Search

The Cochrane Collaboration (CC) celebrates its 20th anniversary in 2013 and the Cochrane Neuromuscular Disease Group (CNMDG) its fifteenth. The Cochrane Database of Systematic Reviews is an internet-based resource of systematic reviews. The CNMDG has contributed over 100 Cochrane Systematic Reviews (CSRs) of interventions in neuromuscular disease, with almost 40 in preparative pre-publication. Over 100 potential titles still await author groups to tackle them. Cochrane Systematic Reviews not only provide the best summary of the evidence for individual interventions for diseases, but have contributed high quality and valuable data to international neuromuscular guidelines, each review coming at 1/10th of the cost of a NICE guideline. This efficient but high quality contribution is due both to the systematized Cochrane methods and the invaluable participation of over 26,000 Cochrane volunteer authors. Without Cochrane Systematic Reviews some questions about interventions for neuromuscular diseases would still remain ‘unanswered’. The CNMDG has made substantial contributions to literature in specific topics areas of both peripheral nerve and muscle disease. In Guillain-Barre Syndrome (GBS) one meta-analysis demonstrates the ineffectiveness of steroids and more importantly their potential harms, not evident from individual trials [1]. Systematized international multilingual searches for other treatments for GBS have uncovered potential new treatments requiring trial, such as the extract of Tripterygium wilfordii [2]. In Duchenne Muscular Dystrophy a meta-analysis of data from 249 children confirmed effectiveness of glucocorticoid corticosteroids in stabilizing muscle strength and improving function [3], and this is now considered the

Introduction Proximal axonotmesis results in the release of neurofilament (Nf) proteins into the cerebrospinal fluid (CSF) in patients with Guillain-Barre syndrome (GBS). High CSF levels of the phosphorylated form of Nf-heavy chain (NfHSMI35) at GBS onset have been reported to be a poor prognostic marker, but routine measurement of CSF NfHSMI35 levels has not been done and the longitudinal profile of CSF NfHSMI35 levels in GBS is not known. Methods This prospective case series describes the clinical, neurophysiological, and biomarker characteristics of 3 patients with severe GBS. Results High and increasing levels of CSF NfHSMI35 in serial CSF samples were associated with poor clinical and electrophysiological outcome. Conclusions These data further suggest that CSF NfHSMI35 could be a prognostic biomarker which might indicate the development of retrograde axonal degeneration or additional proximal axonal damage during the course of GBS. Muscle Nerve, 2013

The American Academy of Neurology has published guidelines for intravenous immunoglobulin (IVIg) treatment of neuromuscular diseases. These guidelines differ from those in Europe owing to different conventions for grading of recommendations. Although IVIg is an effective treatment for inflammatory neuropathies and neuromuscular diseases, it is much more expensive than alternative therapies.

Dosing guidelines for immunoglobulin (Ig) treatment in neurological disorders do not consider variations in Ig half-life or between patients. Individualization of therapy could optimize clinical outcomes and help control costs. We developed an algorithm to optimize Ig dose based on patient's response and present this here as an example of how dosing might be individualized in a pharmacokinetically rational way and how this achieves potential dose and cost savings. Patients are "normalized" with no more than two initial doses of 2 g/kg, identifying responders. A third dose is not administered until the patient's condition deteriorates, allowing a "dose interval" to be set. The dose is then reduced until relapse allowing dose optimization. Using this algorithm, we have individualized Ig doses for 71 chronic inflammatory neuropathy patients. The majority of patients had chronic inflammatory demyelinating polyradiculoneuropathy (n = 39) or multifocal motor neuropathy (n = 24). The mean (standard deviation) dose of Ig administered was 1.4 (0.6) g/kg, with a mean dosing interval of 4.3 weeks (median 4 weeks, range 0.5-10). Use of our standardized algorithm has allowed us to quickly optimize Ig dosing.

We report a rare case of myofasciitis and meningitis with deafness caused by systemic enterovirus infection in the setting of hypogammaglobulinaemia induced by rituximab. Whilst effective and generally safe, anti- CD 20 antibody therapy is increasingly recognised to result in unusual infectious complications to be considered in a treated patient presenting with neurological symptoms. These cases may pose diagnostic difficulties and can have atypical presentations. We present this rare complication of rituximab therapy, with histopathological confirmation of myofasciitis. In the older literature, enterovirus associated myofasciitis may have erroneously been termed dermatomyositis and we review the literature to demonstrate this important nosological point.

Background Antiepileptic drugs have been used in pain management since the 1960s; some have shown efficacy in treating different neuropathic pain conditions. The efficacy of zonisamide for the relief of neuropathic pain has not previously been reviewed. Objectives To assess the analgesic efficacy and associated adverse events of zonisamide for chronic neuropathic pain in adults. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (via CRSO), MEDLINE, EMBASE, and two clinical trials databases (ClinicalTrials.gov. and the World Health Organisation Clinical Trials Registry Platform) to 1 August 2014, together with reference lists of retrieved papers and reviews. Selection criteria We included randomised, double-blind studies of at least two weeks' duration comparing zonisamide with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 and over. We included only full journal publication articles and clinical trial summaries. Data collection and analysis Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We considered the evidence using three tiers. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design); second tier evidence derived from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison; and third tier evidence derived from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We planned to calculate risk ratio (RR) and numbers needed to treat (NNT) and harm (NNH) for one additional event using standard methods expected by The Cochrane Collaboration. Main results We included a single study treating 25 participants (13 zonisamide, 12 placebo) with painful diabetic neuropathy over 12 weeks. No first or second tier evidence was available for any outcome. The small size of the study and potential major bias due to a high proportion of early study withdrawals with zonisamide precluded any conclusions being drawn. There were two serious adverse events (one death) in zonisamide-treated participants, which were apparently not related to treatment. Authors' conclusions The review found a lack of evidence suggesting that zonisamide provides pain relief in any neuropathic pain condition. Effective medicines with much greater supportive evidence are available.

Metagenomic next-generation sequencing (NGS) was used to diagnose an unusual and fatal case of progressive encephalitis in an immunocompromised adult presenting at disease onset as bilateral hearing loss. The sequencing and confirmatory studies revealed neuroinvasive infection of the brain by an astrovirus belonging to a recently discovered VA/HMO clade.

Axon calibre is crucial to efficient impulse transmission in the peripheral nervous system. Neurofilament numbers determine gross axonal diameter, but intra-axonal distribution depends on the phosphorylation status of neurofilament sidearms. Myelin-associated glycoprotein (MAG) has been implicated in the signalling cascade controlling neurofilament phosphorylation and hence in the control of axon calibre. In an electron microscopic morphometric study we measured nearest neighbour neurofilament distances (NNND) in the axons of sural nerves from patients with anti-MAG paraproteinaemic neuropathies and compared these with normal human sural nerves and those from patients with Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy. Axon calibre was similar in all groups. In normal human sural nerves, axonal NNND was correlated with axonal diameter (r = 0.56). In diseased axons this correlation did not exist. The NNND was significantly reduced in demyelinated axons (30.5+/-2.2 nm) and those with widely spaced myelin (28.9+/-1.3 nm) from patients with anti-MAG antibodies compared with normal axons from normal patients (39.8+/- 3.2 nm) or those with demyelinating neuropathy (35.8+/-4.6 nm). This reinforces the hypothesis that MAG is involved in the control of neurofilament spacing through sidearm phosphorylation and demonstrates a MAG-mediated pathogenic effect of the anti-MAG antibody in peripheral nerves.

Chronic immune sensory polyradiculopathy (CISP) is a recently described restricted form of chronic inflammatory demyelinating polyradiculopathy (CIDP) [1]. It preferentially affects large myelinated fibres of the posterior roots, is associated with normal peripheral nerve conduction studies, and may respond to immunomodulatory treatment. We describe a patient with clinical features of CISP and additional cranial nerve involvement. A 61 year old woman presented with a 10 year relapsing-remitting neurological disorder. She initially presented with nausea, headache and photophobia followed by diplopia and unilateral ptosis consistent with an oculomotor nerve palsy. Intracranial CT, MRI, MRA, catheter angiography and CSF were all normal. Symptoms resolved over 18 months but an inflammatory cause was suspected after a relapse and treatment with 2 g/kg intravenous immunoglobulin (IVIg) was effective. Further relapses with additional poor balance, facial numbness and distal sensory symptoms responded promptly to IVIg. Intravenous methylprednisolone worsened her symptoms. Neurological examination revealed a partial right oculomotor nerve palsy. Pin prick sensation was reduced in a right trigeminal nerve distribution. Limb power was normal but reflexes were reduced in the upper limbs and absent in the lower limbs with flexor plantars. Romberg’s test was positive. Pin prick was reduced on the ulnar aspect of the right forearm and up to the mid-shins bilaterally. Vibration sense was reduced up to both ankles and proprioception impaired up to the right ankle. Examination after IVIg revealed that ophthalmoplegia, ptosis and a timed Romberg’s test had all improved. Systemic inflammatory/autoimmune blood tests were unremarkable and these included full blood count, ESR, CRP, ANA, ANCA, complement, rheumatoid factor, ENA, protein electrophoresis, immunofixation, acetylcholine receptor antibodies, immunoglobulins, ganglioside serology, lyme serology, treponemal serology and anti-neuronal antibodies. CSF was acellular with normal glucose and a raised protein level of 0.71 g/L (normal 0.15–0.65 g/L). Oligoclonal bands were absent. Neurophysiological data are presented in the appendix. In summary, the absolute values of all neurophysiological investigations listed were normal. However, the ulnar nerve SNAPs were significantly asymmetrical and the motor F-waves prolonged. Thermal thresholds were abnormal in the feet and right hand. Somatosensory evoked potentials were poorly formed in the right lower limb. Asymmetry of motor evoked potential latencies following cervical spine stimulation was consistent with a lesion distal to the intervertebral foramina. Electronic supplementary material The online version of this article (doi:10.1007/s00415-011-6326-0) contains supplementary material, which is available to authorized users.

We describe a previously healthy 53 year old woman with a progressive multifocal neurological syndrome. She developed gradually progressive patchy numbness and horizontal diplopia over 3 years, night sweats and 15 kg weight loss over 1 year, and weakness of the face and four limbs over 9 months. Previous treatment for her symptoms included dual anti-platelet agents then warfarin for a positive lupus anticoagulant, oral fludarabine (50 mg for 5 days) following a diagnosis of mild chronic lymphocytic leukaemia (CLL) on bone marrow biopsy, and two courses of oral steroids (25 mg/day prednisolone; 20 mg/day dexamethosone each tapered over 4 weeks). Neurological symptoms progressed despite these treatments. On examination she mobilised with a frame. There were partial right III, VI and bilateral VII cranial nerve palsies. There was wasting of intrinsic hand muscles, distal lower limb muscles and right deltoid. There was asymmetric proximal and distal weakness in all limbs ranging from no active contraction of right deltoid, flicker of contraction of left hamstrings to mild weakness of ankle dorsiflexors. There was patchy loss of reflexes and flexor plantars. She had sensory loss to light touch and pinprick in multiple dermatomes. The working diagnosis was CLL-associated immunemediated radiculopathies and cranial neuropathies. She was treated with rituximab 375 mg/m and hydrocortisone 100 mg weekly for 8 weeks without additional steroids (repeated previous steroid-associated central serous retinopathy). She made a near complete response. Three months after the rituximab her only residual symptom was with feeling a little unsteady. The only abnormalities on neurological examination were slight diplopia on right gaze and reduced vibration sensation to the ankles. Investigations (Table 1) had dramatically improved. She was maintained on oral cyclophosphamide 50 mg/day, however, had a minor relapse after 5 months and received a repeat rituximab course with good effect. She is neurologically stable on maintenance rituximab 375 mg/m every 3 months. Mechanisms by which CLL could be associated with neurological symptoms include direct leukaemic infiltration, indirectly through immune-mediated effects, opportunistic infection related, treatment related or chance association. Neurological syndromes are found in 11% of CLL patients mostly relating to opportunistic infections [1]. Cases of CLL associated with GBS [2, 3], MillerFisher syndrome [4], subacute IDP [5], mononeuritis multiplex [5] and polyneuropathy [5] are reported. A case with multiple radiculopathies and cranial neuropathies was reported recently [6], however, direct leukemic infiltration of nerve roots was evident on imaging and CSF. In our patient repeated MRI and CSF examinations showed no evidence of direct leukaemic infiltration. J. M. Morrow (&) M. P. Lunn M. M. Reilly MRC Centre for Neuromuscular Diseases, Department of Molecular Neurosciences, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Box 102, WC1N 3BG London, UK e-mail: j.morrow@ion.ucl.ac.uk

The association between cytomegalovi- rus (CMV) and Guillain-Barresyn- drome (GBS) was first noted in 1967 (1) and was soon endorsed by other reports and case series. The largest previous case series showed that CMV infection was associated with GBS in 8% of 229 pa- tients from a European and North American trial (2). In this issue of Clinical Infectious Diseases, Orlikowski et al (2) confirmed this finding in a larger population of people with GBS by using the resources of the French reference centre in Garches, Paris, which has been a major source of useful research into the disease. Of 506 patients with GBS, 63 (12.5%) had serological evidence of primary CMV infection. It is difficult to distinguish between primary and reactivation of infection, an important problem, because 50% of the nonimmunosuppressed people in de- veloped countries have serological evi- dence of exposure to CMV. The serological methods used by Orlikowski and colleagues incorporated a test for high immunoglobulin (Ig) G avidity to exclude positive results due to re- activation. Low-avidity IgG antibody is found in primary infection before affinity maturation has occurred. The serological results were supported by the finding of CMV DNA in the plasma by poly- merase chain reaction (PCR) in 36 (62%) of 58 subjects who had positive serological test results. The sensitivity of CMV PCR nears 100% for acute in- fection, but it would be expected to be reduced in the late infectious phase, when GBS occurs because virus is being cleared. Unfortunately no conva- lescent-phase samples were available for analysis because of the intervening treat- ment and quantitative PCR was not performed for enough patients to publish the result. The authors used contemporary French epidemiological data to calculate, for the first time, that the risk of GBS following CMV is in the order of 0.6-2.2 cases per 1000 persons. There were no control subjects in the Orlikowski et al (2) study, but 2 earlier studies had shown that the frequency of recent CMV infection preceding GBS significantly exceeded that of control subjects: in the United Kingdom, 11% of 99 case patients and only 1% of control patients had evi- dence of recent CMV infection (3); in the Netherlamds, 13% of 154 case patients and only 2% of control subjects (4) had evidence of recent CMV infection. The study by Orlikowski et al (2)

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5′ region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.

BACKGROUND: Antiepileptic drugs have been used in pain management since the 1960s; some have shown efficacy in treating different neuropathic pain conditions. The efficacy of levetiracetam for relief of neuropathic pain has not previously been reviewed. OBJECTIVES: To assess the analgesic efficacy and adverse events of levetiracetam in chronic neuropathic pain conditions in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6) (via the Cochrane Library), MEDLINE, EMBASE, and two clinical trials databases (ClinicalTrials.gov. and the World Health Organisation Clinical Trials Registry Platform) to 3 July 2014, together with reference lists of retrieved papers and reviews. SELECTION CRITERIA: We included randomised, double‐blind studies of two weeks duration or longer, comparing levetiracetam with placebo or another active treatment in adults with chronic neuropathic pain conditions. Studies had to have a minimum of 10 participants per treatments arm. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction; intention‐to‐treat analysis without imputation for dropouts; at least 200 participants in the comparison; 8 to 12 weeks duration; parallel design); second tier evidence from data that failed to meet one or more of these criteria and that we considered at some risk of bias but with at least 200 participants in the comparison; and third tier evidence from data involving fewer than 200 participants that was considered very likely to be biased or used outcomes of limited clinical utility, or both. MAIN RESULTS: We included six studies: five small, cross‐over studies with 174 participants, and one parallel group study with 170 participants. Participants were treated with levetiracetam (2000 mg to 3000 mg daily) or placebo for between four and 14 weeks. Each study included participants with a different type of neuropathic pain; central pain due to multiple sclerosis, pain following spinal cord injury, painful polyneuropathy, central post‐stroke pain, postherpetic neuralgia, and post‐mastectomy pain. None of the included studies provided first or second tier evidence. The evidence was very low quality, downgraded because of the small size of the treatment arms, and because studies reported results using last observation carried forward (LOCF) imputation for withdrawals or using only participants who completed the study according to the protocol, where there were greater than 10% withdrawals. There were insufficient data for a pooled efficacy analysis in particular neuropathic pain conditions, but individual studies did not show any analgesic effect of levetiracetam compared with placebo. We did pool results for any outcome considered substantial pain relief (≥ 50% pain intensity reduction or ‘complete’ or ‘good’ responses on the verbal rating scale) for four studies with dichotomous data; response rates across different types of neuropathic pain was similar with levetiracetam (10%) and placebo (12%), with no statistical difference (risk ratio 0.9; 95% confidence interval (CI) 0.4 to1.7). We pooled data across different conditions for adverse events and withdrawals. Based on very limited data, significantly more participants experienced an adverse event with levetiracetam than with placebo (number needed to treat for an additional harmful event (NNH) 8.0 (95% CI 4.6 to 32)). There were significantly more adverse event withdrawals with levetiracetam (NNH 9.7 (6.7 to 18)). AUTHORS' CONCLUSIONS: The amount of evidence for levetiracetam in neuropathic pain conditions was very small and potentially biased because of the methods of analysis used in the studies. There was no indication that levetiracetam was effective in reducing neuropathic pain, but it was associated with an increase in participants who experienced adverse events and who withdrew due to adverse events.

A 76-year-old man with a pre-existing diagnosis of myasthenia gravis was admitted to an intensive care unit with pneumonia and type II respiratory failure. In addition, muscle weakness, widespread myokymia, neuropsychiatric disturbance and autonomic disturbance were present. Antivoltage gated potassium channel antibodies, antistriated muscle antibodies and antiacetylcholine receptor antibodies were positive. Nerve-conduction studies demonstrated findings consistent with patchy demyelination. Electromyography confirmed widespread myokymia, and there was evidence of diffuse encephalopathy on electroencephalography. Diagnoses of Morvan syndrome and chronic inflammatory demyelinating polyradiculopathy (CIDP) were made. Treatment with intravenous immunoglobulin, plasma exchange and high-dose steroids were ineffective, and the patient remained dependent on mechanical ventilation. The coexistence of possibly three humorally mediated autoimmune diseases led to treatment with rituximab. Rituximab treatment was followed by an improvement in muscle strength, allowing successful weaning from mechanical ventilation, diminution in myokymia and improved cognition. At follow-up, there was reversal of the neuropsychiatric manifestations and normal muscle strength. This case suggests that rituximab may be useful in the treatment of autoimmune neurological disease refractory to other immunosuppressant therapies. Specifically, it adds further evidence for the use of rituximab in CIDP. As indications for rituximab in humorally mediated disease continue to expand, international multicentre randomised controlled trials are required to prove the effectiveness of this important emerging biological agent.

Monoclonal antibodies reactive with the HNK-1 epitope of myelin-associated glycoprotein (MAG) and the sulphate-3-glucuronyl paragloboside (SGPG)-like glycolipids are often found in the serum of patients with IgM paraprotein-associated demyelinating neuropathy. The presence of such antibodies in patients with chronic polyneuropathy has recently been associated with evidence of active cytomegalovirus (CMV) infection by the polymerase chain reaction. We wished to test these findings and examined sera from patients with MAG-reactive or MAG-nonreactive paraproteinemic neuropathy and patients with paraproteinemia only for the presence of CMV DNA and anti-CMV antibodies. CMV DNA was not detected in sera from any patient group. Furthermore, anti-CMV antibody prevalence was normal and similar in all 3 groups. We therefore report no evidence of an association between CMV infection and anti-MAG/SGPG antibodies associated with paraproteinemic peripheral neuropathy.

OBJECTIVES To evaluate the response of four patients with IgM paraproteinaemic neuropathy to a novel therapy—pulsed intravenous fludarabine. BACKGROUND The peripheral neuropathy associated with IgM paraproteinaemia usually runs a chronic, slowly progressive course which may eventually cause severe disability. Treatment with conventional immunosuppressive regimens has been unsatisfactory. Fludarabine is a novel purine analogue which has recently been shown to be effective in low grade lymphoid malignancies. METHODS Four patients were treated with IgM paraproteinaemic neuropathy with intravenous pulses of fludarabine. Two of the four patients had antibodies to MAG and characteristic widely spaced myelin on nerve biopsy and a third had characteristic widely spaced myelin only. The fourth had an endoneurial lymphocytic infiltrate on nerve biopsy and a diagnosis of Waldenstrom’s macroglobulinaemia. RESULTS In all cases subjective and objective clinical improvement occurred associated with a significant fall in the IgM paraprotein concentration in three cases. Neurophysiological parameters improved in the three patients examined. The treatment was well tolerated. All patients developed mild, reversible lymphopenia and 50% mild generalised myelosuppression, but there were no febrile episodes. CONCLUSION Fludarabine should be considered as a possible treatment for patients with IgM MGUS paraproteinaemic neuropathy.

Background Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010. Objectives To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain. Search methods On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain. Selection criteria We selected all randomised or quasi-randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. Main results We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose-dependent effect. Most adverse effects were minor, but 12.6% of participants stopped the drug due to adverse effects. Serious adverse events were rare. Authors' conclusions There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy. Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare. Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.

A small but clinically important group of peripheral neuropathies with an inflammatory pathogenesis provide important insights into mechanisms of autoimmune disease. The pathology of the Guillain–Barre and Fisher syndromes is driven by antibody-dependent and complement-mediated attack on peripheral nerve axons or myelin. Much of the understanding of these diseases emerges from insights into the pathogenesis of the acute motor axonal neuropathy phenotype of GBS, first described in China half a century after GBS was described. Half a century further on and the pathogenesis of the chronic inflammatory neuropathies is less well understood and seems to be more T cell driven. Treatments based on rational pathogenic mechanisms are being tried in the therapy of these conditions with evidence for their efficacy supporting postulated mechanisms of disease.

Background The emergence of influenza A(H1N1) 2009 was met with increased reports of associated neurological manifestations. We aimed to describe neurological manifestations of influenza in adults and children in the United Kingdom that presented at this time. Methods A 2-year surveillance study was undertaken through the British adult and pediatric neurological surveillance units from February 2011. Patients were included if they met clinical case definitions within 1 month of proven influenza infection. Results Twenty-five cases were identified: 21 (84%) in children and 4 (16%) in adults. Six (29%) children had preexisting neurological disorders. Polymerase chain reaction of respiratory secretions identified influenza A in 21 (81%; 20 of which [95%] were H1N1) and influenza B in 4 (15%). Twelve children had encephalopathy (1 with movement disorder), 8 had encephalitis, and 1 had meningoencephalitis. Two adults had encephalopathy with movement disorder, 1 had encephalitis, and 1 had Guillain-Barre syndrome. Seven individuals (6 children) had specific acute encephalopathy syndromes (4 acute necrotizing encephalopathy, 1 acute infantile encephalopathy predominantly affecting the frontal lobes, 1 hemorrhagic shock and encephalopathy, 1 acute hemorrhagic leukoencephalopathy). Twenty (80%) required intensive care, 17 (68%) had poor outcome, and 4 (16%) died. Conclusions This surveillance study described a cohort of adults and children with neurological manifestations of influenza. The majority were due to H1N1. More children than adults were identified; many children had specific encephalopathy syndromes with poor outcomes. None had been vaccinated, although 8 (32%) had indications for this. A modified classification system is proposed based on our data and the increasing spectrum of recognized acute encephalopathy syndromes.

Background Antiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled 'Anticonvulsants for acute and chronic pain'. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009. Objectives To provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use. Methods We included reviews published in theCochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data. We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards - at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention-to-treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation. Main results No studies reported top tier results. For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more. For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias. Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine. Authors' conclusions Clinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin. There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.

Charcot-Marie-Tooth (CMT) disease type 1A is the most common form of CMT. The main clinical features are distal weakness, sensory loss, and skeletal deformities. Although pain is a frequent complaint, small fiber involvement in CMT1A has not been studied extensively.We assessed pain and small fiber involvement in 49 CMT1A patients using a variety of pain scales, pain questionnaires, and thermal thresholds.Forty-three of 49 patients (88%) complained of pain. The pain was localized to the feet in 61% of patients. Only 18% of patients had neuropathic pain. Cold and warm detection thresholds were elevated in 53% and 12% of patients, respectively.Our findings confirm that CMT1A patients have significant pain, which is more likely to be multifactorial in origin and suggests that a proportion of patients have small fiber dysfunction affecting mainly thinly myelinated Aδ fibers.

This study aims to investigate if patients with inflammatory neuropathies and tremor have evidence of dysfunction in the cerebellum and interactions in sensorimotor cortex compared to nontremulous patients and healthy controls.A prospective data collection study investigating patients with inflammatory neuropathy and tremor, patients with inflammatory neuropathy without tremor, and healthy controls on a test of cerebellar associative learning (eyeblink classical conditioning), a test of sensorimotor integration (short afferent inhibition), and a test of associative plasticity (paired associative stimulation). We also recorded tremor in the arms using accelerometry and surface EMG.We found impaired responses to eyeblink classical conditioning and paired associative stimulation in patients with neuropathy and tremor compared with neuropathy patients without tremor and healthy controls. Short afferent inhibition was normal in all groups.Our data strongly suggest impairment of cerebellar function is linked to the production of tremor in patients with inflammatory neuropathy.

Limbic encephalitis typically presents with memory impairment, seizures and psychiatric disturbances. Even 10 years ago, autoimmune limbic encephalitis was considered almost always paraneoplastic but many other causes are now recognised, including autoimmune processes independent of a malignancy.1 In a recent series, clinical brainstem involvement (ataxia, dizziness, diplopia) occurred in 13 of 50 paraneoplastic limbic encephalitis cases, with hypothalamic involvement in 11 of 50.2 Parinaud's syndrome has not been reported as a feature of paraneoplastic limbic encephalitis. Parinaud's syndrome, first described in 1886,3 involves a combination of eye signs—most commonly, limitation of up and down gaze, failure of convergence, dissociation of lid and eye movements (ptosis, lid retraction) and convergence–retraction nystagmus. Reported underlying lesions usually localise to the dorsal midbrain. The most common causes are pinealomas, stroke and multiple sclerosis. There have been no reported immunological causes. We describe an extremely challenging case associated with an underlying neoplasm. A 52-year-old male professional opera singer had been well apart from coronary artery stenting following myocardial infarction. He presented in October 2010 with ‘difficulty focusing’ while walking in the New Forest in the UK, finding it difficult to change from looking at the horizon down on to a map. Walking through a crowd felt draining, as was making out facial detail while walking. He had to feel his way around a plate of food as he could not look down at it and could not check if he …

We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype–phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM. Electronic supplementary material The online version of this article (doi:10.1007/s12017-012-8216-8) contains supplementary material, which is available to authorized users.

Background: Cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42), total tau (T-tau) and phosphorylated tau181 (P-tau) are finding increasing utility as biomarkers of Alzheimer’s disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by aliquot storage volume and whether addition of detergent-containing buffer mitigates any observed effects. Methods: AD and control CSF was distributed into polypropylene tubes in aliquots of different volumes (50–1500 μL). Aβ1-42, T-tau and P-tau were measured with and without addition of Tween 20 (0.05%). Results: Measured concentrations of Aβ1-42 increased two-fold with aliquot storage volume. A volume increase of 10 µL caused an Aβ1-42 increase of 0.95 pg/mL [95% confidence interval (CI) 0.36–1.50, p=0.02] in controls, and 0.60 pg/mL (CI 0.23–0.98 pg/mL, p=0.003) in AD samples. Following addition of Tween 20, the positive relationship between Aβ1-42 and aliquot volume disappeared. T-tau and P-tau were not significantly affected. Conclusions: CSF aliquot storage volume has a significant impact on the measured concentration of Aβ1-42. The introduction of a buffer detergent at the initial aliquoting stage may be an effective solution to this problem.

Introduction POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes) syndrome is a rare multi-system disorder characterised by a monoclonal plasma cell disorder and peripheral neuropathy in combination with a myriad of other clinical features. Several patient cohorts have previously been described leading to the formulation of diagnostic criteria. For the purposes of establishing a specialist centre in the United Kingdom we collected data of our patient cohort and compared it with previous reports. Methods Demographic data for patients currently known to our clinic with an established diagnosis of POEMS (n=52) was extracted from an already existing database. Clinic letters for these patients were retrospectively screened for clinical features, diagnostic criteria, treatments given and response to treatment, occasionally supplemented by review of historical investigation results. The data was collected in a newly established database designed to facilitate future prospective data collection. Results Our cohort currently consists of 52 patients from a mixed ethnic background, with a male to female ratio of 4.2:1 (n=42 vs 10 respectively) and a median age of 57; median age at diagnosis was 49. The majority of patients were referred to our centre from across the United Kingdom between 2009 and 2015. The prevalence of diagnostic criteria broadly resembles previously published cohorts (see table). 17 patients received radiotherapy for limited disease while 31 patients underwent autologous haematopoietic stem cell transplant (ASCT); 18 patients received at least one line of systemic chemotherapy. A subgroup review of patients who underwent ASCT showed sustained clinical improvements in 83% of patients reviewed; 61% of patients who received radiotherapy had a documented sustained improvement. Patients receiving chemotherapy showed a more variable response; of note, 4 out of 6 patients treated with a combination of lenalidomide and dexamethasone were documented to have had significant clinical improvement. 3 patients died during the period of follow-up at the ages of 70, 63 and 63, respectively. Death occurred between 4 and 15 months following diagnosis; none of the deceased patients underwent ASCT or radiotherapy. Discussion We report the basic demographic and clinical outcomes of a new cohort of patients with this rare condition. Our cohort broadly resembles other previously published reports, as does our experience with therapeutic options. Radiotherapy appears to be effective in stabilising or improving limited disease confined to a solitary plasmacytoma or few lytic foci, while autologous stem cell transplantation achieves sustained improvement in the majority of patients with more diffuse disease. Chemotherapy offers further treatment options for patients not suitable for either of those, with lenalidomide becoming an increasingly promising agent. Retrospective data collection and the establishment of a database for prospective study will enable us to further investigate this group with a view to expand our understanding of this poorly understood disease. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Objectives Regular intravenous immunoglobulin (IVIg) is commonly used for autoimmune neurological conditions. In our hospital, 388 patients received 203,571 grams of IVIg in 2014/15 amounting to 3127 patient-days. Given potential side effects, cost and impact to patients, we reconfigured our service to improve clinical assessment prior to IVIg administration and reduce waiting times. Methods We mapped a typical patient journey and minimised processes that did not add value. Through workshops with juniors, consultants, nurses, managers and pharmacists we identified drivers for delays and suboptimal assessments, and raised awareness of the issue. Finally, we trialed a clerking proforma with prompts for risk factors and a junior doctor-led ‘2-Step IVIG clinic’ for IVIg day admissions. Results We audited 62 patients over 12 weeks. Following our interventions, mean waiting time from arrival to IVIg administration was reduced from 71.2 (median 55, IQR 5–160) to 20.7 minutes (median 20, IQR 5–30). Pre-IVIG clinical assessment was also improved with 100% of patients assessed for thromboembolism (from 45.5%), infection (from 90.9%) and comorbidities (from 72.7%). Conclusion Our project highlights the importance of a multidisciplinary approach, allowing us to implement significant changes in the unit9s structure, reduce unnecessary waiting times and ensure safe administration of IVIg.

Sensory ganglionopathies are uncommon but potentially very disabling. They have heterogeneous etiologies including autoimmune, paraneoplastic, toxic, and inflammatory although many remain idiopathic despite intensive investigation. Asymmetric sensory loss is relatively common at the onset, but with time, symptoms usually spread to involve all limbs symmetrically.We report 6 patients with a persistent strikingly asymmetrical sensory ganglionopathy with acute or subacute onset and slow progression.Peripheral nerve biopsies in 5 patients showed axonal loss without significant inflammation; a dorsal root ganglion biopsy in 1 patient showed neuronal loss and inflammatory infiltrate. Four patients received immunomodulatory treatment, but overall the response to treatment was poor.Asymmetrical sensory ganglionopathies may have an inflammatory basis. Immunomodulatory therapy may be considered early in the disease course, although in this series there was a limited response to treatment.

Proximal axonotmesis results in the release of neurofilament (Nf) proteins into the cerebrospinal fluid (CSF) in patients with Guillain-Barré syndrome (GBS). High CSF levels of the phosphorylated form of Nf-heavy chain (NfH(SMI35) ) at GBS onset have been reported to be a poor prognostic marker, but routine measurement of CSF NfH(SMI35) levels has not been done and the longitudinal profile of CSF NfH(SMI35) levels in GBS is not known.This prospective case series describes the clinical, neurophysiological, and biomarker characteristics of 3 patients with severe GBS.High and increasing levels of CSF NfH(SMI35) in serial CSF samples were associated with poor clinical and electrophysiological outcome.These data further suggest that CSF NfH(SMI35) could be a prognostic biomarker which might indicate the development of retrograde axonal degeneration or additional proximal axonal damage during the course of GBS.

Background Tremor is known to occur in patients with neuropathies although its reported prevalence varies widely. Tremor has been shown to cause disability in children with Charcot–Marie–Tooth disease but no data exit about the disability caused by tremor in inflammatory neuropathies. Little is known about the response of neuropathic tremor to treatment and why it selectively occurs in some people and not others. Methods This case control study investigates the presence and severity of tremor in 43 consecutively recruited patients with inflammatory neuropathies at the National Hospital for Neurology and Neurosurgery, London. Clinical assessment, including Fahn–Tolosa–Marin Scale for tremor, sensory scores, power scores and Overall Neuropathy Limitations Scale, were recorded. Results of nerve conduction studies were retrieved and assessed. Nine patients9 tremors were recorded with accelerometry. Results Tremor was most common in IgM paraproteinaemic neuropathies, as previously reported, but also occurred in 58% of those with chronic inflammatory demyelinating polyradiculoneuropathy and 56% of those with multifocal motor neuropathy with conduction block. We describe, for the first time, tremor in the majority of patients with multifocal motor neuropathy with conduction block. Tremor in all of these patients seems generally refractory to treatment except in a small number of cases where tremor improves with treatment of the underlying neuropathy. We provide evidence that tremor may add to disability in patients with inflammatory neuropathy. Mean tremor frequency was 6 Hz and did not vary with weight loading. We demonstrate for the first time that although tremor severity correlates with F wave latency, it is not sufficient to distinguish those with, from those without, tremor. Conclusion Tremor in inflammatory neuropathies is common, adds to disability and yet does not often respond to treatment of the underlying neuropathy. When present, tremor severity is associated with F wave latency.

Objective: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6 , encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8 , might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN). Methods: A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function. Results: Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme. Conclusions: We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.

Background Serum monoclonal anti-myelin-associated glycoprotein (anti-MAG) antibodies may be pathogenic in some people with immunoglobulin M (IgM) paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. This is an update of a review first published in 2003 and previously updated in 2006 and 2012. Objectives To assess the effects of immunotherapy for IgM anti-MAG paraprotein-associated demyelinating peripheral neuropathy. Search methods On 1 February 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials (RCTs). We also checked trials registers and bibliographies, and contacted authors and experts in the field. Selection criteria We included randomised controlled trials (RCTs) or quasi-RCTs involving participants of any age treated with any type of immunotherapy for anti-MAG antibody-associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity. Our primary outcome measures were numbers of participants improved in disability assessed with either or both of the Neuropathy Impairment Scale (NIS) or the modified Rankin Scale (mRS) at six months after randomisation. Secondary outcome measures were: mean improvement in disability, assessed with either the NIS or the mRS, 12 months after randomisation; change in impairment as measured by improvement in the 10-metre walk time, change in a validated linear disability measure such as the Rasch-built Overall Disability Scale (R-ODS) at six and 12 months after randomisation, change in subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; change in serum IgM paraprotein concentration or anti-MAG antibody titre at six months after randomisation; and adverse effects of treatments. Data collection and analysis We followed standard methodological procedures expected by Cochrane. Main results We identified eight eligible trials (236 participants), which tested intravenous immunoglobulin (IVIg), interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Two trials of IVIg (22 and 11 participants, including 20 with antibodies against MAG), had comparable interventions and outcomes, but both were short-term trials. We also included two trials of rituximab with comparable interventions and outcomes. There were very few clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial and more responsive outcomes are being developed. A well-performed trial of IVIg, which was at low risk of bias, showed a statistical benefit in terms of improvement in mRS at two weeks and 10-metre walk time at four weeks, but these short-term outcomes are of questionable clinical significance. Cyclophosphamide failed to show any benefit in the single trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. Two trials of rituximab (80 participants) have been published, one of which (26 participants) was at high risk of bias. In the meta-analysis, although the data are of low quality, rituximab is beneficial in improving disability scales (Inflammatory Neuropathy Cause and Treatment (INCAT) improved at eight to 12 months (risk ratio (RR) 3.51, 95% confidence interval (CI) 1.30 to 9.45; 73 participants)) and significantly more participants improve in the global impression of change score (RR 1.86, 95% CI 1.27 to 2.71; 70 participants). Other measures did not improve significantly, but wide CIs do not preclude some effect. Reported adverse effects of rituximab were few, and mostly minor. There were few serious adverse events in the other trials. Authors' conclusions There is inadequate reliable evidence from trials of immunotherapies in anti-MAG paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. IVIg has a statistically but probably not clinically significant benefit in the short term. The meta-analysis of two trials of rituximab provides, however, low-quality evidence of a benefit from this agent. The conclusions of this meta-analysis await confirmation, as one of the two included studies is of very low quality. We require large well-designed randomised trials of at least 12 months' duration to assess existing or novel therapies, preferably employing unified, consistent, well-designed, responsive, and valid outcome measures.

Schwann cell dedifferentiation following nerve injury is important to permit neural survival and axonal regrowth. Animal studies have shown that the transcription factor c-Jun is upregulated in Schwann cells of injured and pathological nerves where it acts as an important regulator of Schwann cell plasticity, promoting dedifferentiation and demyelination. This pilot immunohistochemical study investigates whether c-Jun is also upregulated in human neuropathies. We examined c-Jun expression in normal and diseased human nerves, as well as in dermal myelinated nerve fibres. Our findings show that although as predicted c-Jun is rarely expressed in normal nerves, it is expressed in Schwann cell nuclei of pathological nerves as predicted by animal studies. Pathological dermal myelinated nerve fibres also show clear nuclear c-Jun expression. Further studies of c-Jun expression will help clarify its role in human neuropathies.

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

A 68 year old man was referred for assessment of a painful right leg. The symptoms had started three years previously with intermittent pain on the lateral aspect of the right calf. The pain had gradually become more persistent and spread to the sole of the foot, the back of the leg, and the buttock. Within six months the painful area had become numb, and within one year he noticed onset of right leg weakness, which was progressive. The pain was severe, worse when lying down, and he required considerable doses of opiates, which did not fully relieve the pain. He had longstanding constipation, but no recent change in bladder or sexual function. He had a history of Gleason grade 3+3 prostatic carcinoma, for which he had undergone radical prostatectomy four years earlier. This had been followed by radiotherapy to the prostate bed, and he was being treated with ongoing goserelin injections. His prostate specific antigen level was 8.17 µg/L when first seen; however, when repeated it was 3.14 µg/L. He also had a history of well controlled non-insulin dependent diabetes and hypertension. On examination the patient was in pain. He had wasting of the right gluteus maximus and hamstrings, without fasciculations. Tone was normal. Hip flexion and knee extension power was Medical Research Council grade 5/5; however, there was weakness of hip extension to 4/5, knee flexion to 3/5, and ankle dorsiflexion and plantarflexion to 0/5. Reflexes were initially absent in the right leg with reinforcement; however, when the patient’s pain was under better control the knee jerk was present but ankle jerk remained absent. He had sensory loss to pinprick in the distribution of L5 to S3 dermatomes on the right, whereas perianal sensation was intact (S4 and S5). There was impaired proprioception and vibration sense to the …

Keywords: bone marrow pathology; Waldenstrom macroglobulinaemia; monoclonal gammopathy of undetermined significance

Summary Background Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. Methods Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. Findings We identified 203 patients with encephalitis. Median age was 30 years (range 0–87). 86 patients (42%, 95% CI 35–49) had infectious causes, including 38 (19%, 14–25) herpes simplex virus, ten (5%, 2–9) varicella zoster virus, and ten (5%, 2–9) Mycobacterium tuberculosis ; 75 (37%, 30–44) had unknown causes. 42 patients (21%, 15–27) had acute immune-mediated encephalitis. 24 patients (12%, 8–17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7–65) and varicella zoster virus (two patients; 20%, 2–56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups—nine (56%, 30–80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR=3·44). Interpretation Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. Funding The Policy Research Programme, Department of Health, UK.

­­Copper deficiency often goes undiagnosed Patients presenting with a neurological syndrome typical of B-12 deficiency may actually be manifesting symptoms of copper deficiency, as has been recognised over the past decade.1 Most commonly, they have a progressive spinal cord syndrome resulting in poor balance due to loss of proprioception. The cases we report show that copper deficiency, which has various causes, is more common than previously realised and often goes undiagnosed. Increased awareness of this condition is vital because early diagnosis and treatment can prevent severe disability. A 65 year old man presented in 2006, having fallen in the shower on closing his eyes; he had burning and tightness affecting his feet and had recently lost weight. Over six months he became bedbound due to poor balance. He had undergone partial gastrectomy in 1973 for a duodenal ulcer. Three years before the neurological symptoms developed, he was diagnosed with asymptomatic B-12 deficiency, which was successfully treated. Initial examination showed a positive Romberg test and an inability to walk heel-to-toe. Cranial nerve examination was unremarkable. Tone and power were normal, ankle jerks were depressed, and one plantar reflex was extensor. Over six months he developed spastic weakness in his legs (hip flexion MRC grade 4), hyper-reflexia, and bilateral extensor plantar reflexes. Sensory disturbance suggested greater abnormality in the posterior columns; vibration sense was reduced to the costal margins, proprioception to the ankle, and pinprick to mid-foot level. Magnetic resonance imaging showed T2 signal abnormality in the posterior cervical cord at C2-4 (figure ⇓). Electrophysiology found lower limb motor abnormalities consistent with a motor neuronopathy, but sensory nerve action potentials were normal. Central motor conduction to the limbs (a method for examining the central motor pathways, in which the difference between the latency of motor evoked potentials …

SUMMARYDefining the causal relationship between a microbe and encephalitis is complex. Over 100 different infectious agents may cause encephalitis, often as one of the rarer manifestations of infection. The gold-standard techniques to detect causative infectious agents in encephalitis in life depend on the study of brain biopsy material; however, in most cases this is not possible. We present the UK perspective on aetiological case definitions for acute encephalitis and extend them to include immune-mediated causes. Expert opinion was primarily used and was supplemented by literature-based methods. Wide usage of these definitions will facilitate comparison between studies and result in a better understanding of the causes of this devastating condition. They provide a framework for regular review and updating as the knowledge base increases both clinically and through improvements in diagnostic methods. The importance of new and emerging pathogens as causes of encephalitis can be assessed against the principles laid out here.

Toxoplasmosis in immune competent patients usually causes asymptomatic infection or mild symptoms, while in immunocompromised and AIDS patients it can be a life threatening condition. We report a case of cerebral toxoplasmosis in a patient with AIDS and review the causes of brain ring enhancing lesions.

Background Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. Objectives To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain. Search strategy We searched The Cochrane Neuromuscular Group Specialized Register (10 March 2009), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2009), MEDLINE (January 1966 to March 2009), EMBASE (January 1980 to March 2009), and www.clinicaltrials.gov to March 2009 and the reference lists of identified publications for trials of duloxetine used for the treatment of painful peripheral neuropathy or chronic pain. Selection criteria We selected all randomised or quasi-randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adult participants. Data collection and analysis Two authors extracted data independently onto a specially designed proforma and cross checked them. Main results Six trials were identified including 2220 participants. Three studies included participants with painful diabetic neuropathy and three treated participants with fibromyalgia. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short-term to 12 weeks with a risk ratio (RR) for 50% pain reduction at 12 weeks of 1.65 (95% confidence interval (CI) 1.34 to 2.03), number needed to treat (NNT) 6 (95% CI 5 to 10). Duloxetine at 60 mg daily is also effective in fibromyalgia over 12 weeks (RR 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNT 8, 95% CI 5 to 17) and 28 weeks (RR 1.58, 95% CI 1.10 to 2.27). Adverse events were common in both treatment and placebo arms but more common in the treatment arm with a dose dependent effect. Most side effects were minor, but 16% of participants stopped the drug due to side effects. Serious adverse events were rare. Authors' conclusions There is moderately strong evidence that duloxetine 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy and fibromyalgia but 20 mg daily is not. Minor side effects are common at therapeutic doses but serious side effects are rare. Direct comparisons of duloxetine with other antidepressants and with other drugs already shown to be efficacious in neuropathic pain would be appropriate and should include unbiased economic analyses.

The inflammatory neuropathies are a large diverse group of immune-mediated neuropathies that are amenable to treatment and may be reversible. Their accurate diagnosis is essential for informing the patient of the likely course and prognosis of the disease, informing the treating physician of the appropriate therapy and informing the scientific community of the results of well-targeted, designed and performed clinical trials. With the advent of biological therapies able to manipulate the immune response more specifically, an understanding of the pathogenesis of these conditions is increasingly important. This review presents a broad overview of the pathogenesis, diagnosis and therapy of inflammatory neuropathies, concentrating on the most commonly encountered conditions.

We report a case of tuberculous myeloradiculitis in a patient with AIDS. The case highlights the difficulty in reaching a diagnosis for the neurological symptoms of a patient with a normal CSF examination and the need for HIV screening of immune-compromised patients with myeloradiculitis.

A patient with primary B cell non-Hodgkin's lymphoma of the sciatic nerve is described. He presented with neuropathic symptoms in the left leg, initially diagnosed as tarsal tunnel syndrome. Magnetic resonance imaging (MRI) identified the abnormality in the sciatic nerve. A fascicular biopsy of the sciatic nerve showed a diffuse large B cell non-Hodgkin's lymphoma. The patient was treated with chemotherapy and rituximab (anti-CD20 monoclonal antibody). Four months later he was in remission, and remains so 48 months from presentation. Primary lymphoma of single peripheral nerves may be a unique subtype of extranodal lymphoma, which usually follows an aggressive course and has a variable response to current therapeutic strategies. MRI is useful, alongside electrophysiological studies, in patients with atypical peripheral nerve symptoms.