PURPOSE:To describe clinical and electrographic characteristics of seizures LGI1-antibody encephalitis, and their correlations with two-year outcomes. METHODS:Video-electroencephalography recordings were performed on a cohort of 16 consecutive patients with LGI1-antibodies from two UK neuroscience-centers over five-years. RESULTS:From 14 of 16 patients (13 males; age-range 53-92years), 86 faciobrachial dystonic seizures were recorded at a median frequency of 0.4 per hour (range 0.1-9.8), and ictal EEG changes accompanied 5/86 events. In addition, 11/16 patients showed 53 other seizures - subclinical (n=18), motor (n=16), or sensory (n=19) - at a median of 0.1 per hour (range 0.1-2) associated with temporal and frontal discharges. The sensory events were most commonly thermal sensations or body-shuddering, and the motor events were frequently automatisms or vocalisations. Furthermore, multifocal interictal epileptiform discharges, from temporal, frontal and parietal regions, and interictal slow-wave activity were observed in 25% and 69% of patients, respectively. Higher observed seizure frequency correlated with poorer functional recovery at two-years (p=0.001). CONCLUSIONS:Multiple frequent seizure semiologies, in addition to numerous subclinical seizures and interictal epileptiform discharges, are hallmarks of LGI1-antibody encephalitis. High overall seizure frequency may predict more limited long-term recovery. These observations should encourage closer monitoring and proactive treatment of seizure activity in these patients.

BACKGROUND:Congenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission. METHODS:Review of case notes of patients with mutations in GMPPB to identify the associated clinical, neurophysiological, pathological and laboratory features. In addition, serum creatine kinase (CK) levels within the Oxford CMS cohort were retrospectively analysed to assess its usefulness in the differential diagnosis of this new entity. RESULTS:All patients had prominent limb-girdle weakness with minimal or absent craniobulbar manifestations. Presentation was delayed beyond infancy with proximal muscle weakness and most patients recall poor performance in sports during childhood. Neurophysiology showed abnormal neuromuscular transmission only in the affected muscles and myopathic changes. Muscle biopsy showed dystrophic features and reduced α-dystroglycan glycosylation. In addition, myopathic changes were present on muscle MRI. CK was significantly increased in serum compared to other CMS subtypes. Patients were responsive to pyridostigimine alone or combined with 3,4-diaminopyridine and/or salbutamol. CONCLUSIONS:Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised CK levels and variable mild cognitive delay. This syndrome underlines that CMS can occur in the absence of classic myasthenic manifestations such as ptosis and ophthalmoplegia or facial weakness, and links myasthenic disorders with dystroglycanopathies. This report should facilitate the recognition of this disorder, which is likely to be underdiagnosed and can benefit from symptomatic treatment.

This chapter on primary muscle diseases explains how analysis of compound muscle action potential (CMAP) amplitude, abnormal spontaneous activity on needle electromyography (EMG), and motor unit action potentials (MUAP) characteristics may be used to give an indication of pathophysiological processes, and goes on to describe the combination and distribution of abnormalities that may be expected in the more commonly encountered myopathies. The conditions considered in detail are inflammatory myopathy (including myositis), critical illness myopathy, disorders with myotonia, inherited myopathy (including muscular dystrophy), and endocrine, metabolic and toxic disorders. Each of these has a characteristic combination of CMAP, spontaneous EMG, and MUAP findings, but the systematic approach to clinical neurophysiology as a way of understanding muscle pathophysiology can be used to investigate the myriad of rare myopathies that may be encountered in clinical practice.

EEG is most often used in the management of patients with diffuse cortical disorders or epilepsy. In encephalopathy, EEG may show localized or diffuse slow waves or electrical discharges with a complex appearance that can be used in diagnosis, monitoring progress and prognosis. Spike and slow wave electrical discharges are characteristic of epilepsy. They too may be diffuse, as in primary generalized epilepsy, or focal as in temporal or frontal lobe epilepsy. Standard, short EEG recordings are specific though relatively insensitive, but are often sufficient to diagnose and classify epilepsy. Prolonged recordings by ambulatory or video telemetry apparatus can be used when more detail is needed; for example, when planning surgical treatment of epilepsy. Visual, somatosensory and auditory evoked potentials are recordings of averaged EEG signals after a sensory stimulus. Delay in the visual evoked potential is the most sensitive of these tests in the diagnosis of multiple sclerosis. Electrophysiological testing of peripheral neuromuscular disorders usually requires a combination of electrical nerve stimulation/recording (nerve conduction studies) and needle electromyography recordings from muscle. Distinct conduction changes can define demyelinating peripheral neuropathies that are often amenable to treatment. Conduction studies are widely used in the diagnosis and management of entrapment neuropathies, of which carpal tunnel syndrome and ulnar neuropathy at the elbow are common disorders. Quantitative techniques are available for the diagnosis of myasthenic disorders, and standard electromyography is used in the management of primary myopathy and motor neuron disease.

Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

Dear Sirs, A 69-year-old male presented with a 16-year history of numbness and paraesthesia of both feet and symptomatic postural hypotension. He reported episodes of painless thermal injuries to his limbs and lower urinary tract symptoms including reduced urinary flow, frequency, nocturnal incontinence and recurrent urinary tract infections. There was a long history of diarrhoea which preceded his sensory symptoms by 10 years and resulted in 20 kg of weight loss, and increasing memory difficulties with greatest difficulty in recalling recent events. His mother had suffered from symptomatic postural hypotension and foot ulceration developing in her sixth decade; she died in her seventh decade. It is not known whether she suffered from chronic diarrhoea or cognitive impairment. He has two brothers whom are unaffected. Blood pressure was 156/92 lying and 79/53 standing. On neurological examination, cranial nerves were normal and there was mild wasting of the intrinsic foot muscles more marked on the right than the left. Tone and motor strength was normal. On sensory examination, pinprick was reduced to the mid-calf bilaterally, vibration sense was reduced to the knees, light touch to the ankles and joint position sense was reduced at the hallux. His ankle jerk reflexes were absent. His gait was hesitant. He was unable to perform tandem gait and Romberg’s sign was positive. Neurophysiological studies are summarised in Table 1 and showed a length-dependant predominantly axonal motor and sensory peripheral neuropathy with subtle demyelinating features. Cognitive testing revealed impairment with major deficits, most prominently in memory and executive function. Table 2 summarises all remaining investigations. Of note is the absence of any evidence of systemic amyloid. Table 1 Summary of neurophysiological studies Table 2 Summary of relevant investigations Genetic testing revealed a recently described Y163X truncation mutation of the gene encoding prion protein (PRNP) [1]. Prion protein is tethered to the cell membrane via a glycosylphosphatidylinositol anchor and the Y163X mutation results in a premature stop codon such that the truncated prion protein is no longer membrane anchored. The PRNP Y163X mutation, follows an autosomal dominant inheritance pattern, presents with adult onset chronic diarrhoea, followed by symptoms of a mixed, predominantly sensory and autonomic neuropathy and late onset cognitive decline and seizures. Pathologically prion protein is deposited throughout peripheral organs primarily the bowel and peripheral nerves, either in between nerve fibres [1] or as ragged deposits in the myelin [2] with significant fibre loss and no evidence of demyelination, and the cortex in the form of amyloid plaques, amyloid angiopathy, tauopathy and unique prion protein fragments. Pan-autonomic failure and peripheral neuropathy is probably due to abnormal prion deposition within the peripheral nervous system. Direct toxic effects of prion protein, deposited in bowel and urinary bladder, may contribute to severe diarrhoea and urinary symptoms. We have not studied adjacent markers on chromosome 20 to define whether there is a common ancestor with the larger pedigree [1]. A 2-bp deletion in codon 178 of PRNP has been described in Japanese kindred causing a familial sensory and autonomic neuropathy with associated cognitive impairment [2]. A different insertional mutation of PRNP resulting in a truncation at position 163 has also been associated with hereditary sensory and autonomic neuropathy [3]. The clinical presentation of prion protein systemic amyloidosis caused by the PRNP Y163X mutation is distinct from previously described forms of hereditary sensory autonomic neuropathy [4] with prominent and early bladder and bowel symptoms, late onset sensory/autonomic neuropathy followed by cognitive involvement. The duration of symptoms and early onset of bowel dysfunction would also be atypical for amyloid neuropathy. Interesting features of this case include some subtle demyelinating features noted on nerve conduction. Occasional cases of amyloid polyneuropathy have also been reported to show demyelinating changes [5]. Mild conduction slowing could represent direct toxicity of the prion protein on Schwann cells or even prion protein haplo-insufficiency as axonal prion protein has been shown to be required for myelin maintenance in mouse models [6]. This case demonstrates the importance of PRNP analysis, which should be considered in the investigation of unexplained diarrhoea with a sensory neuropathy and is an important differential of familial amyloid polyneuropathy.

Isolated paediatric neurosarcoidosis (IPN) is exceptionally rare and only seven cases have been reported so far in the literature. We report the clinical and radiological profile of a 7 year-old boy with epilepsia partialis continua (EPC) who was initially thought to have Acute Disseminated Encephalomyelitis (ADEM), but was subsequently found to have isolated neurosarcoidosis. Additionally, we performed a literature search on Medline and Embase and secondary sources of data such as reference list of articles reviewed. Whilst cranial neuropathy is the commonest presenting feature in adults with neurosarcoidosis, paediatric patients are more likely to present with seizures. Diagnosis presents a clinical challenge as a result of its protean manifestations. Due to its rarity, there remains a lack of evidence base to inform the best choice of treatment for these children. Our patient was successfully treated with a combination of various immunomodulants.

Electroencephalography (EEG) has been in continuous development over at least 70 years and is firmly established as a tool in the management of epilepsy. For a while, the technique fell into disregard because of difficulties with interpretation, specificity and sensitivity. Whilst clinicians have to be aware of these problems, they have been largely addressed by recent computer digitization of signals, which permits longer standard recordings and monitoring linked to a simultaneous video. These techniques are not only an essential component of a specialist epilepsy service, where inpatient video-EEG telemetry is vital both for diagnosis and assessment before neurosurgical treatment, but also in general and acute medical settings, particularly for the management of status epilepticus. Further developments in computing will extend the use of EEG in all of these roles and long-term monitoring for diagnosis and management of coma will become more widely available.

BACKGROUND:Clustered acetylcholine receptor antibodies (clustered AChR-Abs) have been detected in a proportion of patients with previously "seronegative" (SN) generalized myasthenia gravis (GMG), but their presence in patients with ocular MG (OMG) and their pathogenicity in vivo are unknown.OBJECTIVE:To test the presence of clustered AChR-Abs and their pathophysiologic properties in patients with SNMG.DESIGN:Screening and diagnostic tests.SETTING:Regional specialist myasthenia center and clinical laboratory.PATIENTS:Serum samples from 16 patients with SN and OMG were tested for binding to clustered AChRs. Results from 28 further SN patients (14 OMG) were correlated with their single fiber electromyography values.MAIN OUTCOME MEASURES:Presence, complement-fixation capacity, correlation with neurophysiologic changes, and in vivo pathogenicity of clustered AChR-Abs.RESULTS:Up to 50% of patients with previous SN-OMG had complement-fixing IgG1 clustered AChR-Abs. IgG binding (n = 28) and complement deposition (n = 21) each correlated with the mean consecutive difference (jitter) on single-fiber electromyography. Injection of purified IgG from 2 patients with clustered AChR-Abs into wild-type or complement regulator-deficient mice reduced miniature end plate potential amplitudes to an extent similar to that found with AChR-Abs, and complement was deposited at the end plates. A trend was noted toward an increase in the number of packets of acetylcholine released (quantal content).CONCLUSIONS:A proportion of patients with SN-GMG or OMG have clustered AChR-Abs that correlate with their electrophysiologic features. Clustered AChR-Abs can passively transfer disease to mice, demonstrating their pathogenicity, and the mechanisms seem similar to those of patients with typical AChR-Abs.

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.

Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions ('synaptopathy') but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124.1127dupTGCC was common, present in 20 out of 24 kinships. All patients were found to have at least one allele with a frameshift mutation in DOK7 exon 7, suggesting that loss of function(s) associated with the C-terminal region of Dok-7 underlies this disorder. In 15 patients, we were able to study the clinical features in detail. Clinical onset was usually characterized by difficulty in walking developing after normal motor milestones. Proximal muscles were usually more affected than distal, leading to a 'limb-girdle' pattern of weakness; although ptosis was often present from an early age, eye movements were rarely involved. Patients did not show long-term benefit from anticholinesterase medication and sometimes worsened, and where tried responded to ephedrine. The phenotype can be distinguished from 'limb-girdle' myasthenia associated with tubular aggregates, where DOK7 mutations were not detected and patients respond to anticholinesterase treatments. CMS due to DOK7 mutations are common within our UK cohort and is likely to be under-diagnosed; recognition of the phenotype will help clinical diagnosis, targeted genetic screening and appropriate management.

Objective: Our aim was to study the path ophysiological process leading to facial muscle atrophy in 13 patients with MUSK antibody positive myasthenia gravis (MUSK-MG), and to compare with findings from 12 acetylcholine receptor antibody positive myasthenia patients (AChR-MG), selected because they suffered from the same degree of disease severity and required similar treatment.Methods: Motor unit action potential (MUAP) and interference pattern analysis from orbicularis oculi (O oculi) and orbicularis oris (O oris) muscles were studied using a concentric needle electrode, and compared with findings in 20 normal subjects, 6 patients receiving botulinum toxin injections (representing a neurogenic model) and 6 patients with a muscle dystrophy (representing a myopathic model). The techniques and control data have been reported previously.Results: The mean MUAP durations for O oculi and O oris were significantly reduced (p < 0.001) in both MG cohorts when compared with healthy subjects, and were similar to those in the myopathic control group. They were significantly different from those obtained from the neurogenic control group (p < 0.001 for both O oculi and O oris). The MUAP findings in O oculi occurred independently from neuromuscular blocking on single fibre EMG (SFEMG) in the same muscle. On turns amplitude analysis (IAA), 50% of MUSK-MG patients and 42% of AChR-MG patients had a pattern in O oculi which was similar to that in the myopathic control group, and 62% of MUSK-MG patients and 50% of AChR-MG patients had a pattern in O oris that was also similar to that in the myopathic control group. The TAA findings for O oculi and O oris in both MG cohorts were different from those obtained from the neurogenic control group.Conclusions: Facial muscle atrophy in MUSK-MG patients is not neurogenic and the pathophysiological changes are akin to a myopathic process. The selected AChR-MG patients also show evidence of a similar pathophysiological process in the facial muscles albeit to a lesser degree.Significance: We propose that muscle atrophy in MUSK-MG is a myopathic process consisting of either muscle fibre shrinkage or loss of muscle fibres from motor units. The duration of disease and long-term steroid treatment may be further contributory factors. (c) 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Glycoside hydrolases are clustered into families based on amino acid sequence similarities, and belonging to a particular family can infer biological activity of an enzyme. Family GH115 contains α-glucuronidases where several members have been shown to hydrolyze terminal α-1,2-linked glucuronic acid and 4-O-methylated glucuronic acid from the plant cell wall polysaccharide glucuronoxylan. Other GH115 enzymes show no activity on glucuronoxylan, and therefore, it has been proposed that family GH115 may be a poly-specific family. In this study, we reveal that a putative periplasmic GH115 from the human gut symbiont Bacteroides thetaiotaomicron, BtGH115A, hydrolyzes terminal 4-O-methyl-glucuronic acid residues from decorated arabinogalactan isolated from acacia tree. The three-dimensional structure of BtGH115A reveals that BtGH115A has the same domain architecture as the other structurally characterized member of this family, BoAgu115A; however the position of the C-terminal module is altered with respect to each individual enzyme. Phylogenetic analysis of GH115 amino sequences divides the family into distinct clades that may distinguish different substrate specificities. Finally, we show that BtGH115A α-glucuronidase activity is necessary for the sequential digestion of branched galactans from acacia gum by a galactan-β-1,3-galactosidase from family GH43; however, while B. thetaiotaomicron grows on larch wood arabinogalactan, the bacterium is not able to metabolize acacia gum arabinogalactan, suggesting that BtGH115A is involved in degradation of arabinogalactan fragments liberated by other microbial species in the gastrointestinal tract.

A proportion of patients with myasthenia gravis (MG) without acetylcholine receptor (AChR) antibodies have antibodies to muscle-specific kinase (MuSK). MG with MuSK antibodies (MuSK-MG) is often associated with persistent bulbar involvement, including marked facial weakness and tongue muscle wasting. The extent of muscle wasting in MuSK-MG, and whether it is also found in the few acetylcholine receptor (AChR-MG) patients who have persistent bulbar involvement, is not clear. We studied 12 MuSK-MG patients and recruited 14 AChR-MG patients matched broadly for age, sex ratio, duration of disease and degree of ocular, bulbar and facial weakness. We used coronal and sagittal T1-weighted (T1W) and T2-weighted (T2W) magnetic resonance imaging (MRI) to assess muscle wasting in facial and tongue muscles. Hyperintense signal on T1W MRI and comparison of axial T1W sequences with cUTE sequences were used to assess fibrous/fatty tissue in the tongue. We compared the results with those of four patients with myotonic dystrophy and 12 healthy individuals. We correlated the changes with clinical and treatment histories, and established a new ocular-bulbar-facial-respiratory (OBFR) score. At the time of study, none of the clinical measures, including the OBFR score, differed between the two MG groups. MRI demonstrated thinning of the buccinator, orbicularis oris (O.oris) and orbicularis oculi (O.oculi) muscles in MuSK-MG patients compared with healthy controls, whereas thinning of these muscles was not significant in AChR-MG. Tongue areas with T1W high signal were increased in MuSK-MG patients and the intensity of the signal on axial T1W sequences was greater in MuSK-MG than in controls. To look for possible correlations between imaging and clinical findings, we pooled results from all MG patients. The duration of treatment with prednisolone at >40 mg on alternate days (AD) correlated positively with the percentage of tongue area with high signal (P = 0.006) and negatively with MRI measurements of individual muscles and with the mean muscle dimensions (P = 0.001). The new OBFR score correlated positively with current Myasthenia Gravis Foundation of America grades and with the percentage of high signal (P = 0.004) and negatively with the mean muscle dimensions (P < 0.001). The results show that bulbar and facial muscle weakness and wasting are associated with significant muscle atrophy and fatty replacement in MuSK-MG, which was not found in the AChR-MG patients. MuSK antibodies per se may predispose to muscle thinning, but the difficulties in obtaining clinical remission under steroid therapy in some patients, resulting in long duration of treatment with higher doses (>40 mg AD), may be an additional factor.

T2 weighted brain MRI revealed bilateral symmetric high signal intensities in the SCC, the globus pallidus, the periaqueductal grey matter of the midbrain, the pontine tegmentum, the dentate nucleus, and the medulla oblongata (fig 1D -H).These lesions were hypointense on T1 weighted images (fig 1I).The shape of the SCC lesions was similar to that of case 1.