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Our aim was to identify clinical outcomes, serological features and possible prognostic indicators of paediatric myasthenia gravis (MG). We collected 74 MG patients with disease onset before the age of 16 years (73% pre-pubertal onset defined as ≤10 years), seen regularly at two UK specialist centres, over a period of 11 years. The cohort was multi-ethnic, with a high number of non-Caucasians (52%). Ocular presentation was seen in 38 (51%) and only 8 (21%) of these generalised. Fifty-two (70%) patients had antibodies to the acetylcholine receptor (AChR) measured by radioimmunoprecipitation, 10 (14%) had antibodies only to clustered AChRs detected by a cell based assay, 3 (4%) had muscle-specific kinase and one (1%) low-density lipoprotein receptor-related protein 4 antibody. Only 8 (11%) had no detectable antibodies. Seventeen patients attained drug free remission (Kaplan Meyer survival curve estimates 25% by 7 years). Several factors were associated with a higher likelihood of free remission: onset age ≤10 years, Asian and Caucasian races, lack of AChR antibodies on RIA, and normal repetitive nerve stimulation at diagnosis. However, in a multifactorial regression analysis, the antibody status was the only significant predictor for drug free remission, with 60% of patients with antibodies only to clustered AChR achieving this outcome. Complete drug free remission is not uncommon in paediatric MG and several factors appear to influence this outcome with antibody status being the most important. These factors can be easily evaluated at diagnosis, and may help to determine whose patients are likely to require more intensive treatments.

Longitudinal studies among people with Multiple Sclerosis (pwMS) have shown that self-efficacy is linked to physical, cognitive and psychological functioning.To determine the distribution of self-efficacy in a large sample of pwMS, examining whether there are distinct groups which show different self-efficacy trajectories over time, and the health status characteristics of any groups identified.Participants completed serial questionnaire packs, including Unidimensional Self-efficacy-MS (USE-MS) scale, for the Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study over an average 46-month period. The resulting longitudinal data were analysed by a group-based trajectory model.5887 pwMS were studied: mean age 50.2 years (SD 12.0); 73.6% female; Relapsing Remitting MS (61.8%), Secondary Progressive (22.9%), Primary Progressive (11.1%), Rapidly Evolving Relapsing Remitting MS (4.2%). Four distinct self-efficacy trajectories emerged, with declining, slightly declining, stable or improving self-efficacy, each showing different patterns of health status indicators such as EQ-5D-5L, disability and depression. USE-MS ≤ 18 at baseline detected all participants in the two declining groups.Future trials on interventions for self-efficacy should assume a priori that those with low levels of self-efficacy (USE-MS ≤ 18 at baseline) are likely to be on a declining trajectory and may need different interventions from those with stable self-efficacy.

Early evaluation of treatment response and prediction of disease evolution are key issues in the management of people with multiple sclerosis (MS). In the past 20 years, MRI has become the most useful paraclinical tool in both situations and is used clinically to assess the inflammatory component of the disease, particularly the presence and evolution of focal lesions — the pathological hallmark of MS. However, diffuse neurodegenerative processes that are at least partly independent of inflammatory mechanisms can develop early in people with MS and are closely related to disability. The effects of these neurodegenerative processes at a macroscopic level can be quantified by estimation of brain and spinal cord atrophy with MRI. MRI measurements of atrophy in MS have also been proposed as a complementary approach to lesion assessment to facilitate the prediction of clinical outcomes and to assess treatment responses. In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group critically review the application of brain and spinal cord atrophy in clinical practice in the management of MS, considering the role of atrophy measures in prognosis and treatment monitoring and the barriers to clinical use of these measures. On the basis of this review, the group makes consensus statements and recommendations for future research., In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group reviews the application of brain and spinal cord atrophy in clinical practice in the management of MS and makes consensus statements and recommendations for future research.

Background Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord that affects adults and children and that causes motor, sensory and autonomic dysfunction. There is a prolonged recovery phase, which may continue for many years. Neuromyelitis optica (NMO) is an uncommon relapsing inflammatory central nervous system condition in which TM can be the first presenting symptom. As TM and NMO affect many patients in the prime of their working life, the disorder can impose a significant demand on health resources. There are currently no robust controlled trials in children or adults to inform the optimal treatment of TM. However, treatment with intravenous immunoglobulin (IVIG) is being effectively used in the management of a range of neurological conditions. Although other interventions such as plasma exchange (PLEX) in addition to intravenous (IV) methylprednisolone therapy can be beneficial in TM, PLEX is costly and technically challenging to deliver in the acute setting. IVIG is more readily accessible and less costly. Objective To evaluate whether additional and early treatment with IVIG is of extra benefit in TM compared with standard therapy with IV steroids. Design A multicentre, single-blind, parallel-group randomised controlled trial of IVIG compared with standard therapy for the treatment of TM in adults and children. Participants Patients aged ≥ 1 year diagnosed with either acute first-onset TM or first presentation of NMO. Target recruitment was 170 participants (85 participants per arm). Interventions Participants were randomised 1 : 1 to treatment with IV methylprednisolone only or treatment with IV methylprednisolone plus 2 g/kg of IVIG in divided doses within 5 days of the first commencement of steroid therapy. Main outcome measures Primary outcome measure – American Spinal Injury Association (ASIA) Impairment Scale at 6 months post randomisation, with a good outcome defined by a two-grade change. Secondary and tertiary outcome measures – ASIA motor and sensory scales, Expanded Disability Status Scale, health outcome, quality of life, Client Service Receipt Inventory and International Spinal Cord Injury Pain, Bladder and Bowel Basic Data Sets. Results In total, 26 participants were screened and two were randomised into the study. With the limited sample size, treatment effect could not be determined. However, we identified barriers to accrual that included strict inclusion criteria, the short enrolment window, challenges associated with the use of the ASIA Impairment Scale as an outcome measure and estimation of the incidence of TM. Conclusions The study did not reach the end point and the effect of IVIG in TM/NMO could not be determined. Investigators should be aware of the potential challenges associated with carrying out a rare disease trial with a short enrolment window. The study question is one that still necessitates investigation. Preliminary work to ameliorate the effect of the barriers encountered in this study is vital. Trial registration EudraCT 2014-002335-34, ClinicalTrials.gov NCT02398994 and Current Controlled Trials ISRCTN12127581. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 31. See the NIHR Journals Library website for further project information. Funding was also received from Biotest AG, Germany (supply of IVIG) and the Transverse Myelitis Society (excess research cost to facilitate study initiation).

Neuromyelitis optica is a relapsing inflammatory disorder of the central nervous system that manifests predominantly with attacks of optic neuritis and longitudinally extensive transverse myelitis; attacks are often severe. In contrast to multiple sclerosis, a secondary progressive phase is rare, and disability in neuromyelitis optica spectrum disorders is related to relapses. Thus, prompt and effective treatment of relapses, and early initiation of long-term immunosuppression to prevent subsequent attacks is required in order to prevent morbidity and mortality.

Background:Several studies have demonstrated benefits of rehabilitation in multiple sclerosis (MS). However, the neuroscientific foundations for rehabilitation in MS are poorly established. Objectives:As rehabilitation and motor learning share similar mechanisms of brain plasticity, we test whether the dynamics of skill learning are preserved in MS patients relative to controls. Methods:MS patients and controls learned a repeating sequence of hand movements and were assessed for short-term learning. Long-term learning was tested in another cohort of patients and controls practising the same sequence daily for two weeks. Results:Despite differences in baseline performance, the dynamics and extent of improvements were comparable between MS and control groups for both the short- and long-term learning. Even the most severely damaged patients were capable of performance improvements of similar magnitude to that seen in controls. After one week of training patients performed as well as the controls at baseline. Conclusions:Mechanisms for short- and long-term plasticity may compensate for impaired functional connectivity in MS to mediate behavioural improvements. Future studies are needed to define the neurobiological substrates of this plasticity and the extent to which mechanisms of plasticity in patients may be distinct from those used for motor learning in controls.

Relapse-free survival (odds ratios and 95% CI) Comparison of proportion of treated versus control patients surviving without relapse of multiple sclerosis 2 years after randomisation in trials of new drugs compared with trials of azathioprine *Cited fully in ref 5. †British and Dutch Multiple Sclerosis Azathioprine Trial Group. Several new drug treatments to reduce the relapse rate in multiple sclerosis (MS) have recently emerged. These drugs are expensive, have to be given by injection, their long-term side-effects are not yet known, and definite evidence of a clear effect on progression of disability is lacking. The use of magnetic resonance imaging (MRI) to study disease activity in recent trials may have been important in the licensing of new drugs. The pharmaceutical industry has also strongly promoted relapse-reduction as an important treatment outcome in MS. Azathioprine has also been shown to decrease the relapse rate in MS, but has not been widely prescribed because of a similar lack of clear evidence for an effect on disease progression, and concern about long-term side-effects. Azathioprine has not been assessed in trials which have used MRI activity as a surrogate measure of outcome. We compared the probability of freedom from relapse at the end of 2 years in the recent trials of Copolymer-1, interferon -1a, interferon -1b, and IVIg with that in a previous meta-analysis of azathioprine treatment (figure). Data were obtained from the published reports and by personal communication with the authors. The odds ratios (95% CI) of being relapse-free at 2 years for the newer treatments compared with placebo were 1·37 (0·82–2·34) for Copolymer-1, 1·68 (0·88–3·16) for interferon -1a, 2·38 (1·25–4·25) for interferon -1b, and 2·07 (1·07–4·00) for IVIg. The overall odds ratio for azathioprine versus placebo was 2·04 (1·42–2·93). Azathioprine seems to be as effective as newer treatments in increasing the proportion of patients who remain free of relapse at 2 years even when used in a population that included patients with progressive disease. The cost of generic azathioprine on the basis of a dose of 150 mg daily is about UK£80 yearly, excluding the costs of blood counts and liver-function tests. The cost of the new drugs are about UK£10 000 per year excluding blood tests, although IVIg is slightly cheaper at about UK£3300 per year excluding daycase bed costs each month. The European Database for the Multiple Sclerosis group are planning to compare azathioprine with interferon beta treatment in the early phase of MS (ERAZMUS: Early azathioprine versus interferon beta treatment in multiple sclerosis).

It is clinically important, to distinguish between idiopathic Parkinson's disease (IPD) and multiple system atrophy (MSA) not only because of the implications for prognosis but also because urinary incontinence is often an early troublesome feature of MSA and by making the correct neurological diagnosis inappropriate urological surgery may be avoided. Onuf's nucleus in the sacral cord is the location of the anterior horn cells innervating the sphincters, and it is among central nervous system sites affected by neuronal cell loss in MSA but not in IPD. A systematic analysis of motor units recorded from the sphincter looking for changes of chronic reinnervation has therefore been used to distinguish between these conditions. Sphincter electromyography (EMG) was carried out in 126 patients with suspected MSA with review of their case notes up to 2 years later. Of those in whom a diagnosis of MSA was made, 82% had had an abnormal sphincter EMG.

Secondary progressive (SP) MS follows on from but is distinct in its clinical picture from relapsing remitting (RR) MS. Diagnosis is usually straightforward except during the transitional stage when the two phenotypes merge. It is clear that most patients that start with relapsing remitting MS will develop SP disease, although the underlying pathogenesis that causes this change is subject to much debate. Clinical features such as pattern and site of symptoms, and age of onset, in the relapsing remitting stage versus progressive disease, suggests a difference in the pathophysiology. Laboratory markers may give insight into the disease mechanisms. Measures of urinary and CSF myelin basic protein-like material (MBPLM) indicate demyelination and subsequent oligodendrocyte and axonal loss. Tertiary neutralising antibodies to MBP antibodies could attenuate remission and lead to continuous progression, and neuronal antibodies found in SP disease may contribute to the axonal loss. In addition, differences in nitric oxide and other inflammatory cytokine patterns might either be secondary to or causative of the pathological mechanisms. Greater understanding of progressive MS is a priority considering permanent disability results almost entirely from this stage of the disease.

Neuromyelitis optica (NMO) is a relapsing demyelinating disorder with a predilection for the optic nerves and spinal cord, associated with autoantibodies to aquaporin-4 (AQP4) water channels in most cases. It affects all races and ages, but has a striking female preponderance and is distinct from multiple sclerosis (MS). This is a pragmatic guide to treating NMO and the associated NMO spectrum disorders (NMOSDs); these include limited forms of the syndrome, such as recurrent longitudinally extensive transverse myelitis (LETM), recurrent severe optic neuritis (ON) or atypical presentations associated with serum AQP4 antibodies. Because these disorders are rare, there is no available evidence from randomised controlled trials. In contrast to MS, NMO has a high early morbidity and mortality because of severely disabling relapses and lacks a progressive phase. For example, studies report death in 25–30% of patients, after a mean of 5 years from onset.1 ,2 About half of the patients develop significant walking difficulties (at a mean time from onset of 7 years) and many patients become dependent on wheelchairs (figure 1). Visual impairment is also common, with blindness affecting at least one eye in 60–70%, at a mean time from onset of 5 years.1–3 Although most available studies (observational and retrospective) include patients treated at various times from onset, immunosuppressive treatments clearly dramatically reduce relapses, that is, around a sixfold reduction compared with pretreatment.4–8 Thus, aggressive treatment of relapses and effective prevention of relapses is the prime aim of treatment and is our single most important message. For the purposes of this review, we assume that the diagnosis of NMO or NMOSD is correct, and that similar disorders such as MS (for which the treatment is different) are excluded. The rarity of NMO and the importance of optimising treatment makes specialist input important. In …

Visuomotor control of the arm was assessed in a single case study of a subject with focal lesions in the cerebellum and brainstem. A dissociation between 'on-line' and 'off-line' visuomotor control was revealed: impairments in 'on-line' visuomotor control included inaccuracy of tracking velocity, increase in spatial pointing variability and a delay in simple reaction time; whereas the patient was able to adapt to a gain change in 'off-line' visual feedback during a pointing task, and his adaptation was less affected than that of control subjects by trial-to-trial random fluctuations in 'off-line' visual feedback. We conclude that focal damage in the cerebellar peduncles may be principally responsible for this dissociation.

The congenital myasthenic syndromes (CMS) are rare inherited disorders of neuromuscular transmission characterised by fatigable muscle weakness. Thus far, genetic analysis has identified mutations in eleven different genes but it is clear that additional phenotypic subgroups exist where the underlying genetics has not yet been defined. Although each syndrome results from defective synaptic transmission at the neuromuscular junction, the patients show a variable set of phenotypes. Here, we provide a brief clinical review.

Epilepsy may present as a symptom of many neurological disorders and often an aetiological explanation cannot be identified. There is growing evidence that autoimmune mechanisms might have a role in some patients. This includes numerous reports of the detection of theoretically relevant serum autoantibodies, experimental data showing that antibodies can be epileptogenic, and a response of some epilepsy syndromes to immunomodulation. The evidence for immunological mechanisms in epilepsy can be examined within the following three main areas: the childhood epilepsy syndromes, epilepsy associated with other immunologically mediated diseases, and the more common unselected groups of patients with epilepsy. ### RASMUSSEN'S ENCEPHALITIS Rasmussen's encephalitis is a rare progressive disorder of unilateral brain dysfunction, focal seizures, and inflammatory histopathology. It usually presents in middle childhood with intractable seizures and progressive neurological deficits culminating in hemiparesis. The seizures are often resistant to antiepileptic drugs. Treatment with corticosteroids, intravenous immunoglobulins (IVIg), or plasmapheresis has been reported to be beneficial in some.1 2 However, no blinded placebo controlled trials have been undertaken to confirm the efficacy of such treatments. In many children with Rasmussen's encephalitis control of their epilepsy may only be obtained by hemispherectomy. The serendipitous finding that rabbits immunised with a fusion protein of glutamate receptor (GluR) 3 (but not GluR 1, 2, 5, or 6) developed seizures and histopathological changes that mimicked Rasmussen's encephalitis initiated the Rasmussen's encephalitis autoimmune hypothesis.3 However, mice immunised with GluR3, which developed high concentrations of anti-GluR3 antibodies and brain pathology reminiscent of the disease did not go on to develop epilepsy.4 Antibodies against GluR3 (and GluR2 at low concentrations) have been detected in the serum of some patients with Rasmussen's encephalitis3; however, confirmatory reports from other groups and studies determining the frequency of these antibodies in consecutive series of patients with the disease are notable …

Patients presenting with subacute amnesia are frequently seen in acute neurological practice. Amongst the differential diagnoses, herpes simplex encephalitis, Korsakoff's syndrome and limbic encephalitis should be considered. Limbic encephalitis is typically a paraneoplastic syndrome with a poor prognosis; thus, identifying those patients with potentially reversible symptoms is important. Voltage-gated potassium channel antibodies (VGKC-Ab) have recently been reported in three cases of reversible limbic encephalitis. Here we review the clinical, immunological and neuropsychological features of 10 patients (nine male, one female; age range 44-79 years), eight of whom were identified in two centres over a period of 15 months. The patients presented with 1-52 week histories of memory loss, confusion and seizures. Low plasma sodium concentrations, initially resistant to treatment, were present in eight out of 10. Brain MRI at onset showed signal change in the medial temporal lobes in eight out of 10 cases. Paraneoplastic antibodies were negative, but VGKC-Ab ranged from 450 to 5128 pM (neurological and healthy controls

Background: Azathioprine (AZA) is a common immunosuppressive drug used for relapse prevention in neuromyelitis optica (NMO). Objectives: The objective of this paper is to assess efficacy, tolerability and retention of AZA in a large NMO cohort. Methods: We conducted a retrospective review of medical records of 103 aquaporin-4 antibody-positive NMO and NMO spectrum disorder (NMOSD) patients treated with AZA. Results: This is the largest reported cohort of AQP4-Ab positive patients treated with AZA. Eighty-nine per cent ( n = 92) had reduction in median annualised relapse rates from 1.5 (IQR 0.6–4.0) to 0 (IQR 0–0.27, p < 0.00005) with treatment. Sixty-one per cent ( n = 63) remained relapse free at a median follow-up of 18 months. Neurological function improved or stabilised in 78%. At last follow-up, treatment was discontinued in 46% ( n = 47). Of these, 62% ( n = 29) were because of side effects, 19% ( n = 9) because of death, 15% ( n = 7) because of ongoing disease activity, and 2% ( n = 1) because of pregnancy. Using Kaplan-Meyer curves, we estimate that 73%, 58%, 47% and 33% of patients will remain on AZA for longer than one, three, five and 10 years, respectively, after initiation of treatment. Conclusions: AZA is a modestly effective treatment for NMO. However, many patients discontinue AZA over time and this seems to reflect poor tolerability more than lack of efficacy.

Axonal damage is a major factor contributing to permanent disability in patients with multiple sclerosis (MS); it has been extensively investigated in the brain using magnetic resonance spectroscopy (MRS). In this study, MRS was used to investigate the degree of neuronal damage in the cervical spinal cord in MS. Spectra were acquired from spinal cord and brain in 11 patients with MS (expanded disability status score [EDSS], range 2.5-7.0) and 11 controls. Brain lesion volume and spinal cord cross-sectional area were measured. Concentration of the neuronal metabolite N-acetyl-aspartate ([NAA]) was reduced in the spinal cord in MS patients relative to controls (reduced by 32%, P < 0.05), indicating significant neuronal damage. Additionally, the spinal cord was significantly atrophied in MS patients (15%, P < 0.001). No significant reduction in brain [NAA] was seen in the MS group. There were no correlations between clinical measures and cord atrophy or brain lesion volume on MRI; however, spinal cord [NAA] correlated with the cerebellar subscore of the neurological assessment (P < 0.005), while brain [NAA] correlated with disease duration (P < 0.05). MRS demonstrated cellular damage within the cord over and above the tissue atrophy seen by MRI. Combining MRI and MRS may therefore give a more complete picture of neurodegeneration in the spinal cord.

OBJECTIVES: Allelic variants of the APOE gene are known to influence the course of many neurological diseases and there is increasing evidence that apolipoprotein E (APOE) is a pivotal component in reinnervation and dendritic remodelling after neuronal injury. Previous studies did not show significant differences in the APOE allele frequencies in multiple sclerosis compared with controls but did not examine for correlation with disease severity. This study explores the relation of APOE genotypes with the disease severity. METHODS: Ninety five patients with multiple sclerosis were studied. Age of onset, type, and activity of the disease were recorded prospectively and genotyping was performed according to standard protocols. RESULTS: APOE allele frequencies of the group as a whole, the relapsing group, or the primary progressive group were not significantly different from those reported from matched historical controls. The epsilon4 allele was found to be more common in patients with a more aggressive type of multiple sclerosis (odds ratio=2.95, p=0.03). CONCLUSIONS: Although APOE does not seem to be implicated in the early pathogenesis of the disease, patients possessing the epsilon4 allele might have a reduced capacity for neuronal remodelling after relapses.

Whilst MRI is routinely used for the assessment and diagnosis of multiple sclerosis, there is poor correspondence between clinical disability in primary progressive multiple sclerosis (PPMS) patients and conventional MRI markers of disease activity (e.g., number of enhancing lesions). As PPMS patients show diffuse and global myelin loss, the aim of this study was to evaluate the efficacy of whole-brain myelin water fraction (MWF) imaging in PPMS. Specifically, we sought to use full-brain analysis techniques to: 1) determine the reproducibility of MWF estimates in PPMS brain; 2) compare MWF values in PPMS brain to healthy controls; and 3) establish the relationship between MWF and clinical disability, regionally and globally throughout the brain. Seventeen PPMS patients and seventeen age-matched controls were imaged using a whole-brain multi-component relaxation imaging technique to measure MWF. Analysis of MWF reduction was performed on three spatial levels: 1) histogram; 2) white matter skeleton; and 3) voxel-wise at the single-subject level. From histogram analysis, PPMS patients had significantly reduced global normal appearing white matter MWF (6%, p = 0.04) compared to controls. Focal lesions showed lower MWF values than white matter in controls (61%, p < 0.001) and patients (59%, p < 0.001). Along the white matter skeleton, MWF was diffusely reduced throughout the PPMS brain, with significant correlations between reduced MWF and increased clinical disability (more severe symptoms), as measured by the Expanded Disability Status Scale, within the corpus callosum and frontal, temporal, parietal and occipital white matter. Correlations with the more specific mental and sensory functional system scores were localized to clinically eloquent locations: reduced MWF was significantly associated with increased mental scores in anterior regions (i.e., frontal lobes and genu of the corpus callosum), and increased sensory scores in more posterior regions closer to the sensory cortex. Individual patient MWF maps were also compared to a normative population atlas, which highlighted areas of statistical difference between the individual patient and the population mean. A significant correlation was found between the volume of significantly reduced MWF and clinical disability (p = 0.008, R = 0.58).Our results show that clinical disability is reflected in particular regions of cerebral white matter that are consistent between subjects, and illustrates a method to examine tissue alteration throughout the brain of individual patients. These results strongly support the use of MWF imaging to evaluate disease activity in PPMS. © 2011 Elsevier Inc.

Natalizumab, an effective treatment for MS, has been shown to exacerbate neuromyelitis optica (NMO) with aquaporin-4 antibodies, but whether this is the case in antibody negative NMO and atypical MS/NMO spectrum disorder overlap syndromes is unknown. We describe a patient with a relapsing optico-spinal demyelinating syndrome, negative for aquaporin-4 antibodies, who experienced a catastrophic brain relapse shortly after a single dose of natalizumab, highlighting that MS immunomodulatory drugs may worsen demyelination in patients with seronegative NMO and atypical MS/NMO overlap syndromes even if they are aquaporin-4 antibody negative. We summarise the treatments considered safe and effective in NMO, and those with potential to exacerbate disease. © 2014 Elsevier B.V.

There is increasing interest in the role of antibodies targeting specific membrane proteins in neurological and other diseases. The target(s) of these pathogenic antibodies is known in a few diseases, usually when candidate cell surface proteins have been tested. Approaches for identifying new antigens have mainly resulted in the identification of antibodies to intracellular proteins, which are often very useful as diagnostic markers for disease but unlikely to be directly involved in disease pathogenesis because they are not accessible to circulating antibodies. To identify cell surface antigens, we developed a "conformational membrane antigen isolation and identification" strategy. First, a cell line is identified that reacts with patient sera but not with control sera. Second, intact cells are exposed to sera to allow the binding of presumptive autoantibodies to their cell surface targets. After washing off non-bound serum components, the cells are lysed, and immune complexes are precipitated. Third, the bound surface antigen is identified by mass spectrometry. As a model system we used a muscle cell line, TE671, that endogenously expresses muscle-specific tyrosine receptor kinase (MuSK) and sera or plasmas from patients with a subtype of the autoimmune disease myasthenia gravis in which patients have autoantibodies against MuSK. MuSK was robustly detected as the only membrane protein in immunoprecipitates from all three patient samples tested and not from the three MuSK antibody-negative control samples processed in parallel. Of note, however, there were many intracellular proteins found in the immunoprecipitates from both patients and controls, suggesting that these were nonspecifically immunoprecipitated from cell extracts. The conformational membrane antigen isolation and identification technique should be of value for the detection of highly relevant antigenic targets in the growing number of suspected antibody-mediated autoimmune disorders. The approach would also be very suitable for the analysis of human or experimental antitumor responses.

Udgivelsesdato: 2009-Mar Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS.

INTRODUCTION This is a pragmatic guide to the management of myasthenia gravis. We will assume the diagnosis is correct (Hilton-Jones 2002) and the reader understands the pathogenesis of the disorder (Newsom-Davis & Beeson 2001), and we will deal only with pharmacological and surgical management. The mode of action of different pharmacological treatments will not be discussed, but their adverse effects will be. At the time of diagnosis, time must be set aside to adequately explain to the patient the nature of the disease and its management. The treatment strategy, the likely time-course of response, the long-term prognosis, potential complications of therapy, and the undoubted uncertainties about some areas of ‘best practice’ must all be discussed – this is clearly more difficult if the clinician sees relatively few cases of myasthenia, but is nonetheless crucial in optimizing patient adherence to therapy, and so outcome. Many countries have a patient support group–e.g.

Autoantibodies to acetylcholine receptors and to voltage-gated calcium and potassium channels are thought to be pathogenic in three peripheral neurological disorders: myasthenia gravis, the Lambert Eaton syndrome and acquired neuromyotonia. However, evidence for the role of antibodies in conditions involving the central nervous system, is scanty or unclear. This review describes the ways in which the roles of autoantibodies have been defined in the peripheral diseases, and discusses the more controversial evidence for involvement of autoantibodies in some central disorders such as multiple sclerosis.

Background: Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disorder associated with considerable relapse-related disability. Immunosuppression is the mainstay of treatment but many patients do not tolerate first-line immunosuppressive agents, or experience ongoing relapses. Objective: To evaluate the effectiveness and tolerability of methotrexate in aquaporin-4 antibody seropositive NMO spectrum disorders. Methods: Retrospective observational case series of 14 aquaporin-4 antibody positive NMO and NMO spectrum disorder patients treated with methotrexate at two specialist centres within the UK. Annualised relapse rates, Expanded Disability Status Scale scores and tolerability were evaluated. Results: Median duration of treatment with methotrexate was 21.5 months (range 6-28 months) and only three patients were prescribed it first line. Median annualised relapse rate signi ficantly decreased following treatment (0.18 during methotrexate therapy vs 1.39 premethotrexate; p

In mysathenia gravis (MG) autoantibodies directed against acetylcholine receptors (AChR), at the neuromuscular junction lead to muscle weakness. These antibodies are directed against extracellular determinants, predominantly on the AChR alpha subunits. Similar antibodies can be induced in animals by immunisation with purified AChR, but immunisation of mice with recombinant human alpha subunit or its extracellular domain has produced conflicting results. To study further the immunogenicity of the human alpha subunit we immunised four inbred stains (C57B1/6, SJL, BALB/c, SWR) with almost full-length recombinant alpha subunit, r37-429, and looked at B cell epitopes by mapping with smaller recombinant fragments and synthetic peptides. The majority of anti-r37-429 antibodies bound to sequences within a region thought to be cytoplasmic, alpha 325-368, and reacted with human AChR. In two C57B1/6 sera, only, most antibodies were directed against an extracellular region, alpha 138-167, but the r37-429 used for immunisation of these two mice appeared to have lost the integrity of its cytoplasmic domain during preparation. Our results suggest that the antigenicity of the cytoplasmic region of the recombinant alpha subunit dominates the immune response in each of the four strains, and may even suppress the formation of antibodies to the extracellular domain. Moreover, although C57B1/6 and SJL mice were able to produce antibodies to alpha 138-167, these antibodies did not react with intact AChR, and none of the mice became weak.

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis (MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusion: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed.

Objective To generate evidence on the longer term cost effectiveness of disease modifying treatments in patients with relapsing-remitting multiple sclerosis. Design Prospective cohort study with historical comparator. Setting Specialist multiple sclerosis clinics in 70 centres in the United Kingdom. Participants Patients with relapsing-remitting multiple sclerosis who started treatment from May 2002 to April 2005 under the UK risk sharing scheme. Interventions Treatment with interferon beta or glatiramer acetate in accordance with guidelines of the UK Association of British Neurologists. Main outcome measures Observed utility weighted progression in disability at two years’ follow-up assessed on the expanded disability status scale (EDSS) compared with that expected by applying the progression rates in a comparator dataset, modified for patients receiving treatment by multiplying by the hazard ratio derived separately for each disease modifying treatment from the randomised trials. Results In the primary per protocol analysis, progression in disability was worse than that predicted and worse than that in the untreated comparator dataset (“deviation score” of 113%; excess in mean disability status scale 0.28). In sensitivity analyses, however, the deviation score varied from −72% (using raw baseline disability status scale scores, rather than applying a “no improvement” algorithm) to 156% (imputing missing data for year two from progression rates for year one). Conclusions It is too early to reach any conclusion about the cost effectiveness of disease modifying treatments from this first interim analysis. Important methodological issues, including the need for additional comparator datasets, the potential bias from missing data, and the impact of the “no improvement” rule, will need to be addressed and long term follow-up of all patients is essential to secure meaningful results. Future analyses of the cohort are likely to be more informative, not least because they will be less sensitive to short term fluctuations in disability.

Recent findings in the animal model for multiple sclerosis (MS), experimental autoimmune encephalomyelitis, implicate a novel CD4+ T-cell subset (TH17), characterized by the secretion of interleukin-17 (IL-17), in disease pathogenesis. To elucidate its role in MS, brain tissues from patients with MS were compared to controls. We detected expression of IL-17 mRNA (by in situ hybridization) and protein (by immunohistochemistry) in perivascular lymphocytes as well as in astrocytes and oligodendrocytes located in the active areas of MS lesions. Further, we found a significant increase in the number of IL-17+ T cells in active rather than inactive areas of MS lesions. Specifically, double immunofluorescence showed that IL-17 immunoreactivity was detected in 79% of T cells in acute lesions, 73% in active areas of chronic active lesions, but in only 17% of those in inactive lesions and 7% in lymph node control tissue. CD8+, as well as CD4+, T cells were equally immunostained for IL-17 in MS tissues. Interestingly, and in contrast to lymph node T cells, no perivascular T cells showed FoxP3 expression, a marker of regulatory T cells, at any stage of MS lesions. These observations suggest an enrichment of both IL-17+CD4+ and CD8+ T cells in active MS lesions as well as an important role for IL-17 in MS pathogenesis, with some remarkable differences from the experimental autoimmune encephalomyelitis model.

Diffusion MRI and magnetic resonance spectroscopic measurements of selectively neuronally localised N-acetylaspartate (NAA) both have been used widely to assess white matter integrity and axonal loss. We have tested directly the relationship between changes in diffusion MRI parameters and NAA concentrations in the corpus callosum (CC) in an in vivo study of patients with MS. Fifteen MS patients (median EDSS 2.5, range 1-4) were studied with T(1) anatomical, T(2)-weighted, and diffusion-sensitised MRI and PRESS single-voxel MRS. A recently described method, tract-based spatial statistics (TBSS) [Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E. et al., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487-1505] also was used to perform exploratory voxelwise whole-brain analysis of white matter diffusion fractional anisotropy (FA). We found a strong correlation between callosal size and both mean FA (r=0.68, p

Congenital myasthenic syndromes are inherited disorders of neuromuscular transmission characterized by fatigable muscle weakness. Autosomal recessive acetylcholine receptor (AChR) deficiency syndromes, in which levels of this receptor at the neuromuscular junction are severely reduced, may be caused by mutations within genes encoding the AChR or the AChR-clustering protein, rapsyn. Most patients have mutations within the rapsyn coding region and are either homozygous for N88K or heteroallelic for N88K and a second mutation. In some cases the second allele carries a null mutation but in many the mutations are missense, and are located in different functional domains. Little is known about the functional effects of these mutations, but we hypothesize that they would have an effect on AChR clustering by a variety of mechanisms that might correlate with disease severity. Here we expressed RAPSN mutations A25V, N88K, R91L, L361R and K373del in TE671 cells and in rapsyn-/- myotubes to determine their pathogenic mechanisms. The A25Vmutation impaired colocalization of rapsyn with AChR and prevented agrin-induced AChR clusters in rapsyn-/- myotubes. In TE671 cells, R91L reduced the ability of rapsyn to self-associate, and K373del-rapsyn was significantly less stable than wild-type. The effects of mutations L361R and N88K were more subtle: in TE671 cells, in comparison with wild-type rapsyn, L361R-rapsyn showed reduced expression/stability, and both N88K-rapsyn and L361R-rapsyn showed significantly reduced co-localization with AChR. N88K-rapsyn and L361R-rapsyn could effectively mediate agrin-induced AChR clusters, but these were reduced in number and were less stable than with wild-type rapsyn. The disease severity of patients harbouring the compound allelic mutations was greater than that of patients with homozygous rapsyn mutation N88K, suggesting that the second mutant allele may largely determine severity. © The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

The role of antibodies to specific neuronal and muscle ion channels in the etiology of neuromuscular transmission disorders is now well accepted. In addition, maternal antibodies can cross the placenta and cause neonatal disease or even alter the development of the infant, raising the possibility that some neurodevelopmental conditions could be caused by maternal antibodies. Voltage-gated ion channels are expressed in the brain as well as at the neuromuscular junction, and in recent years it has become clear that antibodies to some central nervous system (CNS) channels can be associated with CNS disease. This review highlights features of these conditions, preliminary investigations into neurodevelopmental disorders, and areas for further study.

This review focuses on the diagnostic tests that may help to confirm myasthenia in patients without acetylcholine receptor antibodies, including the newly discovered anti-muscle-specific receptor tyrosine kinase antibody and other investigations. We discuss management dilemmas, particularly those that revolve around treatments whose efficacy is questionable or unproved, such as thymectomy. We review the important issue of how treatments are assessed, and examine future treatment trial designs.

We assessed axonal loss in the normal appearing white matter of the corpus callosum in postmortem brains of patients with multiple sclerosis, using quantitative measures of both axonal density and white matter atrophy. The calculated total number of axons was reduced significantly (mean +/- SD, 5.4 x 10(7) +/- 3.1 x 10(7)) compared with normal controls (11.6 x 10(7) +/- 2.2 x 10(7), p = 0.001) with a reduction both in axonal density (median, 34%; range, 16-56%; p = 0.004) and area (mean +/- SD: multiple sclerosis, 584 +/- 170 mm2; controls, 871 +/- 163 mm2; p = 0.004). These results confirm substantial axonal loss in the normal appearing white matter and demonstrate that measures of both axonal density and white matter volume are necessary to appreciate the full extent of axonal loss.

We investigated the relationship between action tremor (AT) and impaired control of movement velocity (MV) in visually guided tracking tasks, in normal subjects and in patients with multiple sclerosis (MS) with or without motor deficits. The effects of withdrawing visual feedback of either the target or the cursor were then investigated. Visually cued simple reaction times (SRTs) were also measured. The effects of thalamotomy on motor performance in these tasks were evaluated in seven patients. In the MS patients with tremor, there was no correlation between AT and impairment in control of MV, but the latter was highly correlated with an increased delay in SRT. Withdrawal of visually guiding cues increased the error significantly in MV, but reduced AT by approximately 30% in magnitude. Frequency analysis indicated that the AT had two components: (a) non-visual-dependent, oscillatory movements, mainly at 4 Hz; and (2) visual-dependent, repetitive movements, with significant power at 1-2 Hz. Thalamotomy significantly reduced AT but hardly improved accuracy in MV. These results suggest that visual feedback of a spatial mismatch signal may provoke a visually dependent repetitive movement contributing to AT. Conduction delays along either the cortico-cerebello-cortical or the proprioceptive pathways and impaired working memory caused by MS may be responsible for the movement disorders in these patients.

Background The UK Multiple Sclerosis Risk–sharing Scheme (RSS) was established in 2002 following NICE9s decision that the cost–effectiveness of interferon (IFN)–β and glatiramer acetate (GA) could not be assessed with existing short–term data. The scheme was set up as a joint undertaking between the Department of Health and the manufacturers of the drugs with input from other stakeholders. The purpose was to ensure cost–effective provision of IFNβ/GA to eligible people through a number of mechanisms, including an initial recalculation of drug pricing and the establishment of specialist nursing and medical structures. One aspect of the scheme was the enrolment of a cohort of at least 5000 people commencing IFNβ/GA with follow–up for 10 years, using these data to adjust drug costs. Methods Patients were enrolled prospectively from 72 UK sites. Baseline demographic data, history, eligibility and EDSS were recorded. Patients were invited to annual review as part of routine care with information recorded on relapses, type of MS, treatment history and EDSS. Efforts were made to maximise retention, including creating the facility for telephone follow–up and EDSS scoring. From 2006, data has been collated by PAREXEL. Following recognition of limitations in the original design, the protocol and statistical analysis plan have undergone revision with input from a newly established, independent Scientific Advisory Group. Results From May 2002 –April 2005, 5610 people with MS consented to participate in the RSS, representing approximately 80% of people starting IFNβ/GA within this period. In December 2012, 4673 remained within the scheme (83.3% retention). Of those no longer within the scheme, 349 (6.2%) have been lost to follow up and 585 (10.4%) have withdrawn consent. Year 10 data has already been submitted on the earliest enrolled and over half the 10 year data should be collected by the end of 2013. By January 2013, we have, in total, 31,874 submitted annual reviews with a further 6092 accounted for as missed visits. All data has been validated and reviewed by data management and any discrepancies reconciled with the sites. Discussion In spite of the short start–up time and ambitious scope of the RSS, this represents a collective effort by UK physicians to recruit and retain the biggest MS treatment cohort worldwide. While it might have been expected that delays in presenting data would adversely affect retention and motivation, drop–out rates are lower than would be predicted from analogous non–interventional studies. Joint analysis of the 4 and 6 year data is due later in 2013 and data collection will be complete by 2015. In order to fulfil our obligations to the scheme, it is important UK neurologists maintain this level of achievement.

Objective: To test the hypothesis that axonal damage extending into primarily normal-appearing white matter is clinically important by comparing the concentrations of N-acetylaspartate (NAA) bilaterally within the internal capsule with lateralization of motor impairment in patients with multiple sclerosis (MS) and persistent asymmetrical motor deficit. Design: We performed magnetic resonance spectroscopy and T2-weighted imaging of the internal capsule, calculated central motor conduction times, and related these results to measures of motor function asymmetry in 12 patients with MS. Results: Levels of NAA from normal-appearing white matter of the internal capsule in patients with MS were significantly lower than those in control subjects (P = .05). Side-to-side differences in NAA levels were also significantly greater in patients with MS than in controls (P = .01). There was a correlation between asymmetry in motor function for the left and right limbs and asymmetry of internal capsule NAA concentrations (r = 0.60; P = .04). This correlation seemed slightly stronger when tests specifically of arm and hand motor asymmetry were considered alone. Central motor conduction times were abnormal in most patients with MS and showed a side-to-side difference that also correlated with asymmetry in motor function. Conclusion: Our demonstration of a graded association between NAA concentrations within primarily normal-appearing white matter of a specific tract and functional impairments referable to that tract suggests that axonal pathology distant from macroscopic lesions might be an important determinant of disability in MS. Arch Neurol. 2000;57:65-70