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Background Motor neurone disease (MND) is a rapidly progressing and rare neurodegenerative disorder characterized by progressive weakness, muscle wasting, and death from respiratory failure within 36 months of symptom onset. To date, clinical trials in MND have failed to identify therapeutic interventions that halt disease progression, possibly because the majority of patients are recruited to trials too late in the disease course. To recruit patients earlier, diagnostic criteria for MND now include evidence of subclinical disease in unaffected muscles, as assessed by needle electromyography (EMG). Whilst other electrodiagnostic tests of subclinical disease could be incorporated into these criteria alongside needle EMG, it is unclear whether this would provide additional diagnostic accuracy/certainty. Here we use beta-band intermuscular (EMG-EMG) coherence (BIMC) as an example of how this issue can be addressed with statistical confidence in future studies. Methods Using the BIMC test as a case study, we provide a statistical framework for the incorporation of expert knowledge into the choice of sample size using expert elicitation and Bayesian assurance calculations. Probability distributions were elicited from seven clinical experts and aggregated to form group consensus distributions. Results The Bayesian assurance calculations led to a smaller required sample size than traditional statistical power calculations. The quantification and incorporation of clinical expert knowledge and uncertainty in sample size calculations can provide better calibrated predictions of study outcomes and ensure the most appropriate sample size is chosen. Clinical experts reported the sensitivity of the Awaji criteria in line with previous studies, providing evidence of the validity of the results. We note that multiple experts understated estimates of specificity compared to the literature, though this may be due to the format of the questions or the design of the case study. Conclusions Bayesian assurance can be used alongside expert elicitation to design diagnostic accuracy studies. While we focus on the BIMC test case study, the methods presented are relevant and can be applied to other emerging tests relevant to MND.

To determine the electrodiagnostic characteristics of facial onset sensory and motor neuronopathy (FOSMN).Electrophysiological data from 10 FOSMN patients in Newcastle-upon-Tyne and Sydney were reviewed. Relevant literature was reviewed.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)].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.These findings will aid the neurologist and neurophysiologist in making a confident diagnosis of FOSMN, thus expediting appropriate care.

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.

The clinical scenario of a woman aged 30–50 years presenting with progressive lower limb spasticity, asymmetric changes on visual evoked potentials (VEPs), somatosensory evoked potentials (SEPs), and motor evoked potentials (MEPs) consistent with central demyelination would commonly indicate primary progressive multiple sclerosis (PPMS).

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.

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.

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.

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.

A 39-year-old lawyer presented with intermittent spasms and pain in his abdominal muscles, particularly the right upper quadrant. These had occurred since his mid-20s and there had been long asymptomatic periods, including 8 years prior to the most recent 4-month exacerbation. Trivial movement triggered a spasm of the abdominal muscles, leading to severe pain, which made breathing uncomfortable and interfered with sleep. The symptoms subsided spontaneously after 4 to 5 days, leaving him with a sore abdomen for several weeks. Past attacks had also been precipitated by specific forms of repetitive exercise such as jogging. He described ill-defined numbness in the left leg, but denied any muscle twitching, weakness, back pain, or sphincter disturbance. There was no significant past medical or family history.

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.

Tranexamic acid (TNA) is a fibrinolytic inhibitor used to control haemorrhage. Impairment of vision, particularly of colour perception, is a rare adverse effect.A 79 year-old man with end-stage renal failure (ESRF) was treated with tranexamic acid for bleeding from duodenal angiodysplasia. Over four days his vision deteriorated bilaterally, and he complained of poor acuity unless in a brightly sunlit environment.On examination, visual acuity was poor within the ward but improved markedly when looking out of the window or shining a bright torchlight on objects. Visual fields, pupillary reflexes, fundoscopy and remaining neurological examination were normal.Full-field electroretinogram (ERG) demonstrated severe photoreceptor dysfunction, especially of rods. TNA was discontinued and vision improved subjectively within days. Serial ERG showed continuing recovery of rod function over several months.Patients with ESRF often have duodenal angiodysplasia, and TNA is commonly used to minimise bleeding. Previously reported effects of TNA on colour vision (chromatopsia) presumably arise through impaired cone function. By contrast, our patient exhibited predominant rod dysfunction, and the clinical manifestation of nyctalopia expands the known spectrum of adverse effects of TNA. Rapid discontinuation of TNA is vital to minimise visual sequelae.

Sirs: In a clinical setting, isolated thunderclap headache is commonly assumed to be benign in origin once subarachnoid haemorrhage (SAH) has been excluded [1]. However, cerebral venous sinus thrombosis (CVST) is an infrequent, alternative cause of sudden-onset headache and is not conclusively excluded by normal conventional CT and LP. CVST is also a recognised rare cause of SAH. Here, we report a case of CVST presenting with thunderclap headache and complicated by delayed SAH. A previously well 53-year-old woman presented with spontaneous, sudden-onset occipital headache as her sole symptom. Neurological examination including fundoscopy was normal, with no evidence of meningism. Acute head CT and subsequent LP performed 16 hours after onset were unremarkable (opening pressure 19 cm, CSF acellular with no bilirubin detectable on spectrophotometry). The headache resolved completely within 24 hours and the patient was discharged with a diagnosis of primary thunderclap headache. The following day, she represented with sudden-onset headache at rest accompanied by mild neck stiffness. Her symptoms resolved before a further suddenonset headache occurred two days later. Examination remained normal throughout. Repeat, unenhanced head CT demonstrated a small, high left frontal SAH along the cranial convexity without involvement of the basal cisterns (Fig. 1a). CT angiography detected no arterial aneurysm, but its venous phase showed changes suggestive of superior sagittal sinus thrombosis, which was confirmed on MR venography (Fig. 1b). Screening for secondary causes of thrombosis was negative. She was initially treated with intravenous unfractionated heparin to allow rapid reversal in case of rebleeding, before being warfarinised under cover from low molecular weight heparin. She remained well at follow-up six months later. Repeat MR angiography showed resolution of the superior sagittal sinus thrombosis, with no other vascular or brain parenchymal abnormalities. Thunderclap headache is an unusual presentation of CVST, perhaps seen in fewer than 20 % of cases [2]. Rarely, there may be no concomitant findings to suggest the presence of a CVST, such as focal neurological signs, seizures or features of raised intracranial pressure. Most patients with CVST have a raised opening pressure and abnormal CSF constituents, but absence of these features does not conclusively rule out the diagnosis. In a previous series of 38 cases, nine patients had both opening pressure and CSF constituents measured, and in one of them all parameters were normal [3]. SAH is a very rare complication of cerebral venous thrombosis, with only 30 cases reported to date. It has been suggested that venous intraparenchymal haemorrhages may rupture into the subarachnoid space, thus causing sudden-onset headache in CVST [2, 4]. However, we hypothesise that our patient’s first headache was caused by the CVST, as there was no evidence of SAH on initial brain CT and bilirubin was not detectable in the CSF. The second or third episode of headache may have been caused by SAH. LETTER TO THE EDITORS

Introduction Facial onset sensory motor neuronopathy (FOSMN) is a rare, slowly progressive bulbar onset motor and sensory neuronopathy. Described only in 2006, it is still under–recognised with fewer than 20 cases reported in world literature. Although there are marked similarities to classical bulbar onset MND, FOSMN is set apart clinically by the striking facial–onset sensory deficits with subsequent development of motor deficits, slow evolution in a rostral–caudal direction and a much better prognosis. Methods We present three cases from three different regions of the UK. Case 2 was presented at ABN 2011. A 62–year–old man presented with a three–year history of perioral paraesthesia, numbness and slurred speech, followed by upper limb weakness, fasciculations and muscle cramps. He was dysarthric, anosmic and anegusic. Sensation to pin prick and fine touch was decreased in all divisions of the trigeminal nerve bilaterally with absent corneal reflexes bilaterally. The tongue was atrophic; fasciculations were noted in the tongue and the upper limbs. Electrophysiological studies revealed widespread neurogenic changes without evidence of polyneuropathy. Extensive investigations for alternative aetiologies were unyielding. A 38–year–old woman presented with bilateral facial sensory loss. Over the following ten years she developed weakness and sensory loss in her arms and legs. Fasciculations and flaccid weakness were noted throughout her upper limbs, and there was finger drop of her fourth and fifth digits. Sensation to pinprick was reduced in her face, upper trunk and arms with some involvement distally in the legs. Proprioception and vibration sensation was normal. Horizontal saccades were slow. Electrophysiological studies revealed widespread denervation. No alternate aetiology was found on extensive testing. There was no response to repeated courses of intravenous immunoglobulin over 12 months. A 69–year–old man presented with a four–month history of numbness affecting his left cheek gradually progressing to involve his right cheek, jaw, forehead and tongue. Speech was dysarthric with reduced sensation to pinprick and soft touch in all divisions of the trigeminal nerve as well as the tongue. Over the next five years he developed wasting and fasciculations of his tongue with widespread wasting and brisk reflexes of the upper limb muscles. No alternate aetiology was detected after extensive tests. Treatment with steroids and subsequently with intravenous immunoglobulin was of no benefit. Conclusions These three cases are similar to previously published reports and support the hypothesis that FOSMN is a sporadic, degenerative disorder distinct from typical MND. 1 TDP–43 mutations were reported by some but are not universally present. Early, accurate diagnosis is essential to allow appropriate counselling regarding the prognosis, which is much better than for bulbar onset MND with survival often exceeding ten years.

Motor neuron disease (MND) involves the degeneration of variable proportions of upper and lower motor neurons (UMNs, LMNs). Electrophysiological tests for LMN degeneration are well established but an analogous biomarker of UMN damage is lacking. We are investigating 15–30 Hz intermuscular coherence (IMC) as a candidate; such coherence is prominent in normal humans and macaques during certain motor tasks. Selective corticospinal tract (CST) ablation in macaques caused loss of significant 15–30 Hz IMC on the side of the lesion, which persisted despite functional recovery. In patients with primary lateral sclerosis (PLS) no significant 15–30 Hz IMC was detected; by contrast, patients with progressive muscular atrophy (PMA) retained significant 15–30 Hz IMC. Similarly, in MND-mimicking conditions 15–30 Hz IMC was typically only diminished where the condition involved UMN damage. In hereditary spastic paraparesis, lower limb 15–30 Hz IMC was diminished but remained statistically significant in 50% of cases. Patients with neuropathies or myopathies typically retained significant 15–30 Hz IMC unless afferent pathways were involved, reflecting the role of afferent systems in generating 15–30 Hz IMC. Two prospectively assessed MND patients (ALS phenotype) showed significantly decreased 15–30 Hz IMC at least 8 months before a definitive diagnosis. Hence, 15–30 Hz IMC is a potential biomarker of UMN dysfunction in MND.