Neurology

A 16-year-old boy presented with rapidly progressive ascending paralysis 1 hour after eating raw salmon. Seafood poisoning was initially considered. Although salmon is not a common cause of toxic seafood poisoning, cases have been reported in the Pacific region. The patient rapidly developed acute left heart and respiratory failure, and investigations revealed a rare tracking intramedullary haematoma of the spinal cord. Structural abnormalities of the central nervous system may present with acute paralysis and spinal shock, mimicking toxicological syndromes. Clinical recordA 16-year-old boy presented to the emergency department with severe epigastric pain, headache and ascending lower limb weakness 1 hour after eating raw salmon. The weakness ascended rapidly over the next hour to involve the upper limbs. In hospital, he was alert, but was soft-voiced and in obvious respiratory distress. He had tachycardia (heart rate, 110 beats per min), hypertension (blood pressure, 205/128 mmHg), tachypnoea (22 breaths per min) and oxygen saturation of 89% (using a non-rebreathing oxygen mask). Although his sensation and mental state appeared normal, he had profound quadriparesis. Pupils were 3 mm in diameter, equal and sluggishly reactive to light. Because of a rapid deterioration in his respiratory status, the patient was intubated, ventilated, and sedated with a propofol infusion before a more complete neurological examination could be completed. The patient’s medical history included thalassaemia minor and a short viral illness 2 weeks previously. He denied using any regular medications or substance misuse. Initial chest radiography revealed clear lung fields, but, 10 minutes after intubation, pinkish frothy sputum was noted from the endotracheal tube, and there were widespread crackles. An urgent echocardiogram showed severe global hypokinesis with a left ventricular ejection fraction estimated as less than 30%. Laboratory tests revealed neutrophilia, but all other results of a full blood count, serum electrolyte concentrations, renal function, liver function tests and coagulation screen were normal. Serum creatine kinase and creatine kinase-MB concentrations were raised, and peaked the following day at 2716 U/L (reference range [RR], 30–135 U/L) and 10 μg/L (RR, < 0.7 μg/L), respectively, suggesting myocardial injury. An electrocardiogram showed sinus rhythm with voltage criteria for left ventricular hypertrophy, but no acute ischaemic changes. Provisional diagnosis at this stage was a neurological or toxicological aetiology. The fact that the patient’s mother also ate the salmon without becoming unwell counted against seafood poisoning but did not exclude it (eg, in puffer-fish poisoning, a specific part of the fish is most poisonous). To exclude a cervical lesion, magnetic resonance imaging (MRI) of the spine and brain was performed urgently, with the intention of proceeding to nerve conduction studies if MRI results were normal. The MRI showed an extensive intramedullary haemorrhage within the spinal cord, originating at the T7/T8 vertebral level, and extending from the conus caudally to the cervicomedullary junction rostrally (Box 1). The patient was managed supportively in the intensive care unit, with complete resolution of pulmonary oedema and normalisation of cardiac function by Day 3. A spinal angiogram confirmed the presence of an arteriovenous malformation arising from the anterior spinal cord at the T9 vertebral level. The malformation was excised the following week, and histopathological examination of the resection specimen confirmed the radiological diagnosis (Box 2). After 6 months of intensive rehabilitation, the patient had restored power in one arm, but remained paralysed below the T9 cord level. DiscussionInitially, this case represented a diagnostic challenge, with acute onset, rapidly progressive ascending paralysis associated with left ventricular failure, and a history of seafood ingestion. MRI gave the correct diagnosis, obviating the need for peripheral neurophysiological investigations. Useful clues to the diagnosis of myelopathy, such as sphincter dysfunction and the level of sensory loss, were difficult to assess because of the patient’s sudden cardiorespiratory deterioration. The initial differential diagnosis is summarised in Box 3. Toxicological considerationsPoisoning from ingested seafood is a global and increasing problem that should be considered in the emergency department. Seafood associated with medically important poisoning include puffer fish (fugu), ciguateric fish, several types of shellfish and mussels, as well as fish from the Scombridae family (eg, mackerel and tuna). Salmon is not known as a major cause of seafood toxin poisoning, although scombroid and ciguatera have been described after salmon ingestion.1-3 Tetrodotoxin from fugu fish causes a rapid descending paralysis and cardiovascular collapse in severe cases.4 Paralysis is uncommon in ciguatera, which is caused by a toxin produced by marine dinoflagellates.5 Paralytic shellfish poisoning is clinically similar to tetrodotoxin poisoning and typically causes a descending paralysis. Autonomic disturbance can also be a feature of marine neurotoxin poisoning. Other toxins that can cause paralysis include botulinum, diphtheria and tick paralysis toxin, but these have slower onset of action and produce prodromal symptoms. Organophosphate poisoning is also worth considering: paralysis and copious bronchial secretions consistent with cholinergic toxicity are seen. Neurological considerationsThe hyperacute onset of our patient’s symptoms suggested an acute inflammatory demyelinating polyneuropathy, especially in view of the preceding infective illness. Even so, the presentation and progression of the weakness were unusually rapid. Similarly, autoimmune neuromuscular junction disorders, such as myasthenia gravis and Lambert–Eaton myasthenic syndrome, run a more subacute, relapsing course. Periodic paralysis can cause sudden weakness, but there is often a history of recurrent attacks. Toxic and inflammatory myopathies and neuropathic heavy metal poisoning have a more chronic and progressive course. The cause in our patient was an intradural intramedullary arteriovenous malformation, the most common form of spinal cord vascular lesion in childhood and adolescence.6 These lesions can haemorrhage and cause catastrophic autonomic dysregulation accompanied by spinal shock. Complications include neurogenic pulmonary oedema, with the sympathetic storm contributing to transient myocardial impairment via direct neurogenic and humoral mechanisms. ConclusionThis patient illustrates an uncommon scenario of rapidly progressive flaccid paralysis presenting to the emergency department. Emergency physicians need to consider a broad neurological and toxicological differential diagnosis in the patient with flaccid paralysis. Structural abnormalities of the central nervous system may present with acute paralysis and spinal shock, mimicking toxicological syndromes. 1 Magnetic resonance image of the cervical spinal cord A sagittal T2-weighted image showed a high signal (arrow) within the cervical cord caused by blood breakdown products (intracellular methaemoglobin). 2 Lesion excised from the spinal cord Histopathological examination of the resection specimen showed abnormally clustered vessels of venous (V) and arterial (A) type intermingled with spinal nerve bundles (N). This vascular configuration is typical of an arteriovenous malformation. (Haematoxylin and eosin stain; original magnification, × 40.) 3 Toxicological and neurological causes of acute paralysis Ascending paralysis Toxicological: tick paralysis (Ixodes spp.) Neurological (peripheral): acute inflammatory demyelinating polyradiculoneuropathy (Guillain–Barré syndrome) Descending paralysis Toxicological: puffer-fish (tetrodotoxin) poisoning, paralytic shellfish poisoning, snake bite, botulism, diphtheria Neurological (peripheral): myasthenia gravis Other Toxicological: ciguatera, neurotoxic shellfish poisoning, organophosphate poisoning Neurological (peripheral): myopathies (including myositis and periodic paralysis), acute poliomyelitis and toxic neuropathies

Naren Gunja FACEM · Robert P Dowsett FACEM · Karl Ng MRCP, FRACP

A woman in her 20s presented to the emergency department, malnourished and dehydrated, and with acute paralysis of the lower limbs. Over the previous 10 days, she had inhaled nitrous oxide from “whipped-cream bulbs” (10–20 per day) for pain caused by a sprained ankle. She had a history of intravenous drug use and was on a methadone program. The nitrous oxide misuse combined with the malnutrition, with low vitamin B12 levels, apparently resulted in subacute combined degeneration of the spinal cord — a rare complication of nitrous oxide misuse. Clinical recordA young woman in her 20s presented to the emergency department with a history of increasing difficulty in mobilising over the previous week. For the 3 days before presentation, she had been confined to the back seat of a car (from which she was extricated with difficulty on arrival at the emergency department). An estimated 60 empty “whipped-cream bulbs” were found on the floor of the car. She had a history of intravenous drug use and was on a methadone program, but there was no other significant medical history. She had sprained her ankle 10 days before presentation, and had been inhaling nitrous oxide from whipped-cream bulbs for the pain (10–20 per day). Further immobility and boredom had increased her usage. On examination, she was pleasant, but dishevelled and malnourished, with evidence of needle track marks from intravenous drug use on her extremities. She had a Glasgow Coma Scale score of 14/15 (best eye response, 4; best verbal response, 4; best motor response, 6); her respiratory rate was 20 breaths/min; heart rate, 95 beats/min; blood pressure, 95/63 mmHg; temperature, 35.6°C; and oxygen saturation in room air was 94%. She had a 1/5 flaccid proximal weakness of the lower limbs (Medical Research Council [United Kingdom] scale), with a flicker of power preserved distally, but absent plantar and knee-jerk reflexes. She had a patchy sensory level to T10, and absent vibration sense to her anterior superior iliac spines bilaterally. There was a proprioception deficit to her feet, knees and hips bilaterally. She was in urinary retention, and 1800 mL was drained through an indwelling urinary catheter. Rectal examination showed atony of the anal sphincter. There were mild pressure areas on the dorsal surfaces of her legs and buttocks, with diffuse oedema of the lower limbs. The rest of the examination was unremarkable. InvestigationsDifferential diagnoses included a space-occupying lesion of the spinal cord, transverse myelitis, HIV myelopathy, Guillain–Barré syndrome, and multiple sclerosis. We were concerned about the presence of a neurological toxin in the whipped-cream bulbs, given the history of neurological deterioration coinciding with the patient’s excessive use of the bulbs. Our diagnosis was initially delayed, as we were unable to ascertain the exact constituents of a whipped-cream bulb. Magnetic resonance imaging (MRI) of the whole spine and brain was performed and was initially reported as showing no abnormality. Initial laboratory investigations showed: a raised serum creatine kinase level of 9000 U/L (reference range [RR], < 150 U/L); acute renal failure, with a creatinine level of 490 μmol/L (RR, 80–140 μmol/L) and a urea level of 41 mmol/L (RR, 2.5–7.5 mmol/L); a troponin leak of 0.7 μg/L (RR, < 0.05 μg/L); and a normocytic anaemia, with a haemoglobin level of 83 g/L (RR, 120–140 g/L) and a mean cell volume of 95 fL. Vitamin B12 levels were 124 pmol/L (RR, > 210 pmol/L). A lumbar puncture was attempted but, on sitting the patient upright, she had a bradycardiac arrest and required cardiopulmonary resuscitation (CPR) for 30 s, resulting in spontaneous return to circulation and heart rate. Her arrested circulation was most likely the result of her being dehydrated (as evidenced by prerenal renal failure). Given her clinically demonstrated neuropathy, it is possible that a combination of autonomic neuropathy and reduced intravascular volume from dehydration, together with orthostatic stress on positioning, resulted in the precipitous fall in blood pressure, bradycardia, and arrest. This would explain the rapid return to cardiac output on return to a supine position, with only transient CPR. A Doppler ultrasound scan of the lower limbs showed bilateral deep venous thrombosis (DVT) to the level of the common femoral arteries. Indirect evidence of pulmonary embolus (PE) included a large alveolar–arterial gradient of > 100 mmHg (RR, 10–25 mmHg) and electrocardiogram changes — tachycardia and a right bundle branch block. It was decided not to perform a computed tomography pulmonary angiography, given the strongly supportive evidence for PE, and an intravenous contrast load was contraindicated given her acute renal failure. A further PE on upright positioning may also have contributed to her cardiac arrest; however, her rapid return to baseline clinical status on returning to a supine position does not support this. Clinical courseThe patient was resuscitated in the emergency department, with fluid loading for prerenal renal failure and as therapy for rhabdomyolysis. She was then transferred to the intensive care unit (ICU) for observation, and given vitamin B12 replacement therapy and methionine. Her acute prerenal failure resolved with rehydration, and she was given an intravenous heparin infusion as anticoagulation therapy for bilateral proximal DVT, and subsequently given warfarin for a target international normalised ratio of 2.0–3.0. Further imaging, such as a ventilation–perfusion scan for the presence of PE, was not performed as it would not have contributed to her management. After 2 days in the ICU, she was transferred to a general medical unit. An MRI scan on review 2 weeks after her admission showed an increased T2 signal within the posterior columns of the spinal cord. She slowly regained partial motor function of her limbs and normal sensory levels over the following 5 months. She was discharged after 7 months of rehabilitation and inpatient care. She was able to walk short distances, with the aid of a walking frame, but had residual neurological deficits affecting the distal lower-limb muscle groups. DiscussionNitrous oxide is a colourless, odourless gas with a weak anaesthetic but useful analgesic action.1 It is used during short, painful procedures. Because of its ability to elevate mood, nitrous oxide is colloquially known as “laughing gas”, and is a common drug of misuse. “Nagging” or “nanging” are terms used to describe the recreational use of nitrous oxide, derived from the repetitive sound distortions experienced by nitrous oxide users.2,3 In a New Zealand survey of first-year university students, 57% were aware of its recreational use and 12% used it regularly.2 Nitrous oxide is readily available from most supermarkets and online, as it is used as the aerator and propellant for whipped-cream dispensers. The average bulb used for aerating whipped cream contains 8 g of nitrous oxide. Pathophysiology and diagnosisSubacute combined degeneration of the spinal cord is a recognised complication of vitamin B12 deficiency or of nitrous oxide exposure (with or without pre-existing normal vitamin B12 levels). This complication is well documented in anaesthesia literature in relation to frequent nitrous oxide exposure in anaesthesia, such as during multiple operations, or analgesic use for repeated dressing changes for burns patients.4,5 Patients with long-term nitrous oxide recreational use are reported to have neurological symptoms ranging from paraesthesias to incoordination and autonomic dysfunction.6-9 There is no known neurological toxicity threshold for nitrous oxide exposure. Toxicity is related not to the frequency or level of nitrous oxide exposure, but to the patient’s levels of vitamin B12. Spinal cord degeneration resulting from a single short exposure to nitrous oxide anaesthesia, in association with vitamin B12 deficiency, has been reported.10,11 The neuropathological changes observed in the affected spinal cord include initial swelling and irregularity of the myelin sheath surrounding the nerve cell axons (reversible), followed by frank demyelination and loss of axons (irreversible).12 This occurs in the central regions of the posterior columns and, to a lesser extent, in the posterolateral regions of the spinal cord. The changes manifest as high-signal lesions on MRI T2-weighted scans caused by increased water content secondary to oedema.10,11 Nitrous oxide inhibits the active form of vitamin B12, rendering it unavailable to form the myelin sheath proteins, resulting in axonal swelling and eventual axonal loss. The mechanism of action is the inactivation of vitamin B12 (cobalamin) from its monovalent, active cobalt form (Co+) to the inactive, bivalent cobalt form (Co2+). The irreversibly inactivated vitamin B12 (Co2+) results in failure of methylation of proteins in the myelin sheaths4 and a loss of nerve cell axon integrity.12 Another contributing factor to the toxicity of nitrous oxide is the role of vitamin B12 as a cofactor of the methionine synthase reaction. The enzyme catalyses the reaction in which homocysteine is converted to methionine; tetrahydrofolate is also formed, which is a cofactor in the metabolism of nucleic acids (eg, DNA).9 Thus, nitrous oxide has a direct effect on DNA synthesis, as well as nerve axon integrity. Other postulated mechanisms of action for central nervous system toxicity of nitrous oxide include inhibitory effects on N-methyl-d-aspartate receptors, stimulatory effects on dopamine neurones, stimulation of descending noradrenergic neuronal pathways, provoked release of noradrenaline in dorsal horn neurones, and sympathetic action via α-1-adrenergic stimulation.8,9 A diagnosis of subacute combined degeneration of the spinal cord can be confirmed by MRI, in association with low serum vitamin B12 levels, but in some cases MRI scans show no abnormality.11 The differential diagnoses include demyelination, neoplasms, infections (eg, with Listeria spp., or HIV), myelopathy, and syringomyelia. Treatment and prognosisTreatment involves ceasing nitrous oxide use and giving vitamin B12 replacement therapy. Administration of methionine may also be required as an adjunct, given the direct effects of nitrous oxide on methionine synthase. Exogenous methionine would provide a direct substrate for methionine synthase, while the body slowly replaces the inactive vitamin B12 and commences repletion of endogenous methionine. Two patients receiving vitamin B12 replacement therapy experienced a worsening of their neurological symptoms until the addition of oral methionine, which halted the neurological decline and accelerated their recovery.9 Reported recovery periods vary from 1 week to 1 year. Partial versus full recovery will depend on the extent of the neuropathological damage to the spinal cord; spinal cord oedema and myelin sheath loss will resolve, but axon loss is permanent.

Michaela Cartner MB BS, FACEM · Michael Sinnott MB BS, FACEM, FRACP · Peter Silburn MB BS, PhD, FRACP

The motor neurone disease handbook Matthew C Kiernan, editor. Sydney: MJA Books, 2007 (vii + 230 pp). ISBN 978 0 9775786 3 4 The diagnosis and management of a patient with motor neurone disease (MND) is, in my opinion, the hardest task in clinical neurology. The patient and family often want an early diagnosis at a time when it is not wise to be too dogmatic. When the diagnosis is finally given and the prognosis discussed, there is an understandable period of despair, which the neurologist tries to ease with regular follow-up visits. Despite the lack of a truly effective therapy, there have been significant advances in the ongoing care of patients with MND, which have been greatly facilitated by the concept of the multidisciplinary team. Matthew Kiernan runs a multidisciplinary MND clinic at the Prince of Wales Hospital in Sydney and has been involved in the development of the Australian MND Registry. He is well qualified to edit this handbook and has assembled a distinguished group of local and international contributors who have provided a comprehensive account of the current status of research and clinical care of patients with MND. All chapters are of a uniformly high standard and the style and content are reader-friendly. As a neurologist I found the chapter by Rod Mackenzie, a colleague with MND, not only very instructive but particularly inspiring. This is a much-needed handbook for neurologists, general practitioners, allied health professionals, and patients and their families. To my knowledge there is no comparable publication and it comes at an important time for those in the MND field. The advent of riluzole, which in controlled trials has shown a capacity to prolong survival, has not only provided some hope for patients and their families, but has focused the attention of neurologists on the need to improve overall care in this disease, similar to the effect of interferon-β in multiple sclerosis more than a decade ago.

John King

Providing spiritual care is about tapping into the concept of spirituality: core meaning, deepest life meaning, hope and connectedness. The search for meaning, connectedness and hope becomes more significant as older people are faced with the possibilities of frailty, disability and dementia. Spirituality, ageing and meaning in life can be discussed in the context of an alternative view of “successful ageing”. A model of spiritual tasks in older age can help explain the spiritual dimension and provide a starting point for spiritual assessment.

Elizabeth B MacKinlay PhD · Corinne Trevitt RN, MN, GradDipGerontics

Alzheimer’s disease (AD) is the most prevalent dementia (accounting for 50%–75% of cases of dementia in people aged over 65 years), followed by frontotemporal dementia (FTD) (10%–20% of cases). AD is characterised histopathologically by Aβ-containing amyloid plaques and tau-containing neurofibrillary tangles, whereas FTD exhibits neurofibrillary tangles alone. Current symptomatic treatments of AD are of limited benefit, as they are not directed at the underlying biological basis of the disease. The development of transgenic animal models has provided insight into disease mechanisms and helped define novel drug targets. More than 50 drugs are currently in clinical trials, and novel and more effective drugs targeting both AD and FTD are expected to become available within 5–10 years.

Jürgen Götz PhD · Lars M Ittner MD · Nicole Schonrock PhD

Born in Sydney on 22 April 1920, John Tyrer was appointed the first full-time Professor of Medicine in Queensland at the age of 34 and shaped medical teaching and research in that state for over 30 years. John graduated in medicine from the University of Sydney in 1941 after a distinguished undergraduate career and trained as a physician at the Royal Prince Alfred Hospital, Sydney. There he carried out the experimental studies on the cardiovascular dynamics of artificially perfused sheep for which he was awarded a Doctorate of Medicine. After assuming the Chair of Medicine of the University of Queensland in 1954, John set about building a modern research-based Department of Medicine at the Royal Brisbane Hospital (then the Brisbane General Hospital), an institution whose traditions had been almost wholly clinical. He systematically recruited research-oriented academic clinicians, initially from outside Queensland and then from within. He established several “temporary clinical lectureships” that were filled by aspiring medical registrars who were given the opportunity to combine clinical responsibilities with research. Many people who spent their formative years being nurtured in such positions subsequently went on to become academic leaders in Australia. By the time of John’s retirement, in 1985, his Department of Medicine was one of the largest and most productive in the University of Queensland, spanning three teaching hospitals. John’s main interest lay in neurology and neuropharmacology, in which he collaborated productively with his colleague Mervyn Eadie. However, he remained an astute general physician with superb clinical acumen and skills. Perhaps his greatest legacy lies in the large number of students and junior colleagues whom he influenced and encouraged. His high academic standards, meticulous record keeping and clarity of thought and speech were salutary and refreshing. John authored or co-authored eight books and over 100 articles. After retirement, he wrote a lavishly illustrated book, The history of the Brisbane Hospital — a mammoth undertaking. John was a Francophile and collaborated with French neurologists such as Raymond Garcin and François Lhermitte. He had a special interest in language and was widely read in classical literature, history and philosophy. John died in Brisbane on 6 June 2006 of advanced bladder cancer. He is survived by his wife Patricia and seven children. Lawrie Powell

Lawrie W Powell

Objective: To compare patterns of epilepsy in Indigenous and non-Indigenous people presenting to hospital.Study design: Retrospective cross-sectional survey of individuals admitted to hospital with a diagnosis of epilepsy (1 January 2001 – 31 December 2004); presenting to the emergency department with a seizure (2004); or presenting to the epilepsy clinic (1 September 2002 – 31 March 2005).Setting: Cairns Base Hospital, the major referral centre for Far North Queensland, including Cape York and the Torres Strait, with a population of 230 000 (13% Indigenous).Main outcome measures: Proportion of Indigenous patients presenting for epilepsy; proportion of Indigenous and non-Indigenous groups affected by each of the main epilepsy syndromes.Results: Of 359 patients attending the epilepsy clinic and 918 patients having electroencephalography (EEG), 11% and 13% were Indigenous, respectively (in proportion with the catchment population). However, 30% (146/486) of patients presenting to the emergency department with seizure, 31% (130/418) of inpatient admissions with epilepsy, and 44% (28/63) of patients admitted with status epilepticus were Indigenous. Indigenous patients were more likely to have an abnormal EEG result (P = 0.025), while non-Indigenous patients presenting to the clinic were more likely to be classified as non-epileptic (31% v 18%). In those with abnormal EEG, the frequency distribution of abnormalities was similar, and, in those with epilepsy, syndrome classification also showed similar frequencies. There was no significant difference in occurrence of epileptogenic abnormalities detected by imaging (13% non-Indigenous v 18% Indigenous) or in alcohol consumption (38% v 37%).Conclusions: Indigenous Australians have similar epilepsy syndromes to the non-Indigenous population, but they present with more serious disease. This discrepancy may relate to inequitable health care utilisation due to cultural issues or geographic isolation.

John Archer FRACP, PhD · Ruth Bunby BAppSc

Clinical records The details of four patients treated at the Head and Neck Unit, Princess Alexandra Hospital, Brisbane, over a 1-year period are summarised in the table. All four patients presented with progressive trigeminal or facial nerve palsies following excision of cutaneous lesions from the head and neck. Patient Age (years) Sex Presentation History of cutaneous head and neck malignancy Specialties involved Delay in diagnosis Investigations Final diagnosis Management Patient 1 40 male 3 years’ progressive paraesthesia of the left upper lip and cheek Nasal tip lesion removed with cryotherapy: no histology available General practice, dermatology, otolaryngology 3 years MRI PNS (SCC) along V2 Intracranial/skull base surgery with postoperative radiotherapy Patient 2 41 male 8 months’ progressive left cheek paraesthesia, jaw pain and trismus Excision of a left lower lip SCC 2 years previously: histology showed small nerve PNS, so postoperative radiotherapy given General practice, maxillofacial, neurology, otolaryngology 6 months MRI (showed hyperintensity of the left masseter consistent with denervation changes) Masseteric muscle biopsy PNS (SCC) along V2 and V3 extending to the pons Palliative radiotherapy Patient 3 67 female 2.5 years’ progressive left facial nerve palsy Extensive facial SCCs, including an aggressive recurrent right cheek SCC treated with radical excision and radiotherapy Neurology, ophthalmology, otolaryngology 2.5 years MRI PNS (SCC) along VII and V2 Intracranial/skull base surgery with postoperative radiotherapy Patient 4 72 female 5 months’ progressive left facial nerve palsy and left forehead and cheek paraesthesia Two skin lesions excised from the right (contralateral to nerve palsies) nasolabial sulcus 20 years previously: no histology available Otolaryngology 5 months Initial MRI (Box 1) reported as “normal”, although on retrospective review PNS was seen. Subsequent MRI (Box 2) showed extension of the tumour to the pons. PNS (melanoma) along V2 and V3 extending to the pons Palliative care MRI = magnetic resonance imaging. PNS = perineural spread. SCC = squamous cell carcinoma. V2 = maxillary division of trigeminal nerve. V3 = mandibular division of trigeminal nerve. VII = facial nerve. The incidence of non-melanotic head and neck skin cancers in Queensland is among the highest in the world.1 Perineural spread (PNS) from these lesions involves either small nerves, identified at pathological examination (incidental), or large nerves, presenting clinically as cranial nerve palsies. Basal cell carcinoma is the more common skin cancer, but incidental PNS is most frequently associated with squamous cell carcinoma.2 In 32 out of 34 patients over a 5-year period, isolated major nerve PNS was due to squamous cell carcinoma (unpublished data). PNS from melanoma and microcystic adnexal carcinoma has also been described.3,4 Because many clinicians are not familiar with PNS involving large cranial nerves, the diagnosis can easily be missed or delayed. The disease is associated with high treatment morbidity and poor prognosis once clinical or radiological evidence becomes apparent, with a 5-year survival rate of 20%–30%.5 Early detection of PNS in large cranial nerves is essential, as the condition is often unsalvageable once the tumour has spread through the skull base. The facial and trigeminal nerves are most commonly affected,6 although forehead tumours can gain access to the orbit via the ophthalmic nerve.7 Symptoms of trigeminal nerve infiltration include formication, dysaethesia, paraesthesia, numbness and pain (often severe and “electric shock-like” in nature).8 Slowly progressive facial nerve palsy may represent seventh cranial nerve infiltration or infiltration within the parotid, whereas diplopia and visual impairment indicate advanced orbital disease. These symptoms can mimic other diagnoses, such as Bell’s palsy or trigeminal neuralgia, but almost always manifest as slowly progressive and irreversible palsies. Close follow-up of patients to ensure resolution of symptoms is mandatory. The four patients we have described illustrate delays between clinical presentation and diagnosis. These delays could have been avoided by establishing the link between unresolving cranial nerve palsies and excision of cutaneous lesions from the head and neck. Patients 2 and 3 had a history of aggressive squamous cell carcinoma of the face treated with radical excision and postoperative radiotherapy. Advanced, recurrent skin squamous cell carcinomas have a higher incidence of PNS, particularly when located close to a cranial nerve, and should alert the clinician to the possibility of neural metastasis.9 Tumour size before excision, postoperative defect size, subclinical extension and Moh’s micrographic surgery levels are significantly larger in patients with PNS than in patients without PNS.10 PNS can be subtle and missed on initial pathology but, because of the propensity for local recurrence, most specialist multidisciplinary units that deal with skin cancer will recommend adjuvant radiotherapy, particularly if the lesion is excised from the trigeminal nerve distribution. In Patients 1 and 4, no histology was available. Small skin lesions are often treated with cryotherapy or curettage, resulting in no pathological report. However, these lesions may still have a propensity for PNS, so their excision should be elicited in the history. In Patient 4, the skin lesions were excised from the side of the face contralateral to the cranial nerve palsies and were unlikely to represent the primary disease. Nevertheless, this case illustrates that patients with a history of cutaneous lesions from any site on the head and neck are at risk of developing PNS. These cases also illustrate that the interval between excision of a lesion and presentation of PNS can be long.11 Clinicians should hold a high index of suspicion even if the interval is several years. A further source of delay is that patients are seen by a variety of clinicians before diagnosis. Cross-referral for second opinions is common, resulting in further delay. Patients 1–3 illustrate how the unfamiliarity of clinicians with the disease process resulted in patients seeking opinions from several specialties before definitive diagnosis. In addition, investigations may be performed to exclude a different pathology or misinterpreted because the clinician is unaware of the phenomenon, resulting in further delay. In Patients 2 and 4, initial imaging revealed changes compatible with PNS, but these were not recognised, either because the radiologist was not familiar with the entity or because the referring clinician may not have raised the possibility of PNS. In Patient 2, the hyperintensity of the masseter muscle on magnetic resonance imaging (MRI) led the clinician to suspect a primary muscular disorder, instead of the correct interpretation of denervation changes from trigeminal nerve involvement. The patient underwent an unnecessary muscle biopsy. Earlier detection may have resulted in Patients 2 and 4 being treated with curative intent instead of palliative care. High resolution MRI is the investigation of choice, and may identify the earliest changes of PNS. However, disease may not be radiologically apparent until it has reached the orbit, cranial fossa or the skull base foramina. Computed tomography (CT) identifies the disease at a late stage when the tumour has eroded adjacent bony margins. MRI has the added advantage of defining the relationship of the perineural tumour to important anatomical landmarks such as the cavernous internal carotid artery; this is important when planning a resection or biopsy. However, subtle changes on MRI may be missed even by experienced radiologists and, given a strong clinical suspicion with normal imaging, nerve biopsies should be performed. Presently, positron emission tomograph (PET) scanning has no role to play in the staging of PNS. Delayed diagnosis of major cranial nerve PNS may result in devastating outcomes for patients, so early detection is crucial. Patients who present with slowly progressive cranial nerve palsies with a history of head and neck cutaneous malignancies should be investigated for PNS with a high index of suspicion. We recommend that all patients who undergo excision of high risk skin malignancies should be advised to seek a medical opinion if they develop facial numbness or weakness in subsequent years. 1 Coronal T2-weighted MRI images of Patient 4 These images were reported as “normal”, although retrospective review shows perineural spread of melanoma with thickening and nodularity along the left V2 (A), V3 (B) and the trigeminal ganglion (C). MRI = magnetic resonance imaging. 2 Contrast-enhanced T1-weighted MRI images of Patient 4 The images show perineural spread of melanoma with perineural thickening and enhancement along the left V2 (A), V3 (B), the trigeminal ganglion (C) and the trigeminal nerve as it exits the pons (D). MRI = magnetic resonance imaging.

Giles C Warner MSc, MD, FRCS · Mitesh Gandhi MRCP(UK), FRCR, FRANZCR · Benidict Panizza MB BS, MBA, FRACS

To the Editor: Motor neurone disease (MND) is a relentlessly progressive neurodegenerative disease with a median survival of 1–3 years. It results in the death of nearly 400 Australians per year.1 The management of MND remains problematic, tending to be offered in a heterogeneous and ad-hoc fashion across Australia. This heterogeneity arises in part from a lack of understanding of the aetiology of the disease and its progression in different patients,2 the absence of established guidelines for standard care,3 and a lack of concentrated experience among medical practitioners, nursing and allied health care workers in treating patients with MND. With new diagnostic techniques, treatments and interventions for MND undergoing trials, there is a clear need for more baseline information on MND management and outcomes and a method for monitoring any changes on a population basis.4 To facilitate this, the Australian Motor Neurone Disease Registry (AMNDR) has been developed. The Registry is governed by a steering committee comprising specialist physicians from each state and territory around Australia, neuroscientists, an epidemiologist and patient representatives. AMNDR was launched in Sydney in June 2004 to coincide with Motor Neurone Disease Global Awareness Day and, to November 2005, had enrolled 351 patients from 67 study locations, with 88% of registrations coming from 10 major sites. As of September 2005, 90 patients had undergone at least one further follow-up assessment. A copy of the registration, assessment and completion case report forms can be viewed on the AMNDR website (http://ww.amndr.org.au). From the patient information collected in the registration data, three distinct clinical phenotypes have emerged (Box). Patients with the “global” MND phenotype (combined upper and lower motor neurone signs in at least two regions) tended to have the shortest survival time. AMNDR was designed to obtain information that will increase the understanding of MND and its progression in different patients. Through the process of registry establishment, those involved in care, management and scientific research related to MND have been galvanised into a more effective and cooperative working unit. Ownership of the database has been retained by all who have contributed to data collection, and the information has been increasingly used to promote research into the causes and treatment of MND, locally and internationally.5 Through participation, it is expected that treating doctors will be able to evaluate their current management and associated patient outcomes relative to other centres around Australia. Demographic data for 351 patients with motor neurone disease enrolled in the Australian Motor Neurone Disease Registry to November 2005, by phenotype Phenotype, site of symptom onset Percentage of all registrations* Mean age at onset in years (SD) Sex ratio (F : M) Mean survival time in months (SD; range)† Deaths (%) Global† Bulbar 27% 64 (13) 1.5 : 1 27 (10; 20–48) 24% Cervical 25% 55 (19) 0.4 : 1 20 (10; 7–33) 13% Lumbar 19% 61 (10) 1.1 : 1 36 (16; 14–63) 24% Flail limb§ Arm 10% 63 (13) 0.07 : 1 95 (85; 30–238) 27% Leg 10% 58 (10) 2 : 1 59 (28; 33–100) 7% Primary lateral sclerosis¶ All regions 11% 54 (9) 0.9 : 1 103 (55; 24–259) 0 * Sum > 100% because of rounding. † Censored at November 2005. ‡ Global phenotype = combined upper and lower motor neurone signs in at least two spinal regions. § Flail limb variants = predominantly lower motor involvement of arms or legs, with prolonged disease duration. ¶ Primary lateral sclerosis = characterised by pure upper motor neurone involvement.

Matthew C Kiernan PhD, FRACP · Paul Talman FRACP · Robert D Henderson FRACP · Rodney Harris BA, GradDipBusStud, MAICD · on behalf of the Australian Motor Neurone Disease Registry Steering Committee

Objective: To describe the management of and outcomes in a population-based cohort of patients with newly diagnosed glioma.Design, setting and patients: Retrospective cohort study of patients with glioma newly diagnosed over the period 1998–2000 in Victoria. Patients were identified from the population-based Victorian Cancer Registry (VCR). Doctors involved in managing the patients were surveyed by a questionnaire sent out in 2003. The cohort was followed until the end of 2004 to obtain at least 4 years’ follow-up data on all patients.Main outcome measures: Reported treatment, referral patterns and survival rates.Results: Over the study period, 992 cases of glioma were identified; 828 completed surveys on eligible patients were obtained (response rate, 93%); 473 patients (57%) had glioblastoma multiforme (GBM); 105 patients (13%) diagnosed with “glioma” had had no histological confirmation. Complete macroscopic resection was performed in 209 patients (25%); 612 patients (74%) were referred for radiotherapy and 326 (54%) for chemotherapy; 39 (5%) were enrolled on a clinical trial. Median survival was 9.2 months for all patients and 7.4 months for patients with GBM.Conclusions: This is the largest reported glioma management survey in the world to date. Much of the patient demographics and approach to treatment were as expected and represent a reasonable “standard of care”. However, there are some areas for improvement, including the absence of histological diagnosis in some patients, lack of multidisciplinary care, low clinical trial enrolment and poor use of ancillary services.

Mark A Rosenthal MB BS, FRACP, PhD · Katharine J Drummond MB BS, FRACS · Michael Dally MB BS, FRANZCR · Michael Murphy MB BS, FRACS, MD · Lawrence Cher MB BS, FRACP · David Ashley MB BS, FRACP, PhD · Vicky Thursfield BSc, GradDipAppl Stats · Graham G Giles MSc, PhD

Elizabeth May Pepper,* Dominique A Cadilhac,† Dora C Pearce,‡ James Burrow,§ Tarun S Weeramanthri¶ * Neurology Registrar, John Hunter Hospital, Newcastle, NSW. † Manager, Public Health Division; ‡ Biostatistician; National Stroke Research Institute, Melbourne, VIC. § Neurologist; ¶ Physician, Royal Darwin Hospital, NT. hornblowerATinternode.on.net To the Editor: Although the age-standardised stroke mortality rates among Australia’s Indigenous people is more than twice that of the non-Indigenous population,1 the medical literature contains only one audit of Indigenous stroke patients in Perth metropolitan hospitals.2 No review of hospital care has been reported. Royal Darwin Hospital (RDH) is the referral centre for Australia’s “Top End”, where 8.7% of Indigenous Australians reside; 40% of RDH inpatients are Indigenous. In 2002, while planning for the RDH stroke service, we audited stroke admissions from the previous year. Among 121 eligible patients admitted between 1 July 2001 and 31 June 2002 with International classification of diseases, 10th revision, Australian modification (ICD-10-AM) codes 160–164 (haemorrhages [subarachnoid, intracerebral, other non-traumatic intracranial] and cerebral infarction), records for 116 (96%) were available, but six patients were excluded because of incorrect coding. Box 1 outlines patient characteristics, while Box 2 examines risk factors and medication use for ischaemic stroke (because haemorrhages were few). Despite the observed differences between subgroups, there were no significant differences in mortality (4/36 for Indigenous v 7/42 for non-Indigenous; P = 0.204) or stroke severity at admission or discharge. Box 3 highlights differences in risk factors between Indigenous males and females. Retrospective data, particularly from a sample identified by medical record coding, should be interpreted with caution. In addition, the potential for random error due to small numbers, and the referral bias inherent in tertiary hospital admissions, mean our results may not truly represent the “Top End” Indigenous population. However, our data corroborate findings that Indigenous Australians suffer premature cerebrovascular disease, and have higher rates of vascular risk factors than other Australians,1 with some risk factor differences between males and females. Further, recent evidence suggests differences in standards of stroke care in regional (Queensland) hospitals.3 We found disparity in hospital care of Indigenous patients, and this requires further detailed investigation. A prospective, community-based study is urgently needed. 1 Baseline characteristics for 110 patients admitted to Royal Darwin Hospital with subarachnoid, intracerebral, and other non-traumatic intracranial haemorrhages and cerebral infarction in 2001–02 Baseline characteristics Indigenous Other P Number of patients 45 65 Female sex 22 (49%) 19 (29%) 0.018 Mean age (years) 54 61 0.005 Rural dwelling 41 (91%) 22 (34%) < 0.001 Ischaemic stroke 36 (80%) 42 (65%) 0.081 2 Risk factors and medication use for the 78 patients who had ischaemic stroke Risk factors and medications Indigenous Other P All patients 36 42 Smoking 23 (64%) 11 (26%) 0.001 Diabetes mellitus 16 (44%) 10 (24%) 0.030 Rheumatic heart disease 8 (22%) 1 (2%) < 0.001 Males 19 (53%) 30 (71%) 0.089 Smoking 14 (74%) 12 (40%) 0.017 Diabetes mellitus 10 (53%) 7 (23%) 0.030 Females 17 (47%) 12 (29%) 0.089 Smoking 9 (53%) 0 0.002 Rheumatic heart disease 6 (35%) 0 0.026 Antiplatelet therapy Before admission 11 (31%) 19 (45%) 0.078 Admission 20 (56%) 38 (91%) < 0.001 Discharge 18/32 (56%) 29/35 (83%) 0.013 Anticoagulant therapy Before admission 4 (11%) 1 (2%) < 0.001 Discharge 4/32 (13%) 6/35 (17%) 0.235 3 Risk factor differences between Indigenous males and females who had ischaemic stroke Males Females P Number of patients 19 17 Hypertension 16 (84%) 6 (35%) 0.003 Non cerebral vascular disease 6 (32%) 1 (6%) < 0.001 Excessive alcohol intake 7 (37%) 1 (6%) < 0.001

Elizabeth May Pepper · Dominique A Cadilhac · Dora C Pearce · James Burrow · Tarun S Weeramanthri

Clinical record A 37-year-old woman presented with a 2-month history of progressive restriction of movement of the left shoulder joint, associated with episodic pain over the region. She was unable to raise her left arm above the shoulder. The pain was mild, deep-seated, non-radiating and relieved by supporting the left elbow. She denied any weakness of the arm muscles. The patient also complained of diminished pain and temperature sensation over the affected limb, as evidenced by painless scalds of the fingers of her left hand — the first about 4 years previously, and the second, 7 days before presentation. She had had mild pain in the left shoulder region infrequently for the previous 17 years, and had noticed enlargement of her left arm since childhood. She had not noticed any lymphadenopathy. She had normal facial sensation and denied any history of diplopia, dysarthria, dysphagia, hoarseness, vertigo, sphincter abnormalities or weakness and ataxia of any extremity. There was no history of neck pain, trauma, radiation or prolonged fever. She had no hypertension or diabetes, and her family and obstetric history were unremarkable. Examination: The patient’s left upper limb was larger than the right (Box, A). The other limbs appeared normal. Girth of the left upper limb was 51.6 cm at the shoulder (right, 46.5 cm); 35.8 cm at the mid-arm (right, 31.4 cm); and 29.1 cm at the forearm (right, 25.2 cm). Wrist and fingers also had wider girth on the left compared with the right, but were equal in length. The swelling of the left upper limb was painless, non-pitting, with no colour change or abnormal sweating. Temperature of the limb was normal. Apart from evidence of a recent scald injury, no other superficial skin changes, vascular prominences or nerve thickening were observed. Loose bodies were present in the left shoulder joint, as evidenced by palpable crepitus. Left shoulder abduction was restricted beyond 90°. No hum, bruit or machinery murmur could be heard on auscultation in any part of the affected limb. The right breast was slightly larger than the left. Neurological examination revealed that pain, temperature and tactile sensation were diminished on the left side from C2 to T6 dermatomes anteriorly, and from C2 to T4 dermatomes posteriorly. Position and vibration senses were well preserved in these segments. All modalities of sensation in other parts of the body were normal. The patient had normal speech and higher functions. The hairline was at C2 level and the height–neck ratio was 11.67 (reference range, < 13). No meningism or cranial or spinal deformities could be identified. Examination of the cranial nerves gave results within normal limits. Apart from a mild weakness of the small muscles of the left upper limb, as evidenced by a positive card test and Grade 4/5 power in the left supraspinatus and deltoid muscles, the motor system appeared normal. Deep tendon reflexes in the left upper limb were present but grossly diminished. Plantar reflexes were bilaterally flexor, with preserved abdominal reflexes. The patient had normal coordination, stance and gait, with no evidence of nystagmus or Horner syndrome. Investigations: Complete blood count and routine biochemistry tests gave normal results. Fasting blood glucose level was 5.4 mmol/L (reference range [RR], < 6.1 mmol/L), and results of oral glucose tolerance were in the reference range. A serum VDRL (Venereal Disease Research Laboratory) test was negative. An x-ray of the left hand showed soft tissue swelling and a slight increase in the size of the metacarpals and proximal phalanges compared with the right (Box, B). X-ray of the left shoulder joint showed loss of normal architecture, multiple bony fragments and loose bodies (Box, C). Skeletal imaging showed no abnormalities of the skull, spine or other limbs. No abnormalities were seen in the affected limb on arteriovenous doppler examination, computed tomography, magnetic resonance imaging, angiography, lymphangiography and skin biopsy. Magnetic resonance imaging of the brain and spine showed a fairly large (12 mm) cerebellar tonsil dipping in the posterior portion of the foramen magnum, with a large syrinx involving the whole of the cervical and thoracic spine to level T8 (Box, D). Management: The patient was advised to undergo posterior fossa decompression, but was unwilling to have surgical intervention and is currently receiving regular follow-up. A syrinx is a cavity in the spinal cord (syringomyelia) or brain stem (syringobulbia).1 Syringomyelia is a chronic progressive degenerative or developmental disorder of the spinal cord, characterised clinically by brachial amyotrophy, cutaneous analgesia and thermoanaesthesia, with sparing of tactile, joint, position and vibration senses, and loss of deep tendon reflexes. Frequently, there are associated developmental abnormalities of the vertebral column, base of the skull, and particularly of the cerebellum and brain stem. About 90% of patients with syringomyelia have type I Chiari malformation (downward displacement of cerebellar tonsils). Patients with syringomyelia typically present with lower motor neurone signs at the level of the lesion, dissociated sensory loss in a cape or hemi-cape distribution on the arms or upper trunk, and spinal long tract dysfunction below the level of the lesion. Few patients show the complete picture, and the clinical features vary with the size, location and shape of the cavity, and the associated neurological condition.1 Common early signs are wasting and weakness of the small muscles of the hand, or loss of feeling in the hand and resulting injuries. Surprisingly, our patient — despite a relatively large syrinx — had no lower motor neurone signs in the upper limb, apart from diminished deep tendon reflexes and mild weakness, and no spinal long tract signs. Syringomyelia can also cause “neuropathic joint”, most commonly in the shoulder, elbow or wrist. The affected joint is often enlarged but painless, and movements evoke loud crepitus,2 as in our patient. While syringomyelia is more commonly associated with limb atrophy, hypertrophy can occur, involving bones, muscles and other tissues in one limb, one half of the body or even the tongue.2 Trophic changes in the skin can include cyanosis, hyperkeratosis and thickening of the subcutaneous tissue, leading to a swelling of the fingers described as “la main succulente”.2 Other findings associated with syringomyelia include increased ratio of arm to body length, size differences between the breasts, and curved fingers,2 (the latter two features documented in our patient). An association with hypertrophy of the limbs, hands or feet is also recognised in syringomyelia,3 and has been reported in four patients from Japan, including three of a series of 26,4,5 and in two patients from India. However, the latter two, in contrast to our patient, had prominent neurological features.6,7 Localised hypertrophy of the hand is also seen in syringomyelia: a radiological study of hand bones in four patients with syringomyelic chiromegaly found enlarged hand bones on the affected side.8 This feature was also evident in our patient. A range of mechanisms have been postulated to explain the segmental hypertrophy in syringomyelia, including stimulation of the sympathetic nervous system, causing defective circulation and oedema.9 An in-vitro study of muscle cells from patients with syringomyelia and muscle hypertrophy found the cells had accelerated growth in the presence of patient serum, suggesting involvement of serum factors and molecules released in response to neural lesions.10 To our knowledge, there are few other documented cases of syringomyelia presenting with both neuropathic joint and limb hypertrophy. Our case highlights this rare clinical presentation of a common spinal cord anomaly. It reminds clinicians that, although conventional teaching commonly associates syringomyelia with limb atrophy, it can be associated with limb hypertrophy. Hence, syringomyelia should be considered as a differential diagnosis in all cases of limb enlargement. Moreover, this case further emphasises the importance of considering a spinal cord anomaly as the aetiology of upper limb neuropathic joint. A patient with syringomyelia A: Hypertrophy of the left upper limb. B: X-ray of the hands showing bony and soft tisse enlargement on the left side. C: X-ray of the left shoulder showing gross disorganisation with multiple bony fragments. D: Magnetic resonance imaging of the cervical spine (T1-weighted) showing a large syrinx with type I Chiari malformation (arrow).

Partha P Chakraborty MB BS · Dipanjan Bandyopadhyay MD · Sanjay K Mandal MD · Subhasis Roy Chowdhury MB BS · Ramtanu Banerjee MD · Shounak Majumdar MB BS · Rana Bhattacharji MD

Objective: To compare changes in autonomic nervous activity in healthy senior individuals while walking with and without a dog, and during routine activities at home and periods of interacting with the dog at home.Design: Controlled crossover study.Participants and setting: 13 healthy volunteers (3 men, 10 women; mean age, 67.5 years) who walked in a park adjacent to Gunma University, Japan, and 4 volunteers among these who underwent monitoring in their own homes.Interventions: Heart rate variability was monitored continuously by means of a palm-sized electrocardiographic monitor (which facilitated spectral analysis of the RR interval) while participants walked for 30 minutes (first with, then without, the study dog, or vice versa); three participants underwent this intervention on 3 consecutive days. Four participants underwent continuous monitoring for 6 hours in their own homes, including two 30-minute periods of free interaction with the study dog.Main outcome measures: High frequency (HF) power values of heart rate variability, which is a measure of parasympathetic neural activity.Results: During dog-walking, HF power increased significantly (P < 0.01); this increase was sustained throughout each dog walk, and was more pronounced during succeeding dog walks. At home, HF power was 1.87 times greater when the dog was present, and 1.57 times greater (P < 0.01) than in the walking experiment.Conclusions: Walking a dog has potentially greater health benefits as a buffer against stress in senior citizens than walking without a dog; and, independent of actually walking, merely patting and talking to a dog also raises parasympathetic neural activity. Power spectral analysis of heart rate variability shows promise as a non-invasive approach to quantifying clinicophysiological research on human health benefits possibly derived from interaction with companion animals.

Masahiko Motooka MMS · Nell L Kennedy PhD · Hiroto Koike MD, PhD · Tomoyuki Yokoyama MD, PhD

The neurology short case. 2nd ed. John G L Morris. London: Hodder Arnold, 2005 (155 pp +CD-ROM). ISBN 0 340 88516 5. The neurology short case. 2nd ed. John G L Morris. London: Hodder Arnold, 2005 (155 pp +CD-ROM). ISBN 0 340 88516 5. The first edition of The neurology short case was one of my regular companions during the lead-up to the 2002 FRACP clinical examination. So when I was asked to review this second edition, I felt a sense of anticipation — it would be interesting to see what revisions had been made. The author is Professor John Morris, Chairperson of the Education and Training Committee of the Australian Association of Neurologists, and a past examiner of the RACP. Widely regarded as one of the great masters and teachers of the traditional art of clinical examination, he is well qualified to write on this topic. Thirteen brief chapters address different clinical presentations (eg, wrist drop, gait disturbance and ptosis). Morris successfully conveys the essence and subtleties of neurological examination in a simple, concise and practical style, while outlining some of the underlying concepts. It is easy to read, understand and put into practice. In the first edition, I found the “Tips” section at the end of each chapter especially useful. In this second edition, my favourite feature is the collection of good quality video clips to be found on the accompanying CD-ROM. With additional chapters on involuntary movement disorders and assessment of the higher function, the new edition is enhanced. The chapter on abnormalities of vision and eye movement will be popular with many clinicians who find the eye examination daunting. Although the target audience is primarily clinical examination candidates, medical students and perhaps general practitioners, neurologists might find The neurology short case a useful teaching tool, particularly with the CD collection. Retailing at $67.95, this book is value for money and I have no hesitation recommending it to my junior colleagues. Lay Kun KhoNeurology Registrar Royal Perth Hospital, WA

Lay Kun Kho

A middle-aged man with type 2 diabetes was brought to hospital with a history of loss of consciousness for an unknown period of time. He had refractory hypotension and hypoglycaemia. A magnetic resonance imaging scan showed an infarct in the splenium of the corpus callosum (Figure). The splenial infarct resembled a “boomerang”, which is characteristic.1 Strokes involving the splenium of the corpus callosum are associated with hypoperfusion,2 and can be seen in association with metabolic changes such as hypoglycaemia, hyponatraemia, hypernatraemia, and renal failure.1 Magnetic resonance image: axial FLAIR [fluid-attenuated inversion recovery] sequence, showing boomerang-shaped signal hyperintensity in the splenium of the corpus callosum.

Jeyaraj Durai Pandian MD, DM · Robert D Henderson MB BS, FRACP

The explosion in psychiatric neuroimaging research has led to the establishment of stressful and dark neuroimaging laboratories in which young researchers sweat in front of computer monitors performing laborious and tedious imaging analysis. These conditions have contributed to the development of a new psychiatric syndrome, described below. Diagnostic criteria“Lesionnaire’s syndrome” predominantly affects younger researchers examining magnetic resonance imaging (MRI) scans of the brain. These researchers: (a) Work in large institutions; (b) Have a fixed belief that volume change in a brain structure causes schizophrenia; (c) Feverishly spend hours tracing brain structures to prove this belief; (d) Alter their beliefs if their attempts are unsuccessful and begin work on a different brain structure or new method; (e) Attribute negative findings to “methodological limitations”; (f) Begin to see non-brain images in brain scans on which they are working. The diagnosis may only be made if the patient satisfies criterion (f) and any three of criteria (a)–(e). The diagnosis cannot be made if the MRI scan has revealed an organic disorder. Case reportA 38-year-old psychiatrist had spent hundreds of hours tracing hippocampal volumes on MRI scans. He would lock himself in a darkened room, staring at a computer monitor, often listening to ’80s music in an attempt to relieve the mind-numbing tedium of the repetitive tracing behaviour. After tracing scans for 4–5 years, he revealed to his colleagues that he had discovered religious images — in particular, a vision of the Crucifixion (Box). He was successfully treated with complete tracing abstinence, but has had episodic relapses of his delusional visions, during which he has been heard to cry out “Maybe if I trace a few more it will reach statistical significance”. In order to ensure that the syndrome was related to the tracing behaviour rather than the music, a further trial was undertaken. Fortunately, re-exposure to ’80s music outside the imaging laboratory did not lead to a relapse in his symptoms.

Dennis Velakoulis MB BS, FRANZCP · Christos Pantelis MD, MRCPsych, FRANZCP · Mark Walterfang MB BS, FRANZCP

Clinical record A 55-year-old woman with chronic epilepsy and psychiatric problems was admitted to hospital in 2004 with a fractured neck of femur after a trivial fall. She had been diagnosed with epilepsy in childhood and treated with phenytoin and phenobarbitone. Management was complicated by multiple, prolonged psychiatric admissions. Anticonvulsant compliance had been verified with measurement of serum phenytoin levels on a number of occasions. As a result of psychiatric problems, the patient became less able to care for herself and, at the age of 46 years, was admitted to long-term psychiatric hostel accommodation. Four years later, she had a non-displaced fracture of the olecranon after a fall; serum 25-hydroxyvitamin D level and bone mineral density were not assessed at that time. During the current admission, the fractured neck of femur was treated surgically. Biochemical testing indicated vitamin D deficiency (Box), which was treated with daily calcium carbonate (1200 mg) and ergocalciferol (vitamin D2) (2000 IU), and substitution of phenytoin with sodium valproate. This patient had recurrent fractures at a young age caused by a preventable complication from long-term use of anti-epileptic medication. Osteoporotic fractures, particularly hip fractures, result in significant individual morbidity and mortality and major financial cost to the community. It is well documented that enzyme-inducing anticonvulsants increase fracture risk by an average of two- to threefold, and that phenytoin causes osteomalacia. A 7-year longitudinal study of 87 people with epilepsy treated with phenytoin showed that they had a fracture rate six times higher than that of the healthy population.1 Fractures were not related to seizures. This high rate of fracture has been confirmed in many subsequent studies.2,3 Phenytoin induces hepatic microsomal enzymes and increases the catabolic clearance of a number of vitamin D metabolites. Hypermetabolism results in vitamin D deficiency, which induces a compensatory increase in serum parathyroid hormone (PTH) and bone turnover. Patients may develop a severe mineralisation defect and consequent osteomalacia. Other enzyme-inducing anti-epileptic drugs, such as primidone and perhaps carbamazepine, have similar effects on vitamin D metabolism. Anti-epileptic drugs have also been shown to cause bone loss in the absence of vitamin D deficiency.4 This effect was greater in patients taking multiple drugs, those with longer duration of epilepsy, and those taking enzyme-inducing drugs.5 This suggests that anti-epileptic drugs have a direct effect on bone turnover and could cause bone loss without inducing vitamin D deficiency. Vitamin D replacement has been studied in patients taking phenytoin. In at least one study, cholecalciferol and ergocalciferol were not bioequivalent.6 Another found that patients taking phenytoin required larger doses of calciferol to reach positive calcium balance than a control group.7 Other factors predisposing to vitamin D deficiency should also be considered. Institutionalisation leads to low sunlight exposure and reduced skin synthesis of vitamin D. This can produce vitamin D deficiency, even in Australia and without the addition of anti-epileptic drugs.8 People living in institutions may require higher replacement doses of vitamin D than those in the community. For example, a dose of 2400 IU calciferol (well above the accepted dose required for nutritional health) was required to reach adequate serum 25-hydroxyvitamin D levels in three-quarters of institutionalised patients treated with anti-epileptic drugs.9 Many medical practitioners fail to consider the diagnosis of osteoporosis or to provide adequate prevention and treatment. In a recent American study of neurologists, only one in four screened for bone disease, and fewer than one in 10 routinely prescribed prophylactic calcium and calciferol for patients taking anticonvulsants.10 There are no published consensus guidelines, but a recent editorial recommended osteoporosis screening in all adults taking anti-epileptic drugs long term.11 We believe appropriate investigations should include annual screening of serum 25-hydroxyvitamin D level. This is particularly important for those who are institutionalised. Patients taking anti-epileptic drugs long term should be advised about optimal dietary calcium intake, smoking cessation and avoidance of excess alcohol consumption, adequate sun exposure and weight-bearing exercise to prevent osteoporosis. Calcium and calciferol could be offered to those who achieve less than three to four serves of calcium daily or those who have a serum 25-hydroxyvitamin D level < 50 nmol/L. A recent position statement in the Journal provided useful advice about vitamin D replacement in people with vitamin D deficiency.12 Vitamin D replacement is particularly important for those taking phenytoin or phenobarbitone. If an osteoporotic fracture has occurred, bone mineral density should be assessed (this is currently not reimbursed by Medicare unless a fracture has occurred), and specific treatment with bisphosphonate drugs could be considered. However, bisphosphonates should be prescribed only after calcium and vitamin D deficiency has been corrected. These measures may help avoid the occurrence of hip fractures in relatively young patients taking anti-epileptic medication long term. Lessons from practice Patients taking anticonvulsant medication have a two- to threefold increased risk of fracture. Lifestyle measures, with exercise, adequate sunlight exposure, smoking cessation and sufficient calcium intake, should be encouraged for all patients with epilepsy taking anticonvulsant medication. Serum 25-hydroxyvitamin D levels should be assessed annually in all those taking anticonvulsant medication long-term. Calcium and calciferol could be offered to those who achieve less than three to four serves of calcium daily and to those with a serum 25-hydroxyvitamin D level < 50 nmol/L. Larger calciferol doses than typically required may be needed to treat vitamin D deficiency induced by anticonvulsant medication. Bone mineral density should be measured in all patients taking anticonvulsant medication long-term who sustain a fracture. Blood test results for a 55-year-old woman with an osteoporotic fracture* On admission Follow-up RR 3 months 9 months Ionised Ca (mmol/L) 1.1 – 1.22 1.14–1.29 Phosphate (mmol/L) 0.7 1.6 1.3 0.8–1.5 Parathyroid hormone (pmol/L) 58.2 14.5 10.9 1.5–8 25-hydroxyvitamin D (nmol/L) 9 34 70 > 50 Creatinine (μmol/L) 51 – – 30–95 Alkaline phosphatase (U/L) 229 112 103 35–105 Haemoglobin (g/L) 143 – – 115–155 Mean cell volume (fL) 97 – – 81–98 RR = reference range. * Results outside the RR are highlighted in bold.

Hannah M Seymour MRCP · Paul Glendenning PhD, FRCPA, FRACP

Treatment has advanced, but a stigma still surrounds this disorder Epilepsy affects some 120 000 to 200 000 Australians. It is defined as a disorder with recurrent unprovoked seizures, but 4%–5% of the population may experience at least one seizure at some point in their lives.1 About half the people who develop epilepsy present in the first two decades of life. A second peak occurs in people older than 60 years. Pathophysiology and clinical geneticsFor 25 years, the classification of epilepsy syndromes has been embedded in the seizure type (partial or generalised onset) and the presence or absence of an underlying brain disorder (symptomatic or idiopathic),2 along with acceptance that there is a genetic basis with complex patterns of inheritance for idiopathic epilepsy. Indeed, in the past decade or so, examination of large pedigrees with multiple affected members has led to the discovery of several epilepsy genes. These gene defects most commonly disrupt the function of voltage-gated or neurotransmitter-gated ion channels, producing alterations in neuronal excitation within brain networks.3 These discoveries have enhanced our understanding of seizure pathophysiology, but they have also begun to cast doubt on the current classification of the epilepsies. The distinctions between partial and generalised and between idiopathic and symptomatic are difficult to support when individuals sharing gene defects present with very different epilepsies.4 Despite this, the known epilepsy genes do not yet explain the most common epilepsies, where gene combinations interacting with environmental or epigenetic factors are expected to provide the answers. NeuroimagingThere have been tremendous advances in neuroimaging technology. Magnetic resonance imaging (MRI) can demonstrate a variety of cerebral pathologies not reliably found with computed tomography (CT). These include hippocampal atrophy in mesial temporal lobe epilepsy, focal and diffuse malformations of cortical development, and vascular malformations and focal encephalomalacia. A CT brain scan is no longer an adequate investigation for epilepsy. The ability to measure volumes of specific brain structures and quantify signal change has opened new areas of neuroscience research in humans with epilepsy. Cross-sectional and, more recently, longitudinal studies of regional brain volumes have provided evidence of progressive brain damage with intractable focal seizures.5 Functional neuroimaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) are valuable in assessment for epilepsy surgery, but have contributed little to our understanding of the aetiology of epilepsy. The development of new PET and SPECT ligands and MRI spectroscopy holds the promise of advances using in vivo neurochemistry. Treatment and prognosisWith therapy, 60%–70% of people with epilepsy will have a good prognosis with complete control of seizures on the first medication tried. In the past 10–15 years we have seen the introduction of lamotrigine, vigabatrin, gabapentin, tiagabine, topiramate oxcarbamazepine and levetiracetam to the therapeutic armoury. These new antiepileptic drugs (AEDs) provide a greater range of options and differing side-effect profiles than existed with the older array of AEDs (barbiturates, phenytoin, carbamazepine and valproate).6 However, 20%–30% of patients will not respond completely to medication and there has been no major change in the proportion of children and adults whose seizures remain refractory to medication — even with the release of these new AEDs. There has been a growing awareness of the futility of years of different AED trials in individuals and AED polytherapy.7 The failure of two well-supervised medication trials in partial epilepsy should alert the physician of the need to consider options such as epilepsy surgery. A randomised, controlled trial of surgery for temporal-lobe epilepsy has shown 58% of the surgical candidates were seizure-free at one year, compared with 8% of medically treated patients.8 Surgery should not be seen as the last resort, but as a complement to medical treatment in refractory cases. Comorbidity of epilepsyDoctors have become very adept at counting seizures to determine the success of interventions. In the past decade, attempts have been made to assess the impact of epilepsy and its treatment upon a person’s quality of life. We are becoming more aware of the effects of the older AEDs on endocrine function and their teratogenic potential.9 Long-term AED use is associated with osteopenia, and vitamin D and calcium supplements are appropriate. More than 30% of patients with epilepsy may suffer depression. The depression is not simply the result of a chronic medical illness; it seems that the two disorders may share a common pathological substrate. Recognition and treatment of depression is important to the success of the treatment of the epilepsy itself.10 The futureIn the next decade or so, we can expect that genetic testing for particular epilepsies will complement and perhaps lessen our current dependence on clinical profiles and electroencephalography. It is conceivable such testing may aid us in selecting the most appropriate AED and predicting hypersensitivity side effects of AEDs. Currently, AEDs are administered to control seizures or the clinical expression of epilepsy, but we have no means to intervene to prevent epileptogenesis. Advances in our knowledge will certainly occur in the next decade. But without a greater understanding of epilepsy and seizures in the community, we will not lessen the stigma that still surrounds the disorder in schools and the work place. Epilepsy is a common disorder and deserves attention in public education programs.

Andrew F Bleasel MB BS, PhD, FRACP

Robert D Henderson,* Pamela A McCombe* * Neurologist, Royal Brisbane and Women’s Hospital, Herston Road, Herston, QLD 4029. Robert_HendersonAThealth.qld.gov.au To the Editor: We read with interest the recent article by Kiernan.1 Many patients with motor neurone disease (MND) are also taking complementary therapies, with the potential for drug interaction with riluzole. A recent patient highlighted this. A man in his 50s with progressive MND commenced riluzole at the time of diagnosis. Initial liver function tests performed after starting the drug gave normal results. Eight months later, with disease progression, he began taking low-dose naltrexone 50 mg dissolved in 50 mL of water, of which he took 4 mL a day. Three months later, he began to feel nauseous, with debilitating lethargy, and developed jaundice. Liver function tests showed: alanine aminotransferase level, 3030 U/L; and asparate aminotransferase level, 2074 U/L. On stopping taking both drugs, his symptoms resolved and the liver function test results gradually became normal. No other contributing cause for the hepatotoxicity was found. From the temporal profile, the hepatotoxicity in our patient was possibly due to the combination of riluzole and naltrexone, although either drug alone could be implicated, or there may have been another mechanism. Riluzole is predominantly metabolised by cytochrome P450 enzymes (CYP1A2), but there is considerable patient variability, and the hepatotoxicity mechanism is largely unknown2 (see also MIMS Online: http://www.mims.hcn.net.au). In recent months, low-dose naltrexone has become popular with patients who have MND, although there are no published data of efficacy. Hepatotoxicity caused by naltrexone is dose-dependent and uncommon.3 Naltrexone is metabolised by glucuronidation in the liver to an active metabolite, but a direct interaction with riluzole through cytochrome P450 enzymes appears unlikely.4 There have been no clinical studies to evaluate interactions with other drugs of either riluzole or naltrexone (apart from opiates).3 This case highlighted for us that patients may be taking other therapies for MND, and that clinicians should be aware of the possibility of serious drug interactions when riluzole is prescribed.

Robert D Henderson · Pamela A McCombe

In reply: Henderson and McCombe describe a patient to highlight an issue raised in a recent editorial:1 that patients with motor neurone disease (MND) may develop abnormal liver function tests for reasons other than riluzole therapy. In their patient, riluzole was prescribed for a year and liver function test results remained stable. Deterioration in liver function coincided with the introduction of naltrexone. Ultimately, riluzole, an established MND therapy, had to be ceased. Naltrexone is an authority medication, prescribed in the setting of alcohol or opioid dependence. MEDLINE searches failed to find any study or indication for naltrexone in the treatment of MND. An internet search, however, revealed a number of personal anecdotes, with a curiously Australian emphasis, suggesting an immuno-modulatory role for naltrexone in MND. A few further clicks of the mouse and the naltrexone ordering site with costings appeared. Patients with incurable diseases commonly seek “alternative” treatments2 at great personal financial cost, calculated at thousands of dollars per patient with MND.3 Often there is insufficient, or, as with naltrexone, no evidence that these treatments are effective.4 Most patients with MND will consider alternative therapy, irrespective of their educational background5 or understanding of disease pathophysiology. How each physician approaches the use of complementary and alternative therapies by their patients may develop into an important issue in the therapeutic relationship. Certainly, being aware of the possibility may prove critical. In the patient described by Henderson and McCombe, an unfortunate outcome of irreversible liver failure in a patient with NMD was averted through conventional monitoring of liver function.

Matthew C Kiernan

Clinical record A 22-year-old woman who was 12 weeks pregnant presented to a country hospital with uncontrollable nausea and vomiting. This was initially controlled with antiemetics, but over the next 4 weeks, she continued to vomit five to six times a day. She presented again at 16 weeks’ gestation when the vomiting became more frequent, and also complained of poor visual acuity and diplopia of several days duration. At the time, there was no gait disturbance, no change in mentation, nor any associated headache. At this stage she was admitted and treated with intravenous fluids including glucose. One week into her admission, her vision deteriorated and she became confused and unsteady on her feet; she was referred to the Royal Melbourne Hospital. On initial examination in Melbourne, she was normotensive (120/80 mmHg) but drowsy. There was no neck stiffness or rash. She now had a prominent gait ataxia and a corresponding mild lower-limb peripheral neuropathy with absent deep tendon reflexes. Additionally, she had bilateral horizontal nystagmus and poor visual acuity (right, 6/36; left 6/18). There was an associated mild right gaze paresis with intact visual fields on confrontation. There was no pain with eye movements. The results of fundoscopy are shown (Figure 1). Her past history was unremarkable. She did not take regular medications, and this was her first pregnancy. Ultrasonography of the fetus and placenta at 17 weeks’ gestation excluded multiple and molar pregnancy. She did not drink or smoke. Haematological and biochemical test results were largely normal, but her serum levels of creatinine (0.04 mmol/L; normal range [NR], 0.05–0.10 mmol/L) and urea (2.2 mmol/L; NR, 2.5–6.1 mmol/L) were slightly low, and her INR (international normalised ratio) was 2.0 (NR, 0.8–1.2). There were also some elevated levels in her liver function test results: γ-glutamyl transferase, 60 U/L (NR, < 50 U/L); alanine aminotransferase, 486 U/L (NR, < 55 U/L); and bilirubin, 32 U/L (NR, 0–19 U/L). Cerebrospinal fluid (CSF) examination and magnetic resonance imaging (MRI) were also undertaken to exclude intracranial causes. The CSF findings were normal, but the MRI revealed bilateral thalamic lesions (Figure 2). Given the new clinical features and her MRI result, a diagnosis of Wernicke’s encephalopathy was made. Thiamine deficiency was suspected to be secondary to hyperemesis gravidarum. Interestingly, her serum thiamine level was only marginally low at 64 nmol/L (normal range, 66–200 nmol/L). Therapy with pyridoxine, folic acid and intravenous thiamine replacement was commenced. She made a rapid clinical recovery. Visual acuity returned to normal within 3 days and her ataxia, gaze limitation and neuropathy improved. Repeat MRI imaging 7 days later showed moderate resolution of the hyperintensities. Our patient went on to successfully deliver a healthy baby girl at 37 weeks’ gestation. 1 Fundal photographs showing gross papillitis of both the right and left optic discs, respectively. A small retinal haemorrhage is shown in the left eye. 2 Magnetic resonance imaging (T1-weighted, T2-weighted axial, and diffusion-weighted image, respectively), with arrows showing bilateral symmetrical thalamic hyperintensities with restricted diffusion. Bilateral thalamic ischaemia is most often seen in thiamine deficiency. This patient’s rapid response to intravenous thiamine replacement confirms the diagnosis of Wernicke’s encephalopathy secondary to thiamine deficiency. Thiamine, or vitamin B1, plays an important role in carbohydrate metabolism through decarboxylation of alpha-keto acids. Moreover, it also functions as a co-enzyme to the apoenzyme transkelotase in the pentose monophosphate pathway for glucose.1 Low thiamine levels can be associated with poor intake or absorption, increased demand, or poor utilisation. It is well understood that thiamine requirements are increased in pregnancy, and this is thought to be the result of sequestration of the vitamin by the fetus and placenta.2 With hyperemesis gravidarum, the deficiency is further compounded by the impaired absorption related to the intractable vomiting.3 In some situations, prolonged use of intravenous glucose without thiamine can be a potent precipitant of Wernicke’s encephalopathy.4 This phenomenon is well documented,5 and in our patient, might have contributed to the evolving deficiency. Abnormal liver function test results are also seen in Wernicke’s encephalopathy, and it is possible that hepatic derangement may have also played a pathogenic role in the evolution of our patient’s disease. 6 Our case is unusual in that visual deterioration was the first symptom of an evolving thiamine deficiency. There was a delayed presentation of the classical triad of Wernicke’s encephalopathy — ataxia, mental confusion and ocular gaze problems. Moreover, in our case, MRI scanning was able to detect sensitive neurological changes, raising the suspicion of thiamine deficiency. This information was important in prompt treatment of the condition when clinical signs began to emerge. Indeed there are reports of the usefulness of MRI imaging in diagnosing cases of Wernicke’s encephalopathy.7 Our patient’s vitamin B1 level was only mildly reduced, but this may have been the result of partial correction with food intake while an inpatient at the country hospital. Unfortunately, intracellular thiamine levels could not be measured before replacement. Intracellular thiamine level is usually a more accurate marker of thiamine deficiency, measured as erythrocyte thiamine diphosphate by high pressure liquid chromatography, and is often abnormal in such cases of Wernicke’s encephalopathy, even when the serum thiamine level is normal. If left untreated, thiamine deficiency can lead to severe neurological, cardiovascular and gastrointestinal sequelae. If not treated, the result is often death. Delayed correction of low thiamine levels may lead to persistent nystagmus, ataxia and poor concentration with multiple tasks.8 For the fetus of an affected mother, slow in-utero development is possible. Ophthalmic symptoms may include subacute, progressive visual loss, with central field defects and associated poor colour vision. Papillitis can be seen in cases of nutritional optic neuropathy. In severe cases, blindness may occur as a result of complete optic atrophy.9 As thiamine deficiency has severe consequences, we believe that vitamin B1 replacement should be considered in all pregnant women with hyperemesis gravidarum. We further suggest that in such cases MRI imaging may play an important role in early diagnosis. Lessons from practice Visual deterioration may sometimes be the first presenting sign of thiamine deficiency. The visual symptoms of Wernicke’s encephalopathy are reversible with prompt administration of thiamine. Early correction of thiamine deficiency is essential in all patients with hyperemesis gravidarum. Intravenous glucose should be given together with thiamine for patients being treated for hyperemesis gravidarum. The best laboratory measure of thiamine deficiency is erythrocyte thiamine diphosphate by high pressure liquid chromatography. Magnetic resonance imaging may help in early diagnosis of patients with Wernicke’s encephalopathy where optic neuropathy is the first clinical sign.

Mervyn D Ferdinands MB BS(Hons) · Janaka Seneviratne FRACP · Owen White MD, PhD, FRACP

Ian W Boyd Executive Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Australian Government Department of Health and Ageing, PO Box 100, Woden, ACT 2606. ian.boydAThealth.gov.au To the Editor: Labate and colleagues note that tramadol is the most frequently suspected cause of provoked seizures at their First Seizure Clinic.1 Early in 2003, the Adverse Drug Reactions Advisory Committee (ADRAC) reported to Australian prescribers the results of the first 4 years of experience with tramadol in Australia.2 At the time, ADRAC noted that 26 cases of convulsions had been reported among a total of 354 reports on tramadol. By January 2005, ADRAC had received a total of 921 reports involving tramadol, of which 66 described convulsions. (Labate et al reported that 83 cases of convulsions associated with tramadol had been reported to ADRAC. This is incorrect, but the mistake probably resulted from an error in interpretation of information supplied by the Adverse Drug Reactions Unit.) In 27 cases, tramadol was the only suspected drug, but in the other 39 cases there were various other suspected drugs. This included 20 reports in which there was a suspected drug interaction. Both oral and injected tramadol have been implicated. The product information for tramadol states that convulsions have been reported in patients using tramadol at the recommended dose levels and that the risk may be greater when doses of tramadol exceed the recommended limits.3 In addition, tramadol may increase the seizure risk in patients taking other medications that lower the seizure threshold. Drugs specifically mentioned in this context include the selective serotonin reuptake inhibitors, tricyclic antidepressants and antipsychotic drugs. In the 39 cases reported to ADRAC in which there were one or more suspected drugs in addition to tramadol, tramadol was being used with selective serotonin reuptake inhibitors (10 cases), tricyclic antidepressants (6 cases) and, in 13 cases, other drugs that may also have the potential to lower the seizure threshold, such as pethidine (2 cases), venlafaxine (2), propofol (2) and bupropion (2). In two of the cases in which tramadol was the only suspected cause and two of the cases with multiple suspected causes, the patients were also taking anticonvulsant drugs for seizure control. ADRAC data indicate that, although tramadol alone can induce seizures, these are more likely to occur in the setting of the concomitant use of other drugs that also have the potential to lower the seizure threshold.

Ian W Boyd

Most cases are caused by a single mutation, paving the way for therapeutic advances for this fatal disease Friedreich ataxia (FRDA), an autosomal recessive disease, is the commonest of the inherited ataxias’, affecting around 1 in 30 000 people.1 With an average age of onset of 10 years, those affected by this condition become wheelchair-bound on average 10 years after onset. The symptom that heralds onset in the vast majority of cases is increasing incoordination. Onset after 30 years of age is rare. Death ensues, on average, 36 years after disease onset and is largely due to hypertrophic cardiomyopathy.2 Other sources of morbidity in FRDA include an increased incidence of diabetes mellitus, dysarthria, swallowing difficulties, scoliosis, optic atrophy, hearing loss and foot deformity.1 FRDA is caused by mutations in the FRDA gene which encodes the protein frataxin. The pathogenic mutation is an expanded GAA triplet repeat in intron one of the FRDA gene in 98% of mutant alleles.1 The other 2% are point mutations. The fact that one mutation accounts for the vast majority of FRDA means that there is a relatively simple diagnostic test available for this disease. The genetic basis of FRDA was elucidated in 1996, and much has since been learnt about its pathogenesis. The first evidence of the role of frataxin came serendipitously, when the yeast equivalent of the FRDA gene (yfh1) was removed and increased levels of mitochondrial iron were detected.3 Human studies have confirmed that FRDA is indeed a disease of mitochondria. The accumulated evidence suggests that the marked reduction in frataxin results in decreased production of iron–sulfur cluster-containing proteins, which leads to deficiencies of some of the mitochondrial respiratory chain complexes and to secondary iron accumulation.2 Oxidative damage has been strongly implicated, although recent evidence brings this into question.4 These genetic and molecular findings have led to a number of therapies being proposed for FRDA. Interventions to maximise quality of life are of paramount importance, while the quest to find disease-modifying therapies continues. Hopes for the obvious prospect of iron chelation therapy have been tempered because none of the current iron chelators approved for clinical use preferentially reduce the levels of iron in mitochondria without also reducing cytosolic iron levels.5 Antioxidant therapy has shown the most promise. High-dose coenzyme Q10 and vitamin E has been shown to reverse the surrogate marker of reduced energy production in muscle magnetic resonance spectroscopy.6 Idebenone, an analogue of coenzyme Q10, reduces cardiac hypertrophy, although it has not been shown to relieve the neurological aspects of FRDA.7 A multicentre placebo controlled trial of idebenone is to start soon in the United States. An antioxidant targeted at mitochondria, mitoquinone, has been developed in New Zealand.8 Because mitochondria have a very strong membrane potential of about 150 mV (positive outside, negative inside), the drug is concentrated in mitochondria about 500-fold compared with antioxidants without a mitochondrial-targeting moiety. Clinical trials of this agent are planned to commence this year. Another approach that has promise is identifying agents that increase frataxin expression.9 The rationale for this approach is that all patients with FRDA produce low levels of normal frataxin, and, in experimental animal models, production of 25% of normal levels is enough to prevent development of disease. Therefore, a 5–10 fold increase in frataxin production may be therapeutic for most patients, while lower levels of induction may still produce significant amelioration of the disease.2 A small number of pharmacological agents have been screened thus far, causing up to a 2.5-fold induction in frataxin expression. It is hoped that high throughput screening of approved drugs and chemical libraries will lead to the identification of more effective and safe inducers. A major challenge facing FRDA clinical investigation is the development of appropriate outcome measures for clinical trials.10 FRDA is rare, and its rate of progression is not predictable, but occurs in a step-wise fashion. Therefore, a multicentre approach is vital to enable development of scales to measure the effects of therapies so that pharmacological discoveries can be quickly translated to patient benefit. The discovery of the underlying genetic mechanism for FRDA has led rapidly to better understanding of its pathogenesis. It is likely that this expanding knowledge will lead to therapies that slow the progression of, and ultimately cure, this fatal disease.

Martin B Delatycki MB BS, FRACP, PhD · Panos A Ioannou PhD · Andrew J Churchyard MB BS, FRACP, PhD

Clinical record A 53-year-old woman with a 10-year history of coeliac disease controlled by a gluten-free diet presented with a 6-month history of dramatic weight loss and pyrexia. Physical examination showed wasting and peripheral oedema. Plasma albumin level was 23 g/L (normal, 34–48 g/L). Computed tomography of head, neck, chest, abdomen and pelvis, gallium and positron emission tomography scans, liver biopsy and bone marrow biopsy were normal. The serum lactate dehydrogenase (LDH) level was 466 U/L (normal, 110–230 U/L), raising the possibility of occult malignancy, especially enteropathy-associated T-cell lymphoma (EATL). Endoscopic duodenal biopsy revealed mild increase in intraepithelial lymphocytes, crypt hyperplasia and villous abnormality in keeping with coeliac disease. Molecular clonality studies of the lymphoid cells in the duodenal biopsy yielded a monoclonal band of T-cell receptor (TCR) γ gene rearrangement in two separate series of biopsies taken 6 weeks apart. Refractory sprue was diagnosed, and the patient received sequential trials of prednisolone, cyclosporin A and infliximab without benefit. High dose cyclophosphamide (2 g/m2) was administered 3 months later for presumed EATL. This resulted in immediate resolution of the fever and improved weight gain. The patient subsequently complained of paraesthesiae in her feet. Neurological examination was normal. Nerve conduction studies suggested an early axonal sensory peripheral neuropathy. Vitamin B12, folate, vitamin A-tocopherol, red blood cell transaminase and transketolase studies, vasculitic screen, glycated haemoglobin, syphilis serology and thyroid function tests were normal. Paraprotein was not detected in serum electrophoresis. Magnetic resonance imaging (MRI) of the brain showed non-specific patchy periventricular areas of high signal not suggestive of the suspected lymphoma. Her systemic symptoms of fever, sweats and weight loss responded to two further doses of cyclophosphamide (1 g/m2), despite worsening neurological symptoms. After 3 months, the patient relapsed with recurrence of pyrexia, and the serum LDH level progressively rose to 838 U/L. Neuropathy progressed to the point where she could not walk. Reflexes were lost, with a glove-and-stocking pattern of sensorimotor disturbance. A repeated nerve conduction study confirmed severe axonal sensorimotor peripheral neuropathy affecting both upper and lower limbs. Cerebrospinal fluid was normal, and there were no malignant cells. Repeated investigations, including brain MRI and upper gastrointestinal endoscopy, did not reveal any further evidence of malignancy. A right sural nerve biopsy showed severe loss of myelinated nerve fibres, and many of the surviving fibres showed varying stages of axonal degeneration (Box 1) associated with a sparse, patchy endoneurial mononuclear cell infiltrate in some fascicles and prominent endoneurial fibrosis on trichrome stain. The CD45RB immunostain showed increased numbers of immunopositive endoneurial lymphoid cells that showed immunopositivity with the T-cell markers CD3 (Box 2) and CD5. The CD68 immunostain showed increased endoneurial macrophages, and ultrastructural assessment confirmed macrophage phagocytosis of degenerate myelinated fibres. CD20 immunostain was negative. The Congo red stain for amyloid was negative. A TCRγ clonality study of the nerve biopsy showed a monoclonal band identical to the previous band detected in the duodenal biopsies, confirming infiltration of the nerve by T-cell lymphoma (Box 3). Subsequent treatment with cyclophosphamide, doxorubicin and dexamethasone was complicated by Enterococcus faecalis septicaemia and florid disseminated intravascular coagulation, leading to the patient’s death. Coeliac disease is associated with an increased risk of malignancy.1 Most of these tumours are T-cell lymphomas, in contrast to the common sporadic B-cell lymphomas that usually occur in the gastrointestinal tract. Enteropathy-associated T-cell lymphoma (EATL) often presents as refractory sprue. The risk of EATL usually decreases to a low level after adhering to a gluten-free diet for 5 years. Common symptoms of presentation include diarrhoea, abdominal pain and weight loss. Patients may also present with acute bleeding, perforation or obstruction.2 Our patient presented with weight loss, pyrexia and, subsequently, neuropathy. Clinical deterioration despite compliance with a gluten-free diet should raise suspicion of EATL. Conversely, as coeliac disease may be undiagnosed at the time of presentation of the intestinal lymphoma, patients with T-cell lymphoma or a gut primary localisation should be tested for coeliac disease. Endoscopy with biopsy is usually the test of choice. Laparotomy is performed in some instances, especially when patients present with an acute abdomen. Our case illustrates a number of interesting features. First, a definitive diagnosis of EATL may be elusive, and persistence in obtaining histological confirmation is warranted. The elevated serum lactate dehydrogenase (LDH) level raised the possibility of an underlying malignancy. Second, in patients with refractory sprue, a clonal TCRγ rearrangement often precedes the onset of overt T-cell lymphoma, which constitutes an early or cryptic form of EATL.3-5 The difficulty is distinguishing antigen-dependent T cells from neoplastic T cells. Management decisions may have to be based on DNA clonality studies alone. Finally, although central nervous system involvement has been reported,6,7 to our knowledge this is the first reported case of peripheral nerve involvement in EATL. Clinical evidence of peripheral neuropathy is observed in 0.1% to 8% of patients with malignant lymphomas,8 and neurotoxic chemotherapeutic agents are frequently presumed to be the cause. Peripheral nerve involvement in T-cell lymphomas is very uncommon.8-10 It is also interesting that the infiltrative neuropathy progressed relentlessly despite an initial good response of systemic symptoms to cyclophosphamide. Both refractory sprue and EATL carry a very poor prognosis, with a 5-year survival rate of 11%. This is related to the unresponsive malabsorption in cryptic EATL, which is often diagnosed late. Associated malabsorption and malnutrition make tolerance of chemotherapy difficult, and treatment-related complications such as gastrointestinal bleeding and perforation also worsen prognosis.2 Favourable outcomes with multi-drug therapy generally occur in patients who have minimal gastrointestinal symptoms before the diagnosis of lymphoma and can tolerate therapy. Chemotherapy should be considered for all patients and should constitute drugs active in intermediate- and high-grade lymphoma. A variety of regimens, including CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone), have been used. The optimal cytotoxic regimen is unclear, as data are limited to uncontrolled retrospective case series. The role of salvage treatments and high-dose chemotherapy at relapse also remains to be investigated.2 Earlier diagnosis and development of more effective treatments are required to improve the outcome for these patients. Lessons from practice Coeliac disease is associated with an increased risk of malignancy, especially intestinal lymphoma or enteropathy-associated T-cell lymphoma (EATL). EATL often presents as refractory sprue, but definitive diagnosis may be difficult and requires T-cell clonality studies. Earlier diagnosis and development of more effective treatments are warranted to improve the poor outcome in these patients. 1 Nerve fibres in varying stages of axonal degeneration Longitudinal section. Transverse section. 2 Positive CD3 immunostaining of lymphocytes 3 Polyacrylamide gel electrophoresis of T-cell receptors Lane 1, positive control; lane 2, negative control; lane 3, normal (polyclonal) control; lanes 4 and 5, duodenal biopsy, 12 Apr 2002; lanes 6 and 7, duodenal biopsy, 19 Jul 2002; lanes 8 and 9, nerve tissue, 9 Oct 2002.

Yoon-Sim Yap MBBS · Adrian Cummins FRACP, MD, PhD · Jennifer Hardingham BSc, PhD · Sunil Dabadghao MD, MBBS · John Norman MBBS, FRACP · Peter Blumbergs MBBS, FRACP, FRCPA

Objective: An Australian stroke services study (SCOPES) has developed a framework to compare different forms of acute stroke services, the gold standard being localised stroke units. We aimed to use this framework to assess changes in the quality of stroke care over time as a sequential audit process.Design and setting: A retrospective medical record audit comparing 100 sequential stroke admissions (July 2002 to June 2003) two years after institution of a mobile stroke service (MSS) with 100 historical controls (September 1998 to October 1999) at a 260-bed hospital in Melbourne. The MSS results were also compared with stroke units in SCOPES.Main outcome measures: Adherence to quality indicators and standard measures of outcome (complications, length of stay and discharge disability) after implementing the MSS.Results: Significant improvements were seen in prophylaxis for deep-vein thrombosis, incontinence management, premorbid function documentation, frequent neurological observations and early occupational therapy. The MSS demonstrated fewer severe complications (9% versus 24%; P = 0.004), reduced median length of stay (discharged patients: 12.0 days versus 18.5 days; P = 0.003) and more patients were independent at discharge (32% versus 9%; P < 0.001). Comparison with SCOPES stroke units showed our MSS could improve in incontinence management and appropriate use of antiplatelet therapy.Conclusion: Institution of the MSS was associated with improvements in the quality of stroke care. This study demonstrates application of an audit procedure for quality improvement in hospital stroke management and the potential to improve stroke services in smaller centres.

Anneke van der Walt MB ChB · Amanda K Gilligan MB BS, FRACP · Amy G Brodtmann MB BS, FRACP · Dominique A Cadilhac MPubHlth · Dora C Pearce MIT · Geoffrey A Donnan MD