Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision thr... more Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifyin...
A 73-year-old lady became bed bound with progressive generalized weakness 2 weeks after the intro... more A 73-year-old lady became bed bound with progressive generalized weakness 2 weeks after the introduction of sodium fusidate for osteomyelitis. She was already on simvastatin for years. Electromyography showed no spontaneous muscle activity from any of the muscles sampled. The temporal relationship of symptom onset after introduction of fusidic acid and full recovery after cessation of the 2 drugs suggests a serious interaction that deserves wider recognition.
Cortical myoclonus with ataxia has only rarely been reported in association with Coeliac Disease ... more Cortical myoclonus with ataxia has only rarely been reported in association with Coeliac Disease (CD). Such reports also suggested that it is unresponsive to gluten-free diet. We present detailed electro-clinical characteristics of a new syndrome of progressive cortical hyperexcitability with ataxia and refractory CD. At our gluten/neurology clinic we have assessed and regularly follow up over 600 patients with neurological manifestations due to gluten sensitivity. We have identified 9 patients with this syndrome. All 9 patients (6 male, 3 female) experienced asymmetrical irregular myoclonus involving one or more limbs and sometimes face. This was often stimulus sensitive and became more widespread over time. Three patients had a history of Jacksonian march and five had at least one secondarily generalised seizure. Electrophysiology showed evidence of cortical myoclonus. Three had a phenotype of epilepsia partialis continua at onset. There was clinical, imaging and/or pathological evidence of cerebellar involvement in all cases. All patients adhered to a strict gluten-free diet with elimination of gluten-related antibodies in most. However, there was still evidence of enteropathy in all, suggestive of refractory celiac disease. Two died from enteropathy-associated lymphoma and one from status epilepticus. Five patients were treated with mycophenolate and one in addition with rituximab and IV immunoglobulins. Their ataxia and enteropathy improved but myoclonus remained the most disabling feature of their illness. This syndrome may well be the commonest neurological manifestation of refractory CD. The clinical involvement, apart from ataxia, covers the whole clinical spectrum of cortical myoclonus.
In a retrospective study of 86 patients with myasthenia gravis (MG), we correlated the acetylchol... more In a retrospective study of 86 patients with myasthenia gravis (MG), we correlated the acetylcholine receptor (AChR) antibody titers with single-fiber EMG studies to explore whether a relationship exists between these parameters. We found that the AChR antibody titers correlated significantly with the mean of the mean consecutive difference of orbicularis oculi (OO, P<0.0001) and extensor digitorum communis (EDC, P<0.0001). The correlation was found to be stronger in OO. The antibody titers also correlated with the percentage of potential pairs with increased jitter in both muscles and, again, the correlation was more significant in OO (P<0.0001) than in EDC (P=0.001). We speculate that this relationship is stronger in OO than in the limb muscles, because the architectural and immunological differences in the motor unit render OO more vulnerable and sensitive to disturbances in neuromuscular transmission.
We performed a retrospective study to validate whether a disposable concentric needle electrode (... more We performed a retrospective study to validate whether a disposable concentric needle electrode (CNE) can be used in place of a single-fiber (SF) electrode for jitter measurements in myasthenia gravis (MG). Normal values for voluntary contraction of orbicularis oculi (OO) and extensor digitorum communis (EDC) were collected from 20 healthy subjects. The method was validated by a retrospective analysis of 56 consecutive MG patients, the "gold standard" being a positive acetylcholine receptor (AChR) antibody titer at the time of the electrophysiological (electromyography) study and the clinical diagnosis. Receiver operating characteristic (ROC) curves were constructed to define maximal sensitivity and specificity of the technique. The sensitivity was 96.4% (95% confidence interval 87.5%-99.6%), with no false-positive results, similar to traditional SF EMG and confirming that the disposable CNE is a justifiable alternative.
Spectral measures of linear Granger causality have been widely applied to study the causal connec... more Spectral measures of linear Granger causality have been widely applied to study the causal connectivity between time series data in neuroscience, biology, and economics. Traditional Granger causality measures are based on linear autoregressive with exogenous (ARX) inputs models of time series data, which cannot truly reveal nonlinear effects in the data especially in the frequency domain. In this study, it is shown that the classical Geweke's spectral causality measure can be explicitly linked with the output spectra of corresponding restricted and unrestricted time-domain models. The latter representation is then generalized to nonlinear bivariate signals and for the first time nonlinear causality analysis in the frequency domain. This is achieved by using the nonlinear ARX (NARX) modeling of signals, and decomposition of the recently defined output frequency response function which is related to the NARX model.
Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision thr... more Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifyin...
A 73-year-old lady became bed bound with progressive generalized weakness 2 weeks after the intro... more A 73-year-old lady became bed bound with progressive generalized weakness 2 weeks after the introduction of sodium fusidate for osteomyelitis. She was already on simvastatin for years. Electromyography showed no spontaneous muscle activity from any of the muscles sampled. The temporal relationship of symptom onset after introduction of fusidic acid and full recovery after cessation of the 2 drugs suggests a serious interaction that deserves wider recognition.
Cortical myoclonus with ataxia has only rarely been reported in association with Coeliac Disease ... more Cortical myoclonus with ataxia has only rarely been reported in association with Coeliac Disease (CD). Such reports also suggested that it is unresponsive to gluten-free diet. We present detailed electro-clinical characteristics of a new syndrome of progressive cortical hyperexcitability with ataxia and refractory CD. At our gluten/neurology clinic we have assessed and regularly follow up over 600 patients with neurological manifestations due to gluten sensitivity. We have identified 9 patients with this syndrome. All 9 patients (6 male, 3 female) experienced asymmetrical irregular myoclonus involving one or more limbs and sometimes face. This was often stimulus sensitive and became more widespread over time. Three patients had a history of Jacksonian march and five had at least one secondarily generalised seizure. Electrophysiology showed evidence of cortical myoclonus. Three had a phenotype of epilepsia partialis continua at onset. There was clinical, imaging and/or pathological evidence of cerebellar involvement in all cases. All patients adhered to a strict gluten-free diet with elimination of gluten-related antibodies in most. However, there was still evidence of enteropathy in all, suggestive of refractory celiac disease. Two died from enteropathy-associated lymphoma and one from status epilepticus. Five patients were treated with mycophenolate and one in addition with rituximab and IV immunoglobulins. Their ataxia and enteropathy improved but myoclonus remained the most disabling feature of their illness. This syndrome may well be the commonest neurological manifestation of refractory CD. The clinical involvement, apart from ataxia, covers the whole clinical spectrum of cortical myoclonus.
In a retrospective study of 86 patients with myasthenia gravis (MG), we correlated the acetylchol... more In a retrospective study of 86 patients with myasthenia gravis (MG), we correlated the acetylcholine receptor (AChR) antibody titers with single-fiber EMG studies to explore whether a relationship exists between these parameters. We found that the AChR antibody titers correlated significantly with the mean of the mean consecutive difference of orbicularis oculi (OO, P<0.0001) and extensor digitorum communis (EDC, P<0.0001). The correlation was found to be stronger in OO. The antibody titers also correlated with the percentage of potential pairs with increased jitter in both muscles and, again, the correlation was more significant in OO (P<0.0001) than in EDC (P=0.001). We speculate that this relationship is stronger in OO than in the limb muscles, because the architectural and immunological differences in the motor unit render OO more vulnerable and sensitive to disturbances in neuromuscular transmission.
We performed a retrospective study to validate whether a disposable concentric needle electrode (... more We performed a retrospective study to validate whether a disposable concentric needle electrode (CNE) can be used in place of a single-fiber (SF) electrode for jitter measurements in myasthenia gravis (MG). Normal values for voluntary contraction of orbicularis oculi (OO) and extensor digitorum communis (EDC) were collected from 20 healthy subjects. The method was validated by a retrospective analysis of 56 consecutive MG patients, the "gold standard" being a positive acetylcholine receptor (AChR) antibody titer at the time of the electrophysiological (electromyography) study and the clinical diagnosis. Receiver operating characteristic (ROC) curves were constructed to define maximal sensitivity and specificity of the technique. The sensitivity was 96.4% (95% confidence interval 87.5%-99.6%), with no false-positive results, similar to traditional SF EMG and confirming that the disposable CNE is a justifiable alternative.
Spectral measures of linear Granger causality have been widely applied to study the causal connec... more Spectral measures of linear Granger causality have been widely applied to study the causal connectivity between time series data in neuroscience, biology, and economics. Traditional Granger causality measures are based on linear autoregressive with exogenous (ARX) inputs models of time series data, which cannot truly reveal nonlinear effects in the data especially in the frequency domain. In this study, it is shown that the classical Geweke's spectral causality measure can be explicitly linked with the output spectra of corresponding restricted and unrestricted time-domain models. The latter representation is then generalized to nonlinear bivariate signals and for the first time nonlinear causality analysis in the frequency domain. This is achieved by using the nonlinear ARX (NARX) modeling of signals, and decomposition of the recently defined output frequency response function which is related to the NARX model.
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