Electrodiagnostic findings in facial onset sensory motor neuronopathy (FOSMN).

OBJECTIVE: To determine the electrodiagnostic characteristics of facial onset sensory and motor neuronopathy (FOSMN). METHODS: Electrophysiological data from 10 FOSMN patients in Newcastle-upon-Tyne and Sydney were reviewed. Relevant literature was reviewed. RESULTS: Findings on standard electrophysiological assessment were in broad agreement with those published: blink reflexes were abnormal in all but one patient; sensory nerve action potentials were reduced but compound muscle action potentials preserved; mixed acute and chronic neurogenic change was identified on needle electromyography in bulbar and cervico-thoracic muscles in approximately 50% of patients. Upper limb somatosensory evoked potential (SEP) central conduction times were increased (n = 4) and progressed on repeat testing (n = 3). Upper motor neuron dysfunction was revealed by several measures [ipsilateral motor evoked potentials (MEPs) (n = 1); reduced short interval intra-cortical inhibition on threshold-tracking transcranial magnetic stimulation (n = 2); absent beta-band intermuscular coherence (n = 3)]. CONCLUSIONS: Electrodiagnostic investigation of FOSMN should include blink reflex testing, SEPs and tests of upper motor neuron function. The combination of progressive lower motor neuron disease and upper motor neuron disease on neurophysiological investigation provides further support for the contention that FOSMN is a rare variant of motor neurone disease. SIGNIFICANCE: These findings will aid the neurologist and neurophysiologist in making a confident diagnosis of FOSMN, thus expediting appropriate care.

Mills' syndrome revisited.

Mills' syndrome is an idiopathic, slowly progressive, spastic hemiparesis. We describe three cases that have been under review for a minimum of 11 years (range 11-19). In all patients, symptoms started in a leg, with a mean age of onset of 59 years (range 53-63). The only abnormality on laboratory investigations was a mildly elevated CSF protein in one case. MRI demonstrated focal T2 hyper-intensity located eccentrically in the cervical cord ipsilateral to the symptomatic side. No cerebral abnormality was demonstrated. Whilst visual and somatosensory evoked potentials were unremarkable, motor evoked potentials were abnormal in all patients: central motor conduction times were significantly prolonged unilaterally in two patients and bilaterally but asymmetrically in the third. Beta-band (15-30 Hz) intermuscular coherence, a potentially more sensitive method of assessing upper motor neuron integrity, was absent unilaterally in one patient and bilaterally in the other two. One patient developed amyotrophy and thus a picture of amyotrophic lateral sclerosis after 16 years, suggesting that Mills' syndrome is part of the motor neuron disease spectrum. Both amyotrophy and subclinical contralateral upper motor neuron disease can therefore be features of Mills' syndrome. However, even with the most sensitive electrodiagnostic techniques, unilateral upper motor neuron disease can remain the only abnormality for as long as 10 years. We conclude that whilst Mills' syndrome should be classified as a motor neuron disorder, it is a distinct nosological entity which can be distinguished from amyotrophic lateral sclerosis, upper motor neuron-dominant amyotrophic lateral sclerosis and primary lateral sclerosis. We propose diagnostic criteria for Mills' syndrome, and estimate a point prevalence of at least 1.2:1,000,000 based on our well-defined referral population in the North of England.

Intermuscular Coherence in Normal Adults: Variability and Changes with Age.

We investigated beta-band intermuscular coherence (IMC) in 92 healthy adults stratified by decade of age, and analysed variability between and within subjects. In the dominant upper limb, IMC was estimated between extensor digitorum communis and first dorsal interosseous as well as between flexor digitorum superficialis and first dorsal interosseous. In the ipsilateral lower limb, IMC was measured between medial gastrocnemius and extensor digitorum brevis as well as between tibialis anterior and extensor digitorum brevis. Age-related changes in IMC were analysed with age as a continuous variable or binned by decade. Intrasession variance of IMC was examined by dividing sessions into pairs of epochs and comparing coherence estimates between these pairs. Eight volunteers returned for a further session after one year, allowing us to compare intrasession and intersession variance. We found no age-related changes in IMC amplitude across almost six decades of age, allowing us to collate data from all ages into an aggregate normative dataset. Interindividual variability ranged over two orders of magnitude. Intrasession variance was significantly greater than expected from statistical variability alone, and intersession variance was even larger. Potential contributors include fluctuations in task performance, differences in electrode montage and short-term random variation in central coupling. These factors require further exploration and, where possible, minimisation. This study provides evidence that coherence is remarkably robust to senescent changes in the nervous system and provides a large normative dataset for future applications of IMC as a biomarker in disease states.

Facial Onset Sensory and Motor Neuronopathy: Further Evidence for a TDP-43 Proteinopathy.

Three patients with the clinical and investigation features of facial onset sensory and motor neuronopathy (FOSMN) syndrome are presented, one of whom came to a post-mortem examination. This showed TDP-43-positive inclusions in the bulbar and spinal motor neurones as well as in the trigeminal nerve nuclei, consistent with a neurodegenerative pathogenesis. These data support the idea that at least some FOSMN cases fall within the spectrum of the TDP-43 proteinopathies, and represent a focal form of this pathology.

A multiple regression model of normal central and peripheral motor conduction times.

INTRODUCTION: The effects of age, height, and gender on magnetic central and peripheral motor conduction times (CMCT, PMCT) were analyzed using a multiple regression model. METHODS: Motor evoked potentials were recorded in 91 healthy volunteers. Magnetic stimulation was performed over the primary motor cortex (cortical latency) and over the cervical and lumbar spines (spinal latency). The spinal latency was taken as an estimate of PMCT and was subtracted from cortical latency to yield CMCT. RESULTS: Lower limb CMCT correlated significantly with height only; there were no significant predictors for upper limb CMCT. Upper and lower limb PMCT correlated with both age and height. CONCLUSIONS: This is among the largest studies of CMCT in normal subjects. The multiple regression model unifies previously reported simple regression analyses, reconciles past discrepancies, and allows normal ranges to be individualized.

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.

Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis.

Western driving regulations for unprovoked first seizures and epilepsy.

PURPOSE: To review the legislation for non-commercial driving licenses in the Western world for unprovoked first seizures (UFS) and recurrence of established epilepsy, and to examine available evidence on the road traffic accident (RTA) risk in people with seizures. METHODS: Regulations for non-commercial driving licenses were sought from appropriate national or state authorities and epilepsy societies. The literature was searched for consensus guidelines and data relevant to risk analysis, including an appropriate seizure-free period (SFP). RESULTS: The SFP varied widely from 3 to 24 months and in most countries no distinction was made between UFS and recurrence of established epilepsy. In the European Union (EU), harmonisation is underway but implementation of the relevant directive has been slow. The excess risk of RTA in epilepsy is minimal, especially compared to other factors such as alcohol, and few accidents result from seizures at the wheel. Risk analysis supports the shortened SFPs that are being enacted in the EU. CONCLUSION: Regulations across the world continue to vary widely, and the available data support rules which are less stringent than those currently in force in many parts of the Western world. The ongoing European harmonisation is encouraging but much work remains to be done in revising legislation elsewhere, and in strengthening the theoretical foundations underpinning driving regulations.

Copper deficiency myelopathy.

Acquired copper deficiency has been recognised as a rare cause of anaemia and neutropenia for over half a century. Copper deficiency myelopathy (CDM) was only described within the last decade, and represents a treatable cause of non-compressive myelopathy which closely mimics subacute combined degeneration due to vitamin B12 deficiency. Here, 55 case reports from the literature are reviewed regarding their demographics, aetiology, haematological and biochemical parameters, spinal imaging, treatment and outcome. The pathophysiology of disorders of copper metabolism is discussed. CDM most frequently presented in the fifth and sixth decades and was more common in women (F:M = 3.6:1). Risk factors included previous upper gastrointestinal surgery, zinc overload and malabsorption syndromes, all of which impair copper absorption in the upper gastrointestinal tract. No aetiology was established in 20% of cases. High zinc levels were detected in some cases not considered to have primary zinc overload, and in this situation the contribution of zinc to the copper deficiency state remained unclear. Cytopenias were found in 78%, particularly anaemia, and a myelodysplastic syndrome may have been falsely diagnosed in the past. Spinal MRI was abnormal in 47% and usually showed high T2 signal in the posterior cervical and thoracic cord. In a clinically compatible case, CDM may be suggested by the presence of one or more risk factors and/or cytopenias. Low serum copper and caeruloplasmin levels confirmed the diagnosis and, in contrast to Wilson's disease, urinary copper levels were typically low. Treatment comprised copper supplementation and modification of any risk factors, and led to haematological normalisation and neurological improvement or stabilisation. Since any neurological recovery was partial and case numbers of CDM will continue to rise with the growing use of bariatric gastrointestinal surgery, clinical vigilance will remain the key to minimising neurological sequelae. Recommendations for treatment and prevention are made.

Copper deficiency myelopathy and subacute combined degeneration of the cord - why is the phenotype so similar?

Copper deficiency myelopathy (CDM) is an increasingly recognised mimic of subacute combined degeneration (SCD) of the cord due to cobalamin (vitamin B(12)) deficiency. It has been suggested that copper deficiency induces myelopathy through dysfunction of cytochrome oxidase, which is known to be copper-dependent. However, cytochrome oxidase is not cobalamin-dependent, so this hypothesis fails to explain the phenotypic similarity between CDM and SCD. We propose that the first step in a final common pathway of CDM and SCD is dysfunction of the methylation cycle. This cycle includes both copper and cobalamin-dependent enzymes and catalyses the net transfer of a methyl group from methyltetrahydrofolate to a variety of macromolecules, including myelin proteins. Dysfunction of the cycle might therefore cause failure of myelin maintenance and ultimately myelopathy. One step of the methylation cycle is catalysed by methionine synthase, which is known to be cobalamin-dependent. Nitrous oxide specifically inhibits this enzyme by inactivating methylcobalamin, causing SCD in animals and humans. Both animal and human data suggest that methionine synthase also requires copper, implying that the enzyme may be involved in the pathogenesis of CDM. Another enzyme involved in the methylation cycle, S-adenosylhomocysteine hydrolase, may be regulated by copper. Although this enzyme is not cobalamin-dependent, its potential impairment in copper deficiency may contribute to the overall dysfunction of the methylation cycle. In cases of congenital deficiencies of methylation cycle enzymes, spinal and cerebral demyelination was observed, providing further support for a critical role of the methylation cycle in myelination. Biochemical dysfunction of the methylation cycle has been reported in HIV myelopathy, which has pathological parallels with SCD. This raises the possibility that other demyelinating myelopathies might involve an impairment of the methylation cycle. Our hypothesis could be tested by measuring CSF concentrations of methylation cycle intermediates in cases of CDM, as these reflect spinal cord tissue levels. If it were confirmed, the hypothesis would not only provide a plausible explanation for the phenotypic similarity between CDM and SCD, but might also open up further therapeutic options such as methionine and betaine supplementation.