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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... more
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.
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The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological... more
The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological mechanism by which the c9orf72 gene expansion leads to neurodegeneration is not yet elucidated. Cortical hyperexcitability is potentially an important pathophysiological process in sporadic ALS and familial ALS (FALS). To investigate whether cortical hyperexcitability forms the pathophysiological basis of c9orf72 FALS using the threshold-tracking transcranial magnetic stimulation technique. Prospective case-control single-center study that took place at hospitals and outpatient clinics from January 1, 2013, to January 1, 2015. Clinical and functional assessments along with transcranial magnetic stimulation studies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 who were longitudinally followed up for 3 years. ...
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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... more
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.
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Critical illness polyneuropathy in burn patients is an underreported condition. It is associated with high mortality rates and prolonged hospital stay and rehabilitation. This study aims to further define the cause and outcome of critical... more
Critical illness polyneuropathy in burn patients is an underreported condition. It is associated with high mortality rates and prolonged hospital stay and rehabilitation. This study aims to further define the cause and outcome of critical illness polyneuropathy following major burn injuries. A retrospective review of all burn patients with neuropathy that presented to Royal North Shore Hospital, Sydney, between the period of 2004 and 2009 was performed. The neurological findings, diagnostic processes, and outcomes were examined. End points such as duration on the ventilator, length of intensive care, and hospital stay were recorded. There were 7 patients in total that exhibited abnormal neurological findings. Ages ranged from 17 to 43 years with all injuries sustained in flame burns. Mean total burnt surface area is 46%. There was no mortality in this series but all 7 had evidence of sepsis and multiorgan failure with an average 42 days spent on the ventilator. Clinical findings var...
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Clinical record We report anoxic convulsions occurring in two medical students competing in a breath-hold dive competition in shallow water. The seizure-like activity occurred during a competition called the “Dolphin Dive”, which was part... more
Clinical record We report anoxic convulsions occurring in two medical students competing in a breath-hold dive competition in shallow water. The seizure-like activity occurred during a competition called the “Dolphin Dive”, which was part of a university medical school swimming ...
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Acquired and hereditary amyloidosis can cause peripheral neuropathy, but the mechanisms by which this occurs have not been established. Threshold tracking techniques allow in vivo assessment of the properties of the axonal membrane and... more
Acquired and hereditary amyloidosis can cause peripheral neuropathy, but the mechanisms by which this occurs have not been established. Threshold tracking techniques allow in vivo assessment of the properties of the axonal membrane and may shed light on pathogenetic mechanisms underlying neuropathic disorders. We studied 10 subjects with primary amyloidosis using conventional nerve conduction studies and quantitative sensory, autonomic, and axonal excitability testing of median motor and sensory fibers. As expected, subjects with amyloidosis had evidence of small- and large-fiber neuropathy on conventional testing. There was no significant difference in axonal excitability between subjects and controls apart from the stimulus required to activate sensory fibers. Amyloid-related neuropathy does not produce a change in membrane potential as either a primary or secondary event. This suggests that ischemia and axonal compression are unlikely mechanisms for the neuropathy. Muscle Nerve 51: 443-445, 2015.
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Poliomyelitis causes selective destruction of anterior horn cells and usually has a stable disease course post-infection. We assessed the excitability characteristics in patients with a stable course after past poliomyelitis and compared... more
Poliomyelitis causes selective destruction of anterior horn cells and usually has a stable disease course post-infection. We assessed the excitability characteristics in patients with a stable course after past poliomyelitis and compared them with changes described in amyotrophic lateral sclerosis (ALS). The excitability characteristics of motor and sensory nerves were studied in 10 subjects with stable past poliomyelitis. Motor rheobase was increased, but there were no significant changes in strength-duration properties or depolarizing threshold electrotonus, as have been seen in previous studies of ALS. There is minimal change in axonal excitability properties in patients with stable past poliomyelitis. The results may signify sufficient compensation in the stable state of the disease. Increased subexcitability in 1 subject with demonstrable hyperexcitability may represent compensation for increased ectopic activity rather than a different process in surviving motor neurons. Muscle Nerve 50: 602-604, 2014.
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In mitochondrial disease, it is likely that energy substrate depletion leads to paralysis of ATPase-dependent pumps, resulting in membrane depolarization. Axonal depolarization has been demonstrated in a crisis, but not in the resting... more
In mitochondrial disease, it is likely that energy substrate depletion leads to paralysis of ATPase-dependent pumps, resulting in membrane depolarization. Axonal depolarization has been demonstrated in a crisis, but not in the resting state. We, therefore, stressed axons using ischemia to see if this would reveal abnormal responses, as occurs in diabetes mellitus. Excitability of median nerve axons at the wrist was studied in 13 patients with MELAS (6 with glucose intolerance) and 17 control subjects in response to ischemia due to inflation of a cuff around the arm for 10 min. There were no significant differences in preischemic measures of axonal excitability or in the intra- and postischemic responses. Although depolarization has been noted to occur spontaneously during a crisis, we could not demonstrate a defect of axonal ATP-dependent mechanisms. The mechanisms underlying axonal excitability and neuropathy in diabetes may not apply to MELAS.
Research Interests: Humans, Ischemia, Female, Male, Arm, and 6 moreAged, Middle Aged, Adult, Action Potentials, Axons, and Median Nerve
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Subtle involvement of peripheral nerves may occur in multiple sclerosis. Motor excitability studies have suggested upregulation of slow K+ currents, probably secondary to altered motoneuron properties resulting from the central lesion.... more
Subtle involvement of peripheral nerves may occur in multiple sclerosis. Motor excitability studies have suggested upregulation of slow K+ currents, probably secondary to altered motoneuron properties resulting from the central lesion. This study concentrates on sensory axons. Excitability of median nerve axons at the wrist was studied in 26 patients. Sensory recordings were possible in 22 patients, and reduced superexcitability was the sole abnormality. There was no evidence for changes in membrane potential or demyelination. The decrease was significant in patients taking immunomodulatory therapy. These findings could be reproduced in a computer model by changing the gating of fast K+ channels. Motor axon findings were consistent with previously reported increased slow K+ current. The sensory findings differ from motor findings. They can be explained by a humoral factor, possibly cytokines, which can penetrate the paranode and have been documented to alter the gating of K+ channels.
Research Interests: Multiple sclerosis, Humans, Female, Male, Middle Aged, and 5 moreAdult, Action Potentials, Axons, Median Nerve, and Myelin Sheath
PAPER, Synthesis 2004(11): 1755-1758 DOI: 10.1055/s-2004-829135. © Georg Thieme Verlag Stuttgart · New York. Synthesis of 2,3,4,5-Tetrahydro-1,5-methano-1H-3-benzazepine via Oxidative Cleavage and Reductive Amination Strategies. ...
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Mitochondrial disorders are characterised by protean neurological manifestations including peripheral neuropathy. The neuropathy is typically an axonal process, with a proposed mechanism being degradation of the membrane potential of the... more
Mitochondrial disorders are characterised by protean neurological manifestations including peripheral neuropathy. The neuropathy is typically an axonal process, with a proposed mechanism being degradation of the membrane potential of the axon due to dysfunction of energy-dependent Na(+)/K(+) ATPase pump. To address this issue, we studied the excitability of motor axons in the median nerve in 16 individuals identified with gene testing or muscle biopsy. Twelve patients had clinical or nerve conduction abnormalities. Strength--duration time constant, threshold electrotonus, current--threshold relationship and recovery cycle were identical to control values. These findings imply that an alternative mechanism to a change in membrane potential is responsible for neuronal injury in these patients.
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Paraneoplastic cerebellar degeneration may occur in association with Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not been previously... more
Paraneoplastic cerebellar degeneration may occur in association with Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not been previously reported. A 67-year-old woman presented with a complex partial seizure and evolving ocular flutter, opsoclonus, myoclonus and 'cerebellar' signs, all of which improved spontaneously within 6 weeks. Approximately 8 weeks after symptom onset, the patient became encephalopathic, she had a further complex partial seizure, and she became areflexic with potentiation of deep tendon reflexes. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel antibodies were identified in the serum, which increased as the signs of opsoclonus and myoclonus resolved. The encephalopathy and clinical features of LEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous improvement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this syndrome may occur in association with LEMS. Antivoltage-gated calcium-channel antibodies are not implicated in the pathogenesis of paraneoplastic opsoclonus-myoclonus syndrome.
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Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation... more
Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition.
Research Interests: Neurology, Australia, Adolescent, Humans, Child, and 11 moreMutation, Female, Male, Young Adult, Infant, Phenotype, Clinical Sciences, Middle Aged, Genotype, Adult, and Neurosciences
In median nerve somatosensory evoked potentials, the cortical N35 amplitude sometimes exceeds the P25 amplitude... more
In median nerve somatosensory evoked potentials, the cortical N35 amplitude sometimes exceeds the P25 amplitude (C3'/C4' referred to Fz; "enhanced N35" feature). Six hundred consecutive patient median nerve SEPs were retrospectively analysed and compared with 27 controls. The feature was more often present in patients with dystonia (62%) than in patients with other disorders (22%; relative risk for the condition 2.8; Fisher's exact p=0.003) or control subjects (7.4%; odds ratio 20; p=0.0006). Similarly, the feature was more often present in patients with myoclonus (38%) than in patients with other disorders (22%; relative risk 1.7; p=0.02) or control subjects (odds ratio 7.5; p=0.006). There was no clear relationship of the feature to short latency SEP abnormalities except in cases of myoclonus. Further comparison was made of the characteristics of 72 patients each, with and without the feature, whose short latency SEP components were normal. The relationship of the feature to dystonia or myoclonus held true in this case-controlled arm of the study. The sensitivity and specificity were 65% and 78% respectively for any form of dystonia; 43% and 79% respectively for any form of myoclonus. The feature was even more specific in both conditions when compared with controls (93%). Most cases of dystonia with an identifiable cause in this study were of secondary forms. It is known that this feature often occurs in association with "giant" SEPs in some myoclonic conditions. However, its occurrence in dystonia may be a useful new finding in an established test, helping to identify a condition where there is increasing evidence for disordered sensorimotor integration.
Research Interests: Neurology, Risk, Electroencephalography, Humans, Sensorimotor integration, and 15 moreFemale, Male, Dystonia, Clinical Sciences, Middle Aged, Adult, Odds ratio, Retrospective Studies, Sensitivity and Specificity, Neurosciences, Median Nerve, Myoclonus, Clinical evaluation, Case Control Studies, and Relative Risk
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Clinical Neurophysiology, Volume 121, Issue 4, Pages e2, April 2010, Authors:Karl Ng; Kishore Kumar; Bruce Brew; David Burke.
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Research Interests: Humans, Muscle, Alcoholism, Female, Male, and 18 moreLiver Function, Peripheral Neuropathy, Aged, Middle Aged, Adult, Peripheral nerves, Alcohol Abuse, Peripheral Nerve, Quantitative Sensory Testing, Lower limb, Liver Failure, Electrodiagnosis, Reference Values, Autonomic Neuropathy, End Stage Liver Disease, Blood Parameter, hyperammonemia, and Oxidative Metabolism
Inclusion-body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) gene. Patients with this disorder may have neuropathic or... more
Inclusion-body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) gene. Patients with this disorder may have neuropathic or myopathic features. Peripheral nerve function and axonal excitability were studied in three members from two families with VCP mutations (p.Arg155Leu and p.Leu198Trp). Patients from the first family had neurogenic patterns on needle electromyography (EMG), whereas those in the second family had myopathic EMG changes. In threshold electrotonus for motor axons, the changes to depolarizing and hyperpolarizing conditioning currents were at or outside control limits in all three patients. Superexcitability was increased, and the relative refractory period was reduced. The strength-duration time constant was normal. In sensory axons of all three patients, there were similar changes in threshold electrotonus, but not in superexcitability. These features are best explained by axonal hyperpolarization. The findings provide insight into the pathophysiological mechanisms in these genotypes and, possibly, into all patients with IBMPFD.