase the rate of recovery from inactivation. 10,14-17 These effects result in increased sodium conductance and prolongation of action potentials, which causes persistent activation of potassium channels, leading to relatively high levels of extracellular potassium.6,10,14-17 Elevated extracellular potassium levels increase the likelihood of afterdepolarisations, which may lead to action potentials on adjacent surface membranes.6 This can result in ongoing muscle contraction and slowed relaxation — the features of paramyotonia.6 Threonine-1313 is a highly conserved residue in the D3–D4 linker; it is important for channel inactivation, and thought to occlude the cytoplasmic portion of the channel.16 The change from the polar hydrophilic threonine to the larger non-polar methionine is thought to impair occlusion of the channel, and therefore impair inactivation.13,16 Although the effects of the mutation have been shown to be potentiated at lower temperatures, as might be expected, no study has shown an increased sensitivity to temperature compared with normal cells.15-17 We have described the clinical, neurophysiological and genetic features of a large Australian family with paramyotonia congenita. The diagnosis of myotonia may be difficult and cause confusion, and the sodium channel disorder described here should be considered in patients with the symptoms described — especially as the symptoms respond to treatments such as acetazolamide and mexiletine, and as there are implications for genetic counselling and prognosis. Clues to the diagnosis include paradoxical myotonia — myotonia that worsens with ongoing exertion — and significant worsening of symptoms in cold conditions. Investigations Biochemistry and neurophysiology The patient’s serum potassium level was 4.2 mmol/L (reference range [RR], 3.2–4.3 mmol/L) and her creatine kinase level was slightly elevated at 191 U/L (RR, < 150 U/L). Routine nerve conduction study results were normal. Electromyography of the left abductor pollicis brevis and flexor digitorum superficialis revealed electrical myotonia and dense fibrillations. Cooling to below 28°C abolished the myotonic discharges and cooling below 22°C resulted in abolition of all spontaneous activity. The cooling test described by Streib1 was also performed. Before cooling, the amplitude of the left median compound muscle action potential recording over the abductor pollicis brevis muscle was 16.7 mV. The arm was then cooled to below 20°C by immersion in an ice bath and then rewarmed to 32°C using heat packs. The compound muscle action potential after rewarming was 4.5 mV (a 73% decrease). Molecular genetics Venous blood from the patient was sent to a commercial laboratory (PathWest, Royal Perth Hospital, Perth) for sequencing of the SCN4A gene. A heterozygous C-to-T nucleotide substitution at position 3938 in exon 22 was identified, resulting in a threonine-to-methionine amino acid change at codon 1313 (T1313M). Venous blood was then obtained from five family members who had symptoms that were similar to those of the patient (Figure, B; IV-1, IV-3, V-3, V-4, VI-4), as well as an unaffected family member (the patient’s half-sister), and mutational analysis was carried out. DNA was extracted by a proteinase K digestion method2 and amplified using the polymerase chain reaction (PCR) (forward primer sequence, 5'-TGGAGGCAGGAAGGGGAACT-3'; reverse primer sequence, 5'-GGCAGCACACACAGGACAGG-3'). The cycling conditions were: 3 min at 94°C × 1; and 30 s at 94°C, 40 s at 57°C, 1 min at 72°C × 30. The PCR reaction mixture contained 100 ng DNA, 0.5 μM of each primer, 80 μM of each deoxynucleoside triphosphate, 20 μM Tris-HCl (pH, 8.5), 50 μM KCI, 1.5 mM MgCI and 0.5 U Taq Ti DNA polymerase (Fisher Biotech, Perth, Australia). Amplified products were separated on 3% agarose gels. The separated fragments were diluted to 10 ng/μL per 100 base pairs and then sequenced by the dideoxy termination method,3 using BigDye Terminator v3.1 chemistry (Applied Biosystems, Foster City, Calif, USA) and the 3100 Genetic Analyzer (Applied Biosystems). Sequencing results showed that the five affected family members were heterozygous for the T1313M mutation and that the unaffected family member did not carry the mutation.

Sharavanan Parasivam MB BS, FRACP · Malgorzata Krupa BSc(Hons) · Mark Slee MB BS, FRACP · Dominic E Thyagarajan MB BS, MD, FRACP

Neuroimaging studies of individuals at risk of psychosis have the potential to identify markers predictive of illness onset and features that progress with transition. To date, reduced brain volumes have shown weak predictive value for onset of psychotic illness. All published longitudinal studies of the transition to psychosis show progressive brain changes that are not seen in at-risk individuals who do not develop the disorder. Although the cause of these changes is unclear, they challenge the conventional neurodevelopmental model of schizophrenia.

Stephen J Wood PhD · Christos Pantelis MD, FRANZCP · Alison R Yung PhD, FRANZCP · Dennis Velakoulis FRANZCP · Patrick D McGorry MD, FRCP, FRANZCP

Neuromuscular disorders. Anthony A Amato, James A Russell. New York: McGraw-Hill, 2008 (viii + 775 pp). ISBN 978 0 07 141612 2. Neuromuscular disorders is a new text that admirably covers the area of peripheral neurology, namely disorders affecting the peripheral nervous system, neuromuscular junction and muscle. The authors, Anthony Amato and James Russell, are eminent neurologists and neurophysiologists from Massachussetts, at the Brigham and Women’s Hospital and Lahey Clinic, respectively. With only two authors, the style is consistent and there is no unnecessary duplication, creating a text both comprehensive and relatively concise. At 775 pages, it is still a weighty book but it very adequately covers the relevant topics in a depth similar to that achieved by the world-recognised textbooks on the subject, which separately cover peripheral nerve and muscle diseases over two volumes. The book is beautifully illustrated, and the use of colour particularly enhances the neuropathology plates and clinical photos, adding clarity to many of the pictorial diagrams. The text also contains many very helpful tables. The index might possibly be incomplete. For instance, meralgia paraesthetica does get reasonable coverage in the text in the chapter on radiculopathy, plexopathy and mononeuropathies, but it is not indexed as such. The entry for lateral cutaneous nerve of the thigh takes the reader to an entry 20 pages earlier, which covers the anatomy but not the clinical features of the syndrome. Similarly, rippling muscle disease is mentioned in the text but not indexed. These are, of course, minor quibbles — this is an excellent reference book which, at less than $300, is good value for money. In an area that has seen a rapid growth of knowledge in the past decade, Neuromuscular disorders is certainly, at present, very up to date.

Chris S Kneebone

Objective: To assess the effectiveness of the PAST (Pre-hospital Acute Stroke Triage) protocol in reducing pre-hospital and emergency department (ED) delays to patients receiving organised acute stroke care, thereby increasing access to thrombolytic therapy.Design: Prospective cohort study using historical controls.Setting: Hunter Region of New South Wales, September 2005 to March 2006 (pre-intervention) and September 2006 to March 2007 (post-intervention).Participants: Consecutive patients presenting with acute stroke to a regional, tertiary referral hospital.Intervention: PAST protocol, comprising a pre-hospital stroke assessment tool for ambulance officers, an ambulance protocol for hospital bypass for potentially thrombolysis-eligible patients, and pre-hospital notification of the acute stroke team.Main outcome measures: Proportion of patients who received intravenous tissue plasminogen activator (tPA), process of care time points (symptom onset to ED arrival, ED arrival to tPA treatment, and ED transit time), and clinical outcomes of patients treated with tPA.Results: The proportion of ischaemic stroke patients treated with tPA increased from 4.7% (pre-intervention) to 21.4% (post-intervention) (P < 0.001). Time point outcomes also improved, with a reduction in median times from symptom onset to ED arrival from 150 to 90.5 min (P = 0.004) and from ED arrival to stroke unit admission from 361 to 232.5 minutes (P < 0.001). Of those treated with tPA, 43% had minimal or no disability at 3 months.Conclusions: Organised pre-hospital and ED acute stroke care increases patient access to tPA treatment, which is proven to reduce stroke-related disability.

Debbie A Quain BA(Nursing) · Mark W Parsons PhD, FRACP · Allan R Loudfoot MBA · Neil J Spratt PhD, FRACP · Malcolm K Evans RN, BA(HealthManagement) · Michelle L Russell RN, CM · Angela T Royan BNursing · Andrea G Moore BNursing · Ferdinand Miteff MB ChB · Carolyn J Hullick FACEM · John Attia MD, PhD, FRCPC, FRACP · Patrick McElduff BMath, PhD · Christopher R Levi BMedSci, FRACP

A 21-year-old, otherwise well man presented with a 3-month history of bilateral deteriorating vision. His visual acuity was 6/60 on the left and 6/12 on the right. Fundus examination revealed bilateral papilloedema, with optic discs grossly swollen and bulging forward (Figure: A, left eye; B, right eye). There were bilateral haemorrhages of the retinal nerve fibre layer surrounding the disc, and macular folds (Figure, arrows). An urgent computed tomography scan revealed a 5.8 cm × 5.3 cm mass in the inferior right frontal lobe, with cystic and necrotic components. The patient was referred for urgent surgical debulking. Histopathological examination of the mass confirmed that it was a high-grade anaplastic astrocytoma.

Vivek B Pandya · Neil S Sharma · Peter Khong · John Males

There is a wide array of options for migraine prophylaxis; many of the available drugs are clearly proven to be effective and yet are underused in Australia. “New” drugs which are gaining favour for migraine prophylaxis include topiramate, candesartan, gabapentin and botulinum toxin. The evidence for efficacy is excellent for topiramate and reasonably good but limited for candesartan and gabapentin. The use of botulinum toxin is controversial and has gained substantial popularity through anecdotal experience rather than convincing published evidence. Transformed or chronic migraine with medication overuse is a particularly difficult problem. New strategies to aid in medication withdrawal are reviewed. The approach to menstrual migraine and migraine with prominent aura may differ from that for typical migraine. Novel approaches are being explored for these problems.

Richard J Stark MB BS, FRACP, MACLM · Catherine D Stark MB BS

To the Editor: Bethanechol is a parasympathomimetic agent similar to acetylcholine that is known to be a selective stimulant of smooth muscle in the gastrointestinal tract and urinary bladder. It is normally used to treat non-obstructive urinary retention and has not previously been known to have any effect on skeletal muscle. Adults with cerebral palsy usually slowly deteriorate over the years, with gradually increasing muscle tone, worsening speech, mobility difficulties and a loss of independence. There has been no change in their management for decades. While working in a residential facility for adults with cerebral palsy, we serendipitously found that bethanechol significantly reduced the muscle spasticity in a patient for whom it was initially used to treat micturition difficulty. Seven other patients who were wheelchair-bound with cerebral palsy were then progressively given bethanechol in increasing doses. All patients and/or their carers were advised that the medication was being used experimentally, and all consented to participate in a clinical trial. The results are summarised in the Box. In all patients, bethanechol treatment was ceased for a week once the clinical benefits had been established, and all deteriorated during that week. None of the patients suffered any detectable side effects from the use of bethanechol, but many were already taking a proton-pump inhibitor that may have protected them from any gastrointestinal adverse effects. A synergistic interaction between bethanechol and another medication (eg, diazepam) was excluded as an explanation for the results obtained, as no other medication was common to all patients. Bethanechol’s effect seems to be long-lasting, as the first patient has now been using it for 6 months with no deterioration in his improved muscle tone. A Medline search revealed no studies in which bethanechol had been used as a treatment for cerebral palsy. Although our sample was very small, the fact that every patient improved indicates that a larger trial of bethanechol for cerebral palsy is warranted. Clinical outcomes for eight patients with cerebral palsy after treatment with bethanechol Sex (age in years) Diagnosis Final daily dose of bethanechol* Clinical effects M (41) Ataxic and spastic quadriplegia 60 mg Reduced muscle spasm, improved joint movement and speech, improved sense of wellbeing F (53) Ataxic and spastic quadriplegia 60 mg Improved arm movement and speech, looser muscle tone, more relaxed F (47) Spastic quadriplegia, kyphoscoliosis 60 mg Able to abduct legs from previously clamped closed position, loss of leg spasm pain, improved speech, muscle spasm induced by touch eliminated M (68) Spastic quadriplegia, dysphagia 60 mg Less stiffness, speech clearer, easier for carers to move, improved sense of wellbeing M (58) Rigid spastic quadriplegia 60 mg Less limb muscle spasm, improved arm and trunk movement, markedly improved speech F (44) Spastic quadriplegia, epilepsy 60 mg Improved arm and leg movement, easier to roll M (49) Spastic quadriplegia, athetosis 30 mg Chronic spasmodic jerks ceased completely, speech better, able to play carpet bowls better, back extension improved M (68) Spastic quadriplegia, kyphoscoliosis 60 mg Less muscle pain, less back spasm, easier for carers to lift, felt happier and more relaxed * Given orally in three divided doses.

Warwick J Carter

Updated guidelines recommend improving access to specialised stroke units and thrombolytic therapy, and the rapid assessment of patients with transient ischaemic attacks for stroke risk Stroke, with its high incidence and serious consequences, is one of the foremost health challenges for Australia and globally. Although stroke rates appear to be decreasing,1 population ageing will intensify the impact of this disease and the need for effective prevention and management strategies.2 Stroke is a complex disease with a range of causes, manifestations, outcomes and treatment approaches, but is too common and costly to be left as the province of a single clinical discipline, neurology. As the therapeutic time window in which to rescue or “protect” the brain from ischaemic damage is extremely short, there is a need for good systems of communication and responsive, expert team care, both in the community and in hospitals, to ensure safe and effective delivery of interventions early after onset and in subsequent phases of acute stroke. Indeed, the single most important therapeutic advance in stroke medicine is arguably the recognition that well coordinated, multidisciplinary care in the form of stroke care units (SCUs) can significantly improve the chances of recovery from stroke. So how can we improve patient access to expert SCU care and therapies that provide the best opportunity for a favourable outcome? A popular approach to improving the quality of health care delivery is the development of clinical guidelines. A good example is the Clinical guidelines for acute stroke management,3 produced by the National Stroke Foundation in 2007. These guidelines update a document published in 2003 and are available from the Foundation’s website (http://www.strokefoundation.com.au). They aim to provide clinicians and patients with all the key information needed to make the best decisions about the benefits and risks of treatment, through the use of systematically developed statements, recommendations and algorithms based on supporting grades of evidence. In addition, the document may provide a degree of medicolegal protection for the treating clinician, and political leverage for developing services both locally and generally. So what can we learn from these stroke guidelines, developed with specific relevance to the local context? The guidelines followed the rigorous standards of development and production set down by the National Health and Medical Research Council (NHMRC) and cover a wide range of clinically relevant topics in a simple, accessible format. The multidisciplinary expert working group that developed the guidelines is to be commended for seeking a wide range of external advice and comment, for incorporating consumer values and preferences in a unique additional grading of the recommendations, and for making sensible judgements for nearly half of the 148 recommendations where high-level randomised evidence was lacking — not surprisingly, mainly in the areas of supportive care and early rehabilitation. A key recommendation emphasised in the updated guidelines is the need for rapid assessment and management by specialists of patients who present not only with established features of an acute stroke but also with a transient ischaemic attack (TIA). TIA has generally been considered more “benign” than stroke and akin to migraine, because of its brevity and reversibility. However, recent studies show that the risk of recurrent stroke early after a TIA is similar to the risk after mild ischaemic stroke: about 10% in the first week and 20% by 3 months.4,5 Thereafter, the annual risks of stroke and myocardial infarction are around 5% and 2%–3%, respectively.6 Given that 30%–40% of patients with ischaemic stroke have had a preceding TIA or minor stroke,7,8 and that evidence is accumulating of the benefits of early interventions such as antiplatelet therapy, blood pressure-lowering therapy and carotid endarterectomy, TIAs provide an important opportunity for stroke prevention.8,9 However, the diagnosis of true stroke-related “focal” TIA is often challenging as it generally relies on patients recalling symptoms from a time when they were possibly impaired. As outlined in the stroke guidelines, a simple measure — the ABCD2 tool (a 7-point score calculated from age, blood pressure, clinical features, duration of symptoms, and diabetes status [Box])10 — can help clinicians, including those in primary care, with patient triage. Those at “high” risk of subsequent stroke have the option of admission to hospital to expedite investigations and management, while those with “low” risk could be followed up quickly in specialist outpatient clinics, where available. Early assessment offers further benefits for patients, through establishing correct diagnoses for TIA-mimics, such as syncope, seizure, anxiety–hyperventilation and vestibular disturbance, allowing specific interventions and avoidance of unnecessary, costly and sometimes risky avenues of management. For all these reasons, and as suggested by Kehdi et al in this issue of the Journal,11 early in-hospital management of patients with TIA may improve outcomes. However, there are major implications for resources and service configuration if rapid expert neurological assessment is to be provided to patients who present to emergency departments with TIA as well as those with stroke. Importantly, the stroke guidelines also included cost-effectiveness analyses of the currently available, clinically proven interventions for prevention and treatment of stroke. Most noteworthy was the finding that substantial economic and health-related benefits could be derived from improved patient access to high-quality stroke services through a modest additional investment of resources. Given that a substantial proportion of the Australian population lives in rural or remote areas, where there are no SCUs or other specialty services, the guidelines recommend the creation of networks linking smaller regional and rural centres to larger centres with SCUs. Furthermore, as the availability of SCUs varies widely even in urban settings, the guidelines recommend that ambulances preferentially transfer patients with suspected stroke to hospitals with SCUs. This recommendation is controversial. Recent audits12 and experience indicate that not all SCUs are resourced appropriately to allow safe and effective use of the thrombolytic agent, recombinant tissue plasminogen activator (rtPA), in carefully selected patients who present within the first few hours after the onset of ischaemic stroke. Given that rtPA is proven to be cost-effective, a reorganisation of services to allow ambulances to route patients directly to “active rtPA SCUs” could allow many more people to benefit from this treatment. How can the recommendations in the stroke guidelines be implemented in the real, service-challenged world, where modifying the behaviour of clinicians and providers is difficult, and clinical settings are often not conducive to change? The transfer of evidence into clinical practice has, to date, been unpredictable and often slow and haphazard for many reasons, including poor knowledge, limited therapeutic expertise, lack of time and, in particular, economic restraints. The use of guidelines can better align clinical management with evidence-based practice, but this is difficult when expertise and services are non-existent or inappropriately resourced. There is limited empirical evidence to support any specific strategy for change over another, but current data suggest that change is possible through comprehensive approaches that target different levels and settings in the health care system.13 The stroke management guidelines are a positive step. Implementation strategies, including the development of policy at the highest, central level, are now needed. A key step would be for the federal government to mandate the recommendation of the National Service Improvement Framework that all people with acute stroke receive SCU or appropriate alternative care around the country.14 Implementation of such policies would provide the best opportunity to improve the outcomes for patients with stroke and the growing population at risk of this devastating illness. ABCD2 tool for assessment of patients with transient ischaemic attack10 A. Age ≥ 60 years = 1 point. B. Blood pressure ≥ 140/90 mmHg = 1 point. C. Clinical features: unilateral weakness = 2 points, speech impairment alone = 1 point. D. Duration > 60 minutes = 2 points, 10–59 minutes = 1 point. D. Diabetes = 1 point. Total. 0–3 = low risk of stroke, 4–7 = high risk of stroke.

Craig S Anderson FRACP, PhD

Objective: To compare outcomes at 28 days and 1 year between patients admitted to hospital and those discharged after presenting to the emergency department (ED) with transient ischaemic attack (TIA).Design and setting: All TIA presentations to EDs in a large metropolitan and rural region of Sydney and its surroundings, New South Wales, between 2001 and 2005 were extracted from state health department databases and followed up over 1 year. Admission and discharge data and subsequent TIA or stroke presentations were identified.Main outcome measures: TIA recurrence or stroke.Results: Of 2535 presentations to an ED with TIA during the 5-year period, 1816 patients were admitted to hospital (71.6%) and 719 were discharged from the ED (28.4%). At 28 days, the discharged group had significantly higher rates of recurrence than the admitted group for all events (TIA or stroke) (5.3% v 2.3%, P < 0.001), stroke (2.1% v 0.7%, P = 0.002), and recurrent TIA (3.2% v 1.6%, P = 0.01). During the 29–365-day follow-up period, there was no significant difference between the discharged and admitted groups for all events (4.2% v 5.1%; P = 0.37), stroke (1.3% v 2.5%; P = 0.06) or recurrent TIA (2.9% v 2.6%; P = 0.65).Conclusion: Patients with an ED diagnosis of TIA may benefit from admission to hospital through a reduced risk of early stroke.

Elias E Kehdi MB BS, MOptom · Dennis J Cordato FRACP, PhD · Peter R Thomas PhD · Roy G Beran FRACP, MD · Cecilia Cappelen-Smith FRACP, PhD · Neil C Griffith FRACP · Ibrahim Y Hanna FRACP · Alan J McDougall FRACP, PhD · John M Worthington FRACP, BSc · Suzanne J Hodgkinson FRACP, PhD

To the Editor: Primary cerebral vasculitis (PCV) is a potentially fatal disease. Early diagnosis and therapy are vital. We describe a case where confounding factors delayed diagnosis. A 42-year-old woman presented with headache, nausea, vomiting, malaise and binocular blindness for 3 days. Two weeks previously, she had presented to the emergency department with headache and vomiting, but investigations, including computed tomography (CT) of the brain and lumbar puncture, gave normal results. She had a history of depression, was a smoker (20 pack-year history), and used cannabis regularly and alcohol occasionally, but denied other recreational drug use. Her mood appeared depressed. Vital signs and findings from a general examination were normal. Eye movements were full, direct and indirect pupillary reflexes were intact, and optic fundi were normal. Results of a CT angiogram were reported as normal by a consultant radiologist. Results of blood tests, including inflammatory markers, and a repeat lumbar puncture, were unremarkable. A toxicology screen was not performed. Depression with conversion disorder was diagnosed, and admission with analgesia was advised. A neurologist’s review on Day 2 did not detect organic disease. The mental health team diagnosed severe depression and prescribed antidepressants. On Day 4, the patient’s condition deteriorated and she become non-communicative with signs of right hemiplegia. An electroencephalogram showed polyrhythmic generalised slow waves consistent with encephalopathy. She was transferred to a tertiary centre where magnetic resonance imaging (MRI) and CT angiography of the brain showed multiple bilateral infarcts (Figure, A) with beaded arteries, the classic appearance of vasculitis. She was given high-dose prednisolone and cyclophosphamide. Investigations were negative for causes of secondary vasculitis. Her condition continued to deteriorate and she died 8 days after admission. Autopsy was refused. Subsequent review of the second CT scan detected irregular cerebral vessels (Figure, B). PCV is an uncommon disorder of the central nervous system, with unknown aetiology and no specific characteristic features, affecting small cerebral arteries but not extracranial vessels. Symptoms and signs vary but include headache, encephalopathy, seizures, personality change, weakness, and altered level of consciousness, as well as superimposed focal cranial neuropathy or hemiplegia. Recognition is difficult, but differentiation from reversible cerebral vasoconstriction syndrome is important.1,2 Brain biopsy is seen as the “gold standard” for diagnosing PCV. CT angiography may show diffuse or localised changes, with vessel beading, aneurysms, and luminal narrowing. MRI may show areas of white and grey matter infarction, or haemorrhage. MRI is more sensitive than CT, but less sensitive than CT angiography. Up to 100% of biopsy-positive cases appear abnormal on MRI. Suspected cases require careful clinical appraisal and either CT angiography or MRI, probably followed by an image-guided brain biopsy.3 Initial reported cases of PCV had a poor prognosis; most patients died within a few weeks.2 Immunosuppressive therapy with glucocorticoids and cyclophosphamide (as used in secondary severe vasculitis) may be beneficial, although there are no clinical trials.4 A future therapeutic alternative may be infliximab, which has been used successfully for one patient with cerebral vasculitis secondary to Behçet’s disease who had known elevated levels of tumour necrosis factor α.5 Despite increasing awareness and advances in angiography, PCV remains an uncommon diagnostic and therapeutic problem which should be considered in cases of severe, non-febrile neurological illness with stroke-like features. A: Magnetic resonance image showing multiple bilateral infarcts. B: Computed tomography angiogram showing irregular cerebral vessels (“beading”, arrows).

Sanjaya S Herath · Dayna B Law · Peter J O Stride · Vernon J Heazlewood · Luke S Gaffney

To the Editor: We report the case of a 71-year-old woman who presented with a 3-week history of lethargy, subacute confusion and drowsiness. She was known to have a seizure disorder for which she had been taking lamotrigine 100 mg and sodium valproate 500 mg twice a day for 2 years. On examination, the woman was disoriented with regard to person and time, and had constructional apraxia and asterixis. The rest of the physical examination was unremarkable. A full blood count, electrolyte levels, coagulation parameters, arterial blood gas measurements and hepatitis serology were normal. Tests for immunological markers of autoimmune liver disease were negative. Liver function tests showed longstanding raised levels of alkaline phosphatase (158 U/L [reference range (RR), 30–110 U/L]) and γ-glutamyl transferase (434 U/L [RR, < 40 U/L]). Serum drug levels were sodium valproate 51.0 mg/L (therapeutic range, 50–100 mg/L) and lamotrigine 9.5 mg/L (therapeutic range, 3–14 mg/L). The venous blood ammonia level was 109 μmol/L (RR, < 50 μmol/L). A liver ultrasound scan was normal. Computed tomography of the brain showed microvascular changes and an old cortical infarct. An electroencephalogram (EEG) showed diffuse slowing, with a predominance of rhythmical theta activity and some delta activity, suggestive of encephalopathy. As hyperammonaemic encephalopathy secondary to sodium valproate therapy (VHE) was considered a possible diagnosis, sodium valproate treatment was discontinued. The patient’s confusion resolved completely and the asterixis disappeared within a week. At the same time, her blood ammonia level fell to 19 μmol/L and her EEG normalised. Eight months after discontinuing sodium valproate treatment, the woman was still asymptomatic. A subsequent percutaneous liver biopsy, to investigate her persistently abnormal liver function, showed features consistent with primary biliary cirrhosis. Sodium valproate is used not only for management of epileptic disorders but also for migraine prophylaxis and treatment of several psychiatric conditions. Although a generally well tolerated drug, it has a few well known side effects, including hyperammonaemia and, rarely, VHE.1-3 The possible pathophysiology of VHE has been described elsewhere.2 Gerstner et al reported on a series of 19 patients with VHE between 1994 and 2003.4 Review of the literature suggests that VHE is under-recognised, leading to considerable delay in the diagnosis of this potentially reversible condition.3,5 In our patient, it is reasonable to presume that sodium valproate precipitated the encephalopathy on a background of evolving unrecognised liver disease. The marked improvement in her clinical manifestations after discontinuation of valproate further supports this presumption. We have drawn attention to this case to highlight that VHE should be considered in patients presenting with confusion. Prompt measurement of the ammonia level and cessation of valproate treatment should be considered if clinically appropriate. Patients with previously unrecognised liver disease may be at particular risk. Acknowledgement: We thank Professor Peter Roberts-Thomson, Director of the Department of Immunology at Flinders Medical Centre, for his expert opinion and advice.

H S Subhash · Robert J Heddle · David W Schultz · John Ring · Campbell H Thompson

To the Editor: The recent report on the use of a stroke thrombolysis protocol by Batmanian and colleagues1 raises many issues. The most recent guidelines regarding thrombolytic therapy for ischaemic stroke recommend that “If thrombolytic therapy is to be used . . . consultation with a neurologist or stroke physician is essential before instigating therapy. Strict adherence to the inclusion and exclusion criteria is important . . .”2 Hence, I find the integral role of a neurologist in Batmanian and colleagues’ protocol reassuring. However, consent to therapy in this setting is not simple. In the protocol, they informed the patient and/or next of kin about the risks and benefits of thrombolysis, but did they seek informed consent? The benefits of thrombolytic therapy are controversial, and equipoise exists. Reflecting this, a multicentre trial3 is underway that includes patients who meet the eligibility criteria of Batmanian et al’s protocol. The evidence cited by Batmanian and colleagues in support of thrombolysis was based on small randomised trials published more than a decade ago.4 Further, the summary results of the meta-analysis they cited are associated with significant heterogeneity and lose statistical significance with the inclusion of additional results from observational studies5 (Box). Moreover, the more recently published audits and the analysis that led to the number-needed-to-treat estimate cited by Batmanian et al were based on comparisons with a reference group dominated by the placebo group of the NINDS (National Institute of Neurological Disorders and Stroke) trial.6 This trial has been criticised for likely faulty randomisation resulting in baseline disparities unfavourable to the placebo recipients. These projections of benefit based on comparisons with a small and non-representative placebo group from a trial published over a decade ago are misleading. A calculation of numbers needed to treat based on such limited evidence, particularly for a soft endpoint such as assessment of disability, is hazardous and potentially misleading.7 There are other important issues associated with this therapy that need to be resolved. For example: Are mortality rates increased in groups receiving tissue plasminogen activator therapy in non-teaching hospitals?;8 Is this therapy safe in older people?; and finally, does this therapy not have the proven mortality risk associated with streptokinase in randomised trials in patients with stroke?4 Thrombolysis for stroke requires more evidence from randomised trials, not more protocols. Trials including older people are especially needed, given the age-dependent mortality risk associated with this therapy. Odds ratios for fatal outcome from published cohorts of patients receiving tissue plasminogen activator therapy within 3 hours of onset of acute ischaemic stroke The addition of two recent observational cohorts, the German Stroke Register and the Cleveland experience, to the meta-analysis of six controlled trials as reported in Wardlaw et al4 increases the summary odds ratio from 0.97 (95% CI, 0.69–1.36) to 1.21 (95% CI, 0.93–1.57). (Figure reproduced from Hurley5 with permission from Wiley-Blackwell Publishing Ltd.) ATLANTIS = Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. ECASS = European–Australasian Cooperative Acute Stroke Study. NINDS = National Institute of Neurological Disorders and Stroke.

James C Hurley

To the Editor: The assertion of Davis and Batmanian and their colleagues that thrombolytic treatment for ischaemic stroke is reasonably safe and highly effective1,2 is not supported by the primary randomised trials of its use.3 Is tissue plasminogen activator (tPA) safe? It remains undisputed that none of the trials for thrombolysis in stroke have shown any mortality benefit.4 All of the trials have shown increases in symptomatic intracranial haemorrhage; in the NINDS trial, the increase was from 0.6% in the placebo arms to 6.4% in the treatment arms — a 1000% relative increase — and 45% of those with symptomatic bleeds died.5 Presumably, any mortality benefit from opening blocked arteries is lost because of the increased mortality from intracranial bleeding. Therefore, the drug is not safe. Is tPA effective? Thrombolysis for acute myocardial infarction was assessed in tens of thousands of patients in many independent studies, with virtually all showing clear mortality benefit. By comparison, the stroke thrombolysis literature is full of negative studies, with only one positive result. The NINDS trial4 stands alone as the only randomised controlled trial (RCT) providing positive evidence for thrombolysis for stroke. Ignoring criticisms of its interpretations and methodology, of which there are many, it had fewer than 600 patients and its results have not been reproduced independently. Breaches of protocol continue to be published. Batmanian and colleagues gave patients tPA after 180 minutes despite all the evidence saying this has no benefit, justifying it by saying the decision had been made at 170 minutes.2 Davis and colleagues1 based their claims of safety and efficacy on registries, subgroup analyses, meta-analyses, and expert panels all based on the same single RCT — the NINDS trial.4 This is low-grade evidence for a potentially lethal therapy. It is time a major RCT was done to repeat the NINDS trial and finally determine whether its result was a statistical anomaly or a real effect. There is no shortage of stroke patients — Batmanian et al found that 14% of patients were eligible for this therapy.2 The paucity of evidence for thrombolysis for stroke does not justify rushing patients to stroke centres, bypassing perfectly good hospitals in the hope of finding some of the 3% of patients eligible for treatment, of whom one in eight (0.38% of all stroke patients) would theoretically have a better neurological symptom score if given thrombolysis.6,7 I feel that it is a waste of time and effort, and a danger to patients, to focus all resources on supplying a potentially lethal therapy that is often incorrectly used and provides a marginal benefit.

Gino J Toncich

A 16-year-old boy with a 3-month history of intermittent postural headaches presented with sudden worsening headache after a game of soccer. The results of a neurological examination were unremarkable. Magnetic resonance imaging showed elongation of the midbrain, bilateral frontoparietal subdural haematomas (Figure, A), and a collection of fluid within the soft tissues overlying the lumbar spine (Figure, B). The cerebrospinal fluid (CSF) opening pressure on lumbar puncture was low (60 mmHg). Spontaneous intracranial hypotension was diagnosed, and the response to conservative treatment was good. Intracranial hypotension is a syndrome characterised by postural headaches and CSF hypovolaemia. Most cases are secondary to a tear in the dura mater following lumbar puncture, with a resultant slow CSF leak and gradual volume depletion. It can also occur secondary to severe dehydration, and, occasionally, no cause is identified, when it is termed “spontaneous”.1 In this case, there was no history of lumbar puncture, and CSF accumulation within the lumbar soft tissues was presumed to be secondary to a spontaneous dural tear in this region. Intracranial hypotension has characteristic imaging features, which include elongation of the midbrain, linear enhancement of the pachymeninges and subdural effusions.2 Patients are predisposed to subdural haemorrhage after minor trauma as a result of “stretching” of the dural veins. Intracranial hypotension is commonly misdiagnosed as migraine, meningitis or a psychogenic disorder.1 Most cases resolve spontaneously, but intractable headaches may be successfully treated with steroids, epidural blood patches or surgery.1 A: Axial T1-weighted magnetic resonance image showing elongation of the midbrain and bilateral subdural haematomas (arrows). B: Sagittal T2-weighted fat-saturated magnetic resonance image showing high-signal cerebrospinal fluid accumulation within the soft tissues of the lower back (arrow).

Edward Hoey · Guneesh Dadayal · Sashidhar Yeluri · Neetu Kumar · Kshitij Mankad

Three patients with Australian parasitic myositis caused by the muspiceoid nematode Haycocknema perplexum are described. Treatment with albendazole led to a slow and incomplete recovery, but treatment with steroids caused life-threatening deterioration. Clinical recordsPatient 1A 23-year-old woman presented to Cairns Base Hospital with a history of 2 years of insidiously progressive weakness, including 1 year of difficulty swallowing. She weighed 42 kg, having lost 18 kg in recent years. There had been no myalgia. The patient had grown up in Queensland and was living in Innisfail, but had travelled around Australia in the 3 previous years, visiting Western Australia, New South Wales and Victoria. Although not acutely unwell or febrile, the patient was thin, with limb weakness and proximal and distal wasting. The facial muscles were wasted and weak, but palatal and ocular movements were normal. She was unable to stand from sitting without using her arms and had bilateral foot drop, but toe extension was preserved (Box 1). Reflexes were absent at the ankles and depressed elsewhere. Sensation appeared intact. Haematological testing showed eosinophilia (1.1 × 109/L; reference range [RR], < 0.4 ×109/L), which was found to have been known since 1998. It had been assumed to be due to intestinal parasites, a common problem in North Qld, but results of subsequent serology testing for Strongyloides were negative, as were stool samples. The serum creatine kinase (CK) level was high (1370 U/L; RR, <160 U/L), and there was mild derangement of liver transaminases (alanine aminotransferase, 60 U/L; RR, < 40 U/L); aspartate aminotransferase, 52 U/L; RR, < 35 U/L). Levels of inflammatory markers were also high (erythrocyte sedimentation rate, 50 mm/h; RR 0–20 mm/h; C-reactive protein, 37 mg/L; RR, < 5 mg/L). Electromyography showed low-amplitude polyphasic potentials, consistent with myopathy, and nerve conduction studies showed a mild coexistent sensory neuropathy. A biopsy of the quadriceps showed the muscle to be pale, flaccid and atrophic. On examination of paraffin sections, the muscle appeared highly abnormal; several muscle fibres contained sarcoplasmic nematode parasites characterised by a simple cephalic end and a sharply tapered caudal end. Unlike other nematodes that cause myositis, these parasites were not encysted. There was patchy interstitial and perivascular inflammation, predominantly with lymphocytes, and numerous necrotic fibres showing florid myophagia (Box 2). The parasite stained red with Gomori’s trichrome and positive with ATPase and cytochrome oxidase. Electron microscopy showed scattered sarcoplasmic parasites. Gravid female parasites were characterised by a thin cuticle, a central triradiated oesophageal lumen, and ova (Box 3). The parasite was identified as the nematode Haycocknema perplexum.1 The patient was treated with albendazole 400 mg twice daily for 8 weeks. Percutaneous endoscopic gastrostomy provided nutritional support initially. Steroids were not used at any stage of treatment. After 2 weeks, CK had fallen to 235 U/L and C-reactive protein to 1.1 mg/L. After 2 months, the patient remained diffusely weak, with ongoing dysphagia, but was able to stand from sitting. Two months after she had completed treatment, the patient’s CK began to rise, without eosinophilia. A second biopsy, of the deltoid muscle, did not show any live parasites, but showed numerous lysosomal structures, consistent with resorption of dead parasites. Significant replacement of muscle with collagenous connective tissue was noted. Twelve months after treatment, the patient had significant ongoing muscle weakness and persistently high CK levels (about 300 U/L), but normal eosinophil counts. Patient 2A 61-year-old man was admitted to a Townsville hospital for investigation of a 3-year history of slowly progressive dysphagia and dysarthria, and 1 year of limb weakness. Concurrent medical problems included diabetes mellitus, renal impairment and biliary duct ectasia. Six months before presentation, hypercalcaemia had been noted and briefly treated with oral prednisone for presumed sarcoidosis, although serum angiotensin-converting enzyme levels were normal. The patient had grown up in Tasmania, but had moved to Mackay in North Qld more than 20 years earlier, and had not travelled outside the region since. On examination, he was unwell and cachectic, with bilateral facial and palatal weakness, diffuse limb weakness and wasting and depressed reflexes, but normal sensation. On the basis of elevated CK (1263 U/L) and inflammatory markers, high-dose oral prednisone was commenced for presumed polymyositis, pending muscle biopsy results. In retrospect, peripheral eosinophilia was known to have been present for at least 2 years. After the patient had received steroids, the eosinophil count normalised. Within days, he deteriorated, requiring admission to intensive care for ventilatory support. After the muscle biopsy results showed parasitic myositis, steroids were gradually withdrawn and albendazole was commenced. The muscle function stabilised, but a biopsy 4 weeks later showed live H. perplexum nematodes. Further biopsy after 9 weeks of treatment showed no live nematodes. The intensive care stay was complicated by dependence on ventilation, sepsis, pneumonia, renal and hepatic failure and encephalopathy. Seven months later he was discharged to a regional hospital for convalescence but died from complications of sepsis and renal failure. Patient 3A 61-year-old man from Mackay, Qld, was admitted to Townsville Hospital with a 2-year history of hand cramping, progressive diffuse weakness eventually causing difficulty climbing stairs, and 1 year of dysphagia. He had lived in North Qld all his life, and had never travelled to Victoria or Tasmania. He had never consumed the meat of native animals or other “bush tucker”. He was diffusely thin and weak, with bilateral incomplete foot drop and depressed reflexes, but intact facial strength and normal ocular movements. The serum CK level was 1230 U/L and, in retrospect, had been 1000 U/L 2 years earlier, but had not been investigated. Alanine aminotransferase was 69 U/L (RR, < 45 U/L); aspartate aminotransferase, 67 U/L (RR < 40 U/L); and peripheral blood eosinophils, 1.36 × 109/L (RR, < 0.4 3 109/L). Review of earlier investigations confirmed persistent eosinophilia over the prior 42 months, at least. Muscle biopsy confirmed H. perplexum. He received 8 weeks’ oral treatment with albendazole. Steroids were not given. Four months later there was some improvement in limb strength and swallowing, although his CK level remained high. DiscussionAlthough H. perplexum myopathy has previously been reported, in two people from Tasmania,1,2 the patients we report had spent most or all of the past few years in tropical northern Australia. We contacted the physicans caring for the earlier patients, who confirmed that they, too, had been exposed to tropical Australia (Box 4). One had travelled extensively in Cape York, Far North Qld, and Kakadu National Park, Northern Territory, 5 years before diagnosis. Around that time, he developed a non-specific illness with raised liver transaminase levels, and liver biopsy showed mild reactive hepatitis with eosinophils. The other was a botanist who had visited the Northern Territory, Tasmania, Europe, Kenya and Indonesia on fieldwork before developing muscle weakness. Clinical features common to H. perplexum myositis patients were the insidious onset of diffuse limb weakness and dysphagia. The documentation of persistent eosinophilia up to 7 years before diagnosis suggests that infection may be subclinical for years. Consistent clinical signs have been diffuse limb wasting and weakness, including bilateral foot drop. Uniform abnormalities included an elevated serum CK, blood eosinophilia and mild elevations of liver transaminases. Although muscle biopsy is required to confirm diagnosis, in one reported case the initial biopsy did not reveal parasites, but a second biopsy after steroid treatment showed H. perplexum. H. perplexum is a minute nematode measuring about 350 m by 20 m. The parasite appears to be able to complete its life cycle within human muscle, as adult nematodes are found within the sarcoplasm of muscle cells, while larvae are found both inside and outside myofibres.3 Electron microscopy shows the characteristic features of H. perplexum: a cuticularised triradiated oesophagus–intestine terminating in dark refringent granules (trophosomes).1 The outer cuticle is thin and has exterior corrugations. The male is shorter and narrower than the female, with the testes occupying 50%–60% of its body. The gravid female has paired uteri where 12 to 24 ova develop into larvae. Auto-reinfection is thought to occur when third-stage larvae escape by bursting through the female nematode’s body, a phenomenon known as endotokia matricida. The resulting damaged myofibres incite an intense inflammatory reaction resulting in myophagia. H. perplexum was first described in the late 1990s, having been identified as the cause of a case of human myositis.2 The parasite is a member of the Robertdollfusidae family of Muspiceoidea nematodes. Distinct species of Muspiceoidea nematodes have been found in the tissues of various Australian vertebrates,4 including mice,3 bats,5 kangaroos and wallabies,6 and koalas.7 In animals, there is some evidence for cutaneous penetration as the mechanism of infection.3 The mechanism by which humans acquire H. perplexum is unknown. Other parasitic myopathies such as trichinosis and cysticercosis are acquired through consumption of poorly cooked meats. Intestinal parasites, including Strongyloides, may be acquired via direct cutaneous penetration, such as when walking barefoot, a common practice in tropical Australia. Mosquitoes, which are very common in tropical Australia during the wet season, could also be a vector for infection. Treatment with albendazole improved muscle strength in all three cases of H. perplexum myopathy, although recovery was slow and incomplete. A biopsy after 4 weeks of treatment showed live nematodes. After 9 weeks of treatment, no live nematodes were seen on biopsy, correlating with a reduction in CK levels and peripheral eosinophilia. Therefore, treatment for at least 8 weeks is suggested to prevent auto-reinfection. Treatment solely with albendazole, without concomitant steroid use, was not associated with adverse reactions from nematode death. Furthermore, steroid therapy resulted in deteriorating muscle function and delayed diagnosis by falsely normalising blood eosinophilia. 1 A 23-year-old woman with progressive muscle weakness (Patient 1) The patient had diffuse wasting of major lower limb muscle groups, including the quadriceps. The white arrow shows wasting of the tibialis anterior muscle, which caused foot drop. The black arrow shows the well preserved digitorum brevis muscle, accounting for preserved toe extension. 2 Micrographs of skeletal muscle (Patient 1) A: Transverse section of quadriceps muscle fibres (M) shows a nematode, Haycocknema perplexum (HP), in cytoplasm, surrounded by interstitial chronic inflammatory cells (INF) (haematoxylin and eosin stain; original magnification, × 400). B: Longitudinal section shows parasitic nematode lying within the muscle fibre (toluidine blue stain; original magnification, × 1000). 3 Electron micrographs of Haycocknema perplexum nematode A: Cross-section through nematode in skeletal muscle (M), showing cuticle (Cu) and oesophagus (O) (original magnification, × 2500). B: Enlargement shows cuticularised triradiated lumen of the oesophagus (original magnification, × 20 000). 4 Clinical and laboratory features of myopathy caused by Haycocknema perplexum Patient Place and year of diagnosis Prior travel Duration of symptoms (years) Dysphagia CK level (U/L)* Eosinophil count (× 109/L)† Outcome 1 North Qld, 2005 Extensive 2 ++ 1370 1.1 Weak, CK ~ 300 U/L 2 North Qld, 2004 None in 20 years 3 ++ 1263 High Weak, died 3 North Qld, 2006 Nil 2 + 1230 1.36 Weak, CK ~ 250 U/L Previously reported cases2 A Tasmania, 1996 Extensive, including Far North Qld 1.5 ++ 1586 2.0 Weak, CK ~ 280 U/L B Tasmania, 1994 Extensive, including northern Australia 5 + 2168 0.8 Good recovery CK = creatine kinase. Qld = Queensland.+ = mild–moderate. ++ = moderate–severe. * Reference range (RR), < 160 U/L. † RR, < 0.4 3 109/L.

Ron Basuroy MRCP · Robert Pennisi FRACGP · Thomas Robertson FRCPA · Robert Norton FRCPA, MRCP · John Stokes FJFICM · Jon Reimers FRACP · John Archer FRACP, PhD

A 2-year-old boy and a 10-year-old girl presented to the emergency department with a decreased level of consciousness. The girl had had persistent vomiting and a seizure. Urine metabolic screening tests were positive for γ-hydroxybutyrate (GHB). Samples from toy beads ingested by both children contained 1,4-butanediol, which is metabolised to GHB in humans. Regulatory authorities were notified, leading to an international recall of the toy beads. Clinical recordsPatient 1 A 2-year-old boy presented to the emergency department (ED) with a decreased level of consciousness. Earlier, he had been playing with his siblings in the backyard. He had been unsteady on his feet an hour before and then became difficult to rouse. There was no history of trauma, ingestion of medicines or plants or intercurrent illness. He had been well previously and was the youngest of 10 siblings. On arrival at the ED, his Glasgow Coma Score (GCS) fluctuated between 7 and 12, with no focal neurological deficit. Pupils were 2 mm, equal and reactive. A pustular vesicle on his right cheek was the only other significant finding. He was afebrile and had no neck stiffness. An electrocardiogram showed sinus bradycardia at 60 beats/min. He was hypotensive, with blood pressure of 59/39 mmHg. Blood glucose level was 5.2 mmol/L. Without a history of ingestion, we initially considered a postictal state or encephalitis. Laboratory investigations, including full blood count, electrolytes, and renal and liver function tests, were all within normal limits. Computed tomography of the brain showed no intracranial abnormality. Lumbar puncture was not attempted because of the child’s fluctuating level of consciousness. He was investigated and treated with cefotaxime and acyclovir for suspected intracranial infection. Urine was sent for toxicology and metabolic screening. Seven hours after presentation, remarkable clinical improvement was noted, and he became fully alert and cooperative. At this point he vomited and also passed a substantial number of coloured beads in his stool. The family were further questioned about a history of ingestion; the boy’s mother divulged that he had been playing with Bindeez brand toy beads (Moose Enterprise, Melbourne, Vic) (Box). With no obvious diagnosis, he was admitted to hospital for observation and further investigation. An electroencephalogram showed no abnormalities. The urine toxicology screen returned with a negative result for illicit drugs. The urine metabolic screen became available on Day 5 and was positive for γ-hydroxybutyrate (GHB). The source of GHB in this patient was thought to be either exogenous (that is, poisoning) or an inborn error of metabolism. The latter was excluded when a repeat metabolic screen from urine taken on Day 3 returned with a negative result for GHB. In searching for an exogenous source of GHB, toy beads from the boy’s home, similar to those ingested, were sent for analysis and subsequently found to contain 1,4-butanediol (1,4-BD). The patient recovered completely and was discharged on Day 7 with no residual sequelae of his poisoning. Patient 2A 10-year-old girl presented to the ED after a 4-minute generalised seizure. She had been unrousable by family an hour earlier. She had then vomited up to 100 Bindeez beads and then had the seizure. She had been well earlier in the day, and there was no history of intercurrent illness or trauma. The patient had a further seven episodes of vomiting and was persistently drowsy. She had a background of Asperger’s syndrome and attention deficit hyperactivity disorder, for which she took extended-release methylphenidate. On arrival at the ED, she was drowsy, with a GCS of 14 and no focal neurological signs. Her heart rate was 70 beats/min, she was normotensive and physical examination was otherwise normal. On advice from the New South Wales Poisons Information Centre, a urine sample was collected, and beads from the patient’s home, similar to those ingested, were sent for analysis. Five hours after ingestion, she became alert and communicated appropriately. She was admitted to hospital for overnight observation and discharged the following day with no further complications. The urine metabolic screen was positive for GHB, and the beads were found to contain 1,4-BD. Public health responseAfter confirmation of GHB poisoning in Patient 1 from 1,4-BD detected in Bindeez toy beads, the NSW Poisons Information Centre was notified. The Centre and the NSW Biochemical Genetics Service alerted the NSW Office of Fair Trading about the product. They in turn contacted the company marketing the product to investigate the formulation of the toy beads. When the manufacturer in Hong Kong was contacted, it supplied a list of ingredients in the production of the toy beads; this list did not include 1,4-BD, but did mention the agent 1,5-pentanediol. Meanwhile, two further samples of Bindeez toy beads were tested at our institution. Both samples tested positive for 1,4-BD. None of the beads tested contained 1,5-pentanediol. With confirmation of similar biochemical analyses from the beads in the second case, the NSW Department of Health and the NSW Office of Fair Trading were further alerted about banning the product. The following day, the NSW Minister for Fair Trading issued an interim ban on the sale of Bindeez products in NSW; other Australian states rapidly followed suit. Further cases of GHB poisoning in Australia came to light during the ensuing days. Staff of the Poisons Information Centre also alerted toxicologists and poisons control centres worldwide where similar products are marketed (eg, Bindeez in the United Kingdom and Aqua Dots in North America) and the potential for GHB poisoning may have existed. With worldwide media coverage and similar cases in North America, an international recall soon followed. DiscussionGHB is an endogenously occurring neurotransmitter derived from γ-amino butyric acid (GABA).1 Its known metabolic precursors are 1,4-BD and γ-butyrolactone. A potent sedative and anaesthetic agent, it was initially synthesised in the 1960s.2 GHB and its precursors have recently found notoriety as recreational and club drugs. In 2000, GHB became a banned substance by the United States Drug Enforcement Agency and classified as Schedule 1 by the US Food and Drug Administration.2,3 1,4-BD is a widely available industrial chemical used as a solvent and in the manufacture of some types of plastics and fibres. When ingested, it is metabolised rapidly by alcohol and aldehyde dehydrogenases to GHB.4,5 Hence, the toxicity and clinical features of 1,4-BD poisoning are similar to those of GHB. While 1,4-BD is not a scheduled drug in Australia, it is a category 1 precursor under the Drug Misuse and Trafficking Regulations 2006, which restrict the supply of 1,4-BD (Pharmaceutical Services, NSW Department of Health, personal communication, 12 Nov 2007). GHB is an agonist at inhibitory GABAB receptors and is excitatory at specific GHB receptors. There is a dose–response relationship in GHB toxicity. Low doses result in vomiting, drowsiness, visual disturbance and disinhibition, while higher-dose effects include confusion, coma, bradycardia and myoclonic (seizure-like) movements.3 Routine urine toxicology screens do not detect GHB in their profile. Specific analysis with gas chromatography–mass spectrometry (GC–MS) or as part of a urine metabolic screen is required. The urine sample from Patient 1 was investigated for possible inherited metabolic diseases, including urinary organic acid analysis by GC–MS.6 This showed a marked increase in GHB (a metabolite seen in succinic semialdehyde dehydrogenase deficiency) but without any increase in 4,5-dihydroxyhexanoate lactone, as would be expected in the inborn error. This pattern strongly suggested an exogenous source of GHB, which was confirmed by the compound being undetectable in a second urine sample taken 3 days later. Treatment of GHB poisoning is primarily supportive and may involve airway and ventilatory intervention, and atropine for symptomatic bradycardia7 Gastrointestinal decontamination with activated charcoal is not indicated, owing to the rapid absorption of this liquid poison. Additionally, there are no specific antidotes that reliably reverse GHB toxicity.7 Where patients are suspected of ingesting Bindeez toy beads (containing 1,4-BD), they should be observed in the ED for depressed level of consciousness. Patients who remain asymptomatic after 4 hours are unlikely to have ingested enough beads to cause toxicity and can be safely discharged from hospital. Patients developing symptoms should be managed in a similar way to those with GHB intoxication. Moderately intoxicated patients may be managed and observed in the coma position until awake, while patients with airway compromise or respiratory failure may require intubation and mechanical ventilation until toxicity resolves. The identification of these cases highlights the important role of poisons centres in toxicovigilance and monitoring of potential clusters of poisoning related to new pharmaceuticals and chemical agents. Rapid electronic communication of these cases to worldwide toxicological networks enables health authorities to make a risk assessment of similar toy products overseas. So far, this has resulted in identification of similar suspected cases of GHB poisoning in children and an international withdrawal of the product. Chinese authorities confirmed that toy beads from the Hong Kong manufacturer contained a substance which metabolised to GHB.8 Bindeez bead set “Make, spray and they stay! Bindeez are magic beads that you use to create colourful and fun designs. Just lay out your design in the special Bindeez tray, then spray them with water and your artwork will magically set in place!” (from an advertisement for the toy).

Naren Gunja MB BS, FACEM · Evelyn Doyle MB BCh, BAO, MRCPCH · Kevin Carpenter PhD, FHGSA · Olivia T Chan BSc, MB BS · Simon Gilmore BPharm, MRPSGB · Gary Browne MD, FRACP, FACEM · Andis Graudins PhD, FACEM, FACMT

Australian health systems must rise to the challenge of providing thrombolysis to more stroke patients The substantial benefits and relative safety of tissue plasminogen activator (tPA) for acute ischaemic stroke within 3 hours of symptom onset have been accepted by stroke clinicians around the world.1 It is one of the most effective treatments in acute medicine, with a 30% increase in excellent outcomes and a “number needed to treat” for clinical improvement as low as three patients.2 A European register of 6483 patients (SITS-MOST, Safe Implementation of Thrombolysis in Stroke Monitoring Study) indicated that tPA is safe and effective, even when used in relatively inexperienced centres.3 The clinical benefits overwhelm a small rate of bleeding complications, chiefly symptomatic haemorrhagic transformation of the infarct. The rate of symptomatic intracerebral haemorrhage was actually lower in this large register than in the earlier randomised clinical trials.3 Small Australian tPA audits have confirmed these conclusions.4,5 Based on level 1 evidence, the therapy was licensed in Australia in 2003, and is recommended in Australian, North American and European stroke guidelines.6 However, despite this overwhelming information, probably some thousands of Australian patients are effectively denied tPA each year.7 This is a major challenge for our health system. Batmanian and her colleagues have made an important contribution,8 demonstrating that a 24-hour comprehensive protocol delivered by a team involving emergency physicians and stroke neurologists can deliver thrombolysis to 14% of their acute stroke patients (→ A protocol-driven model for the rapid initiation of stroke thrombolysis in the emergency department). This figure is in line with the best international stroke centres. The involvement of emergency physicians is essential to optimise the delivery of tPA, particularly given the worldwide shortage of stroke specialists. With a protocol aimed at rapid triage, assessment and investigation of stroke patients, Batmanian et al have shown that nearly all eligible patients can receive thrombolytic therapy. Their centre at St Vincent’s Hospital (Sydney) and other Australian centres are participating in the ongoing SITS international registry, aimed at auditing the efficacy and safety of tPA for acute stroke. Nearly 400 Australian patients have now been entered on this registry, with safety of tPA consistent with the benchmark European figures (Dr M Parsons, neurologist, John Hunter Hospital, Newcastle, personal communication). A key barrier to the use of tPA is delayed arrival to hospital after stroke onset. In the St Vincent’s study, 40% of patients arrived within 3 hours, a higher rate than in many centres. Improved access to tPA and other acute stroke therapies can be enhanced by public education about stroke symptoms (such as the FAST: Face, Arm, Speech, Time campaign of the National Stroke Foundation in Australia), followed by rapid ambulance transport to a hospital with an organised acute stroke team. The public must be educated to call an ambulance, not a general practitioner, when stroke symptoms occur. Australian studies have confirmed that ambulance officers can accurately diagnose most strokes.9 Ideally, paramedics inform the emergency department of their impending arrival, facilitating the 60-minute “door to needle” target time for tPA therapy. Implicit in achieving good outcomes after therapy is rapid access to a stroke care unit (SCU), the benchmark for optimising outcomes in a condition with a high mortality rate and the commonest cause of disability in our society.10 Stroke strategies in most Australian states have been developed to increase the access of acute stroke patients to SCUs, which are expert multidisciplinary and geographically localised units, using evidence-based protocols for acute stroke therapy. In Australia, these are generally not intensive care units (ICUs), although cardiac monitoring is desirable during the acute period. In the St Vincent’s study, patients were monitored in the ICU for up to 24 hours, because the protocol mandated a 1 : 2 nursing care ratio. We generally admit tPA patients to our SCU during or after the initial 1-hour infusion in the emergency department. Our SCUs use a 1 : 4 nursing ratio. We do not consider that ICU management is needed for most patients, but acknowledge that differing models will suit different institutions. Acute reperfusion therapy is the most promising approach for acute stroke. The evidence for efficacy of tPA within 3 hours is overwhelming, although there is still some debate about treatment in the very elderly, patients with very severe neurological impairment, or those with extensive early ischaemic changes on computed tomography (CT) scan. Meta-analysis of the tPA trials shows that there are treatment responders beyond 3 hours. A number of trials, such as the ECASS 3 and the IST 3 trials, are aimed at extending the current time window for intravenous tPA. Intra-arterial thrombolysis or mechanical clot retrieval may be alternative approaches for selected patients who do not respond to tPA within 3 hours, or within later time windows.11 Thrombolysis is based on the recanalisation of occluded arteries and reperfusion of the ischaemic penumbra, a region of injured brain that is potentially salvageable with rapid restoration of blood flow. Identification of the penumbra using magnetic resonance imaging or perfusion CT may also allow individualised therapy at longer windows.12 In 2007, we do not recommend routine use of intravenous tPA beyond 3 hours, but strongly encourage Australian clinicians to enrol patients into trials addressing these hypotheses. Intravenous tPA is relatively simple to use, particularly with an effective partnership between emergency physicians and stroke clinicians, using appropriate protocols and stroke unit care. It is highly effective and relatively safe. In the 12 years since it was proven, the major systems failure in most countries has been delivering it to more patients. In Australia, we should not shirk from this challenge.

Stephen M Davis MD, FRACP · Peter J Hand MD, FRACP · Geoffrey A Donnan MD, FRACP

Objective: To assess efficacy and safety of a 24-hour comprehensive protocol-driven model for rapid assessment and thrombolysis of stroke patients in the emergency department.Design: Prospective open observational study.Participants and setting: All patients with acute stroke presenting within 3 hours to the St Vincent’s Hospital (Sydney) emergency department between 1 December 2004 and 30 July 2005.Main outcome measures: Proportion of patients treated, patient demographics, clinical outcome, adverse events and time to treatment parameters.Results: 134 patients (100 stroke; 34 transient ischaemic attack) were admitted to the stroke unit during the study period. Of the 100 stroke patients, 40 presented within 3 hours of symptom onset. Fifteen patients had no contraindications and received intravenous thrombolysis. At 3 months, 10 patients (67%) were independent (modified Rankin score [mRS], 0–2) and seven (47%) had an excellent functional outcome (mRS ≤ 1). Symptomatic intracranial haemorrhage was not observed. The median time from symptom onset to tissue plasminogen activator treatment was 155 minutes (range, 105–197 min). Median onset-to-door, door-to-computed tomography, and door-to-needle times were 48, 25, and 87 minutes, respectively.Conclusion: Rapid assessment of stroke in the emergency department according to a comprehensive protocol allows identification and treatment of acute ischaemic stroke patients eligible for thrombolysis.

Julia J Batmanian BSc(Med), MB BS(Hons) · Meeyin Lam BAppSc(Physio), MIPH · Caitlin Matthews BSc(Hons), MB BS(Hons) · Andrew Finckh MB BS, FACEM · Martin Duffy MB BS, MMed(ClinEdi), FACEM · Robert Wright FRACP, FFARACS, FJFICM · Bruce J Brew MB BS, MD, FRACP · Romesh Markus PhD, FRACP, MB ChB

We treat patients, not levels The goal of therapy with antiepileptic drugs (AEDs) is to prevent all seizures, using drugs that produce minimal side effects. Success in achieving this goal must be assessed clinically. Routine ordering of tests to measure AED levels is misguided, given that the tests are costly and often unnecessary.1 Therapeutic drug level monitoring was introduced because of a belief that drug levels in the blood were a more reliable indicator of efficacy than drug dose alone. Although this relationship applied to phenytoin, the main drug in use three decades ago, it does not apply to many AEDs. The concept of a “therapeutic range” is a statistical concept, applying to populations rather than individuals. There are many patients whose condition is perfectly well controlled with so-called subtherapeutic doses, while other patients may require more than the recommended therapeutic dose. For most patients, management need not involve serum drug measurements. They are certainly unnecessary for the so-called second generation AEDs or for benzodiazepines, which are selectively taken up by the brain and for which serum level measurements are not meaningful for management.2 Sodium valproate (SVP) is widely used. The relationship between SVP serum levels and efficacy has not been confirmed, and serum testing is often inappropriate, as reported in this issue of the Journal (→ Serum sodium valproate testing: is it appropriate?).3 On conventional doses of SVP (which should be kept under 1000 mg per day in women of childbearing age), most compliant patients achieve a serum level within the so-called therapeutic range, which is wide (350–700 μmol/L). Previous studies have shown that results of SVP assays do not influence the doses used in management.4 If the results are not acted on, the tests are a waste of time and money. On the other hand, patients can be destabilised if the results of SVP assays directly influence doctors to alter doses regardless of clinical indications.5-7 For the AEDs topiramate, vigabatrin, oxcarbazepine, gabapentin and levetiracetam, insufficient data are available to justify serum level monitoring. In fact, for vigabatrin, which acts by permanent inhibition of an enzyme related to neurotransmitters, measuring levels is totally unnecessary.4 Lamotrigine may represent a special category. The metabolism of this drug is induced by sex hormones in the oral contraceptive pill and is also altered during pregnancy. In these circumstances, the drug is rapidly eliminated. It may be helpful to measure lamotrigine concentrations in each trimester to keep them at pre-pregnancy levels by adjusting the dose. At delivery, the dose must be reduced. There is no accepted therapeutic range for lamotrigine, and the concept of individual ranges has been proposed. Once a level is established that is associated with good control of the patient’s seizures, this level may be a target to be aimed at when changes are made to AED doses and co-medications in that particular patient. However, routine measurements are not recommended.8 Thus, with the exception of phenytoin (and possibly lamotrigine), none of the AEDs are suitable candidates for therapeutic drug monitoring assays in routine practice, as such tests put a high cost burden on the health service without significant patient benefit. The International League Against Epilepsy guidelines state that AED serum concentrations must not be measured indiscriminately and that adjusting doses merely to achieve cosmetic correction of levels is inadvisable. However, compliance problems can be an indication for performing an assay.9 In conclusion, we treat patients, not levels. The rationale for performing drug assays should be based on clear indications for why they are to be ordered. Clinical symptoms, inadequate response and possible toxicity may be valid indications, but the most important one appears to be suspicion of non-compliance.

Frank J E Vajda MD, FRCP, FRACP

Objective: To assess whether serum sodium valproate (SVP) testing in the hospital setting is being performed according to evidence-based criteria.Design and setting: Retrospective audit of serum SVP concentration measurements performed on inpatients and emergency department patients at The Canberra Hospital from May to July 2005.Main outcome measures: Indication for performing the test, assessed against evidence-based criteria; timing of blood sample collection; whether the test result altered patient management; whether the request form allowed laboratory staff to assess the appropriateness of the test; cost of performing inappropriate tests.Results: We retrieved 211 test results performed on a total of 95 patients. Notes on 89 patients were available for analysis. Based on evidence-based criteria, 15% of tests were done for an appropriate indication and 29% of the samples were taken at an appropriate time. At most (using generous criteria), 57% of test results made a difference to patient management. Forty-four per cent of request forms contained sufficient detail to allow the pathology department to assess the appropriateness of the test. An estimated $13 236 would be spent unnecessarily on SVP testing at our hospital over a 1-year period.Conclusions: Most serum SVP level measurements were requested inappropriately, and many were not taken at the correct time, thereby rendering the results uninterpretable. Better education of requesting clinicians could significantly reduce the number of unnecessary tests and thus reduce the cost to the health service.

Chamishani Rathmalgoda · Julia M Potter MB BS, PhD, FRCPA · Christian J Lueck PhD, FRACP, FRCP

Why all patients with a pituitary mass need to be seen by an endocrinologist For the average general practitioner, pituitary disorders are relatively uncommon. However, post-mortem and magnetic resonance imaging (MRI) studies show that about 10% of the population may harbour a pituitary mass, although most are small, non-functioning microadenomas.1 Pituitary adenomas are the commonest intracranial neoplasm, making up about 10%–15% of such lesions.2 In most large series, prolactinomas are the most prevalent subtype, at between 40% and 50%; non-functioning adenomas account for about 30%, with other functioning adenomas (secreting growth hormone, causing acromegaly; secreting adrenocorticotropic hormone, causing Cushing’s disease; or secreting glycoprotein hormones, such as intact follicle-stimulating hormone, luteinising hormone and thyroid-stimulating hormone) making up the remainder.3 We would like to put forward the view that the endocrinologist should be the key practitioner in a multidisciplinary approach to pituitary masses. Within the Australian health system, most patients in whom a pituitary mass is discovered are referred directly to a neurosurgeon. Many non-endocrinologists making such referrals do not realise the critical importance of the neurosurgeon’s specific pituitary surgical experience in patient outcome. Initial assessment of a patient with pituitary disease includes differential diagnosis, making decisions regarding necessity for surgical intervention, and medical management, including correction of any underlying hypopituitarism or hormone excess. On occasion, an endocrinologist may detect subtle variations in a patient’s presentation that can significantly alter management. Therefore, we encourage practitioners to refer patients initially to an established multidisciplinary pituitary team using a shared management approach — a team in which an endocrinologist works in conjunction with a pituitary neurosurgeon. Other relevant health professionals may include a neuroradiologist, ophthalmologist and radiation oncologist. Such teamwork can ensure optimal benefits for patients at all stages of management. With respect to functioning adenomas, most prolactinomas do not require surgery, even when a significant visual field defect is present. Mild increases in serum prolactin levels can be seen with some non-functioning pituitary lesions because of the interruption of dopamine delivery down the pituitary stalk. A level elevated more than 10-fold has traditionally been diagnostic of prolactinoma, for which the initial management should, in most circumstances, be with dopamine agonists.4 More recent evidence indicates that, for about 99% of histologically confirmed non-functioning adenomas, the serum prolactin level can be up to 2000 mIU/L; the authors of that article recommended a trial of dopamine agonist in patients with a macroadenoma and serum prolactin levels of more than 2000 mIU/L.5 There are tumours that secrete enough adrenocorticotropic hormone or growth hormone to produce only subtle clinical features of Cushing’s syndrome or acromegaly, respectively. Because the perioperative management of a patient with Cushing’s disease and acromegaly differs from the management of a patient with a non-functioning mass, it is important to detect these cases of subclinical pituitary hypersecretion before surgery, so the correct functional diagnosis is made from the outset.6 This also gives the endocrinologist the opportunity to use medical therapies such as somatostatin receptor analogues in the pre- or postoperative setting where appropriate. Patients with hypopituitarism benefit from hormone replacement.7 Although giant, vision-threatening tumours do occur, most cases do not generally require emergency surgical intervention, so there is time, in consultation with the neurosurgeon, for adequate assessment and stabilisation of the patient’s hormone state before surgery. Patients with clear hypopituitarism should begin taking maintenance doses of glucocorticoid and thyroxine before surgery. Sex steroid replacement can be delayed until after postoperative assessment. Successful resection of a macroadenoma may result in reversal of the hypopituitarism.8 Appropriately timed postoperative pituitary function testing and correct interpretation of the results is required for optimal outcome. Not all pituitary or suprasellar masses are pituitary adenomas. Sometimes characteristics on MRI can distinguish between the other various causes.9 The presence of diabetes insipidus is a strong clue that the mass is not a pituitary adenoma.7 Inflammatory (eg, Langerhans’ cell histiocytosis and lymphocytic hypophysitis) and other neoplastic lesions (eg, craniopharyngioma and germinoma) are commonly associated with diabetes insipidus, whereas it is very rare for an uncomplicated pituitary adenoma to present in this way. Preoperative recognition of non-adenomatous lesions may alter management. For example, lymphocytic hypophysitis often responds to high doses of glucocorticoids, even when a large mass with visual field compromise exists;10 Langerhans’ cell histiocytosis responds well to low-dose radiotherapy;11 and germinomas, which may be associated with increased serum or cerebrospinal fluid β-human chorionic gonadotropin levels, are best treated with a combination of chemotherapy and radiotherapy.12 With a collaborative, multidisciplinary approach to patient care, the endocrinologist can evaluate the likely differential diagnosis, in conjunction with the pituitary neurosurgeon and neuroradiologist, relevant investigations can then be performed, and a collective decision can made on the most appropriate management for each particular patient. Trans-sphenoidal pituitary surgery is a highly specialised procedure, and it is clear from published data that the experience and skill of the neurosurgeon is of paramount importance in determining outcome, particularly for secretory lesions. A review from the United States showed that higher surgical volume is associated with significantly reduced mortality, fewer complications and a reduced length of hospital stay.13 The best results were achieved by units where more than 25 patients were operated on per year.13 It has been estimated in the United Kingdom that only one pituitary neurosurgeon is needed for each five million of population.14 In a country such as Australia, it would seem pragmatic to have a small number of specialised neurosurgeons who do virtually all the pituitary surgery. However, such a scenario seems a long way off and would be fraught with political, personal and inter-hospital rivalries. Nevertheless, informal management networks can be forged by altering referral patterns. In Birmingham, UK, the cure rate for acromegaly almost doubled when the endocrinologists sent all their patients to one neurosurgeon, compared with when eight neurosurgeons in the city were performing pituitary surgery.15 This is another key reason why we believe referrals for patients with pituitary masses would be best directed to an established multidisciplinary team involving, as two key members, an endocrinologist with primary responsibility for pre- and postoperative assessment, and an experienced pituitary neurosurgeon. Pituitary masses are the commonest intracranial neoplasm. The initial point of referral should be an endocrinologist within an established multidisciplinary team. We are aware that a number of teaching hospitals in the major Australian cities have developed considerable expertise in the multidisciplinary management of pituitary lesions. In our opinion, this approach provides a high standard of care and contributes to the ongoing training experience of endocrinology and neurosurgery registrars. We believe patients who wish to be cared for in the private sector would also benefit from being managed jointly by an endocrinologist and a specialised pituitary neurosurgeon, if not by a full multidisciplinary team.

Warrick J Inder MB ChB, MD, FRACP · Frank P Alford MB BS, MD, FRACP