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Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive disease that manifests with multiorgan presentation characterized by gastrointestinal, extraocular, and both peripheral and central nervous system involvement. MNGIE is caused by mutation in the TYMP (thymidine phosphorylase) gene, resulting in loss of thymidine phosphorylase enzyme activity. This causes its substrates, thymidine and deoxyuridine, to accumulate in tissues and plasma, while also causing secondary alterations in mitochondrial DNA. To date, more than 80 mutations have been reported in this gene. We present herein the clinical, neuroimaging, electrodiagnostic, and molecular findings of a patient with MNGIE caused by a novel homozygous missense mutation (C1175T > G) of the TYMP gene.

Immunoglobulin (Ig) therapy is a first-line treatment for CIDP, which can be administered intravenously (IVIg) or subcutaneously (SCIg) and is often required long term. The differences between these modes of administration and how they can affect dosing strategies and treatment optimization need to be understood. In general, the efficacy of IVIg and SCIg appear comparable in CIDP, but SCIg may offer some safety and quality of life advantages to some patients. The differences in pharmacokinetic (PK) profile and infusion regimens account for many of the differences between IVIg and SCIg. IVIg is administered as a large bolus every 3–4 weeks resulting in cyclic fluctuations in Ig concentration that have been linked to systemic adverse events (AEs) (potentially caused by high Ig levels) and end of dose “wear-off” effects (potentially caused by low Ig concentration). SCIg is administered as a smaller weekly, or twice weekly, volume resulting in near steady-state Ig levels that have been linked to continuously maintained function and reduced systemic AEs, but an increase in local reactions at the infusion site. The reduced frequency of systemic AEs observed with SCIg is likely related to the avoidance of high Ig concentrations. Some small studies in immune-mediated neuropathies have focused on serum Ig data to evaluate its potential use as a biomarker to aid clinical decision-making. Analyzing dose data may help understand how establishing and monitoring patients' Ig concentration could aid dose optimization and the transition from IVIg to SCIg therapy.

Reducing body myopathy (RBM) is a rare muscle disorder, with marked presence of characteristic intracytoplasmic aggregates in affected muscle fibers. RBM is associated with FHL1 gene mutations. Clinical presentations of RBM have ranged from early fatal to adult onset progressive muscle weakness. We present herein the clinical, electrodiagnostic, and muscle biopsy findings of a 17-year-old female with progressive muscle weakness and contracture. Muscle biopsy showed atrophic fibers that contained menadione nitroblue tetrazolium (NBT) positive reducing bodies. Genetic testing revealed a variant of uncertain significance in the FHL1 gene at a position known to be pathogenic when substituted by other amino acids (p.His123Arg). This variant was later reclassified as pathogenic.

Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post‐hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo‐controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non‐deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Summary Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding National Institutes of Health, National Institute of Neurological Disorders and Stroke.

PATH study group., In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre‐randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow‐up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post‐study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal., Editorial support was provided by Meridian HealthComms Ltd, funded by CSL Behring.

Mika Saarela työryhmän jäsenenä. Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1: 1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials. gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP.

Background Neuropathy is a rare adverse side effect of disulfiram therapy and is under-recognized. There have been few case reports documenting this side effect. Case presentation Two cases of disulfiram peripheral neuropathy are discussed. The first case is that of a 25-year-old Caucasian woman who was exposed to disulfiram therapy for a total of 8 months and developed pain and stiffness that prevented her from walking. The second case is that of a 46-year-old Caucasian woman who developed sudden-onset numbness in her lower extremities with progression to pain. Her symptoms improved over the course of 2 months after cessation of disulfiram therapy. In both cases, symptoms improved after cessation of disulfiram therapy. Conclusions Disulfiram neuropathy occurs in persons with a history of chronic alcohol use. It is under-recognized and often attributed to alcoholic neuropathy given its comorbidity with alcoholic neuropathy. A greater understanding of this side effect may reduce neurologic complications related to disulfiram neuropathy and aid in early withdrawal of this offending agent.

Objectives Chronic inflammatory demyelinating polyradiculoneuropathy is a treatable neuropathy that is challenging to diagnose and has a broad spectrum of presentations. We report the clinical, electrodiagnostic, and radiographic presentations in three patients whose workup revealed hypertrophic nerve roots. Methods We retrospectively reviewed the clinical, electrodiagnostic, and imaging data for patients diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy over a 3-year period. Results All patients had features of proximal and distal neuropathy with progressive or recurrent courses. Diagnosis and management were significantly altered by the concomitant clinical findings and/or radiographic findings. Conclusions Our cases highlight the use of magnetic resonance imaging to evaluate for nerve root hypertrophy as an additional tool to electrodiagnostic testing in the setting of refractory or atypical neuropathy condition. Awareness of the radiographic features will assist in confirmation of the diagnosis, institution of the appropriate therapy, and prevention of inadequate or delay of treatment.

Introduction Bilateral phrenic neuropathy is an uncommon complication of diabetes mellitus. Case presentation We present a patient with diabetes mellitus who developed dyspnea from diaphragmatic paresis secondary to bilateral phrenic neuropathies on the background of subclinical generalized polyneuropathy documented by electrodiagnostic studies. The patient was treated with intravenous immunoglobulin with improved diaphragmatic function. Conclusion Phrenic neuropathy is a rare but important complication of diabetes mellitus. We report the first case of the beneficial use of intravenous immunoglobulin in diabetic phrenic neuropathy.

INTRODUCTION Delayed progressive cervicobulbar palsy with secondary lingual, facial, and neck myokymia after radiation therapy to the head and neck is a known but rare event with few reported case descriptions. CASE PRESENTATION We report a case with a video description of a young Asian woman who developed progressive dysarthria and dysphagia after approximately 1 year after radiation treatment for nasopharyngeal carcinoma. Her symptoms, clinical, and electromyographic findings are discussed and were felt to be secondary to a cervicobulbar neuronopathy secondary to the previous radiation she received. A brief literature review was performed and pathophysiological mechanisms and treatment options are discussed. CONCLUSION Delayed progressive cervicobulbar neuronopathy with myokymia is an uncommon complication of radiotherapy for nasopharyngeal carcinoma. Clinicians should be aware of this entity to prevent misdiagnosis with other neuromuscular and nonneuromuscular diseases.

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

POEMS is a rare syndrome characterized by the unique constellation of polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes. Correct diagnosis is often delayed in early stages of the syndrome when patients exhibit only isolated polyneuropathy due to the clinical and electrodiagnostic similarities with chronic inflammatory demyelinating polyneuropathy. We describe a case in which early suspicion for POEMS uncovered underlying malignancy, and we review the clinical, electrophysiological, pathological, and laboratory findings characteristic of POEMS. The importance of high clinical suspicion is key in the proper diagnosis and management of this complex syndrome.

Autosomal-dominant transthyretin (TTR)-related amyloidosis usually manifests in the third to fifth decade with a length-dependent axonal neuropathy and prominent involvement of the small diameter nerve fibers.Objectives:To describe the clinical and para-clinical findings in patients with hereditary transthyretin amyloidosis (hATTR), formerly known as transthyretin-related familial amyloid polyneuropathy (TTR-FAP).Methods:Electrodiagnostic, cerebrospinal fluid (CSF), and TTR gene findings in two patients misdiagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP).Results:A 78-year-old, right-handed, Caucasian male (patient 1) and a 69-year-old, right-handed, Japanese male (patient 2) were referred for late-onset sensory symptoms of the hands and feet as initial manifestations. The first patient, after several years, developed progressive leg weakness affecting his gait and balance, as well as dysautonomic complaints. The second patient had relatively rapid progression with bilateral foot drop and ambulation difficulty after a few months. In both patients, CSF findings were unremarkable. Lumbar spine magnetic resonance imaging did not reveal abnormal thickening or enhancement of the lumbar plexus and exiting nerve roots. Both patients were initially diagnosed with CIDP before being referred to our institution. Patient 2 was started on intravenous immunoglobulin by his primary neurologist, which was maintained for a year without a meaningful response. Repeat electrodiagnostic study at our institution revealed non-length-dependent axonal sensory loss and features of acquired demyelinating neuropathy. TTR gene testing identified pathogenic variants p.Val30Met or V30M, and p.Ala 117Ser or A117S, in the first and the second patient, respectively.Conclusion:hATTR can mimic CIDP clinically and electrodiagnostically. The presence of significant sensory axonal loss, rapid course, and lack of response to immunomodulation therapy should prompt consideration of this diagnosis and TTR gene testing.

Background – Painful diabetic neuropathy is a common complication of diabetes and often resistant to treatment with standard analgesics. Treatment of diabetic neuropathy with antiepileptic drugs may provide pain relief. Aim –To evaluate the long-term safety and tolerability of oxcarbazepine in two studies investigating the treatment of diabetic neuropathy. Objectives – Patients with diabetes and a history of neuropathic pain were included. Study 1 was a multicenter, open-label study comprising a screening and 12-month treatment phase. Study 2 was a multicenter, open-label extension to a double-blind, randomized study. Oxcarbazepine was initiated at 300 mg/day and titrated over 4 weeks to tolerability or a maximum dose of 900 mg b.i.d. Safety was assessed by monitoring adverse events (AEs), serious AEs (SAEs), hematology, blood chemistry, urinalysis values, and vital signs. Results – Adverse events were most frequently reported in the nervous and gastrointestinal systems; 20.5% and 21.6% of patients withdrew because of AEs in study 1 and study 2, respectively. SAEs were reported in 13.7% and 14.4% of patients in study 1 and study 2, respectively. Conclusions – Long-term treatment with oxcarbazepine is generally well tolerated in patients with painful diabetic neuropathy. Rapid titration of oxcarbazepine may be responsible for discontinuations resulting from AEs during early stages of treatment.

Neuromuscular Division, Keck School of Medicine, University of Southern California, Los Angeles, CA, US

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), which is caused by demyelination of the peripheral nerves, is characterized by progressive weakness and impaired sensory function in the arms and legs. CIDP is a treatable condition in which early diagnosis is crucial to limit chronic disability. CIDP can mimic other neuropathies and it is important to identify these in order to ensure prompt treatment. Patients with other causes of neuropathy should be suspected of having CIDP if there is rapid progress or proximal weakness. Intravenous immunoglobulin (IVIG), corticosteroids, and plasma exchange are first-line therapies. The IVIG CIDP Efficacy (ICE) trial, the largest trial reported of any CIDP treatment, demonstrated that IVIG therapy reduced disability and functional impairment, as well as improved quality of life. Autoantibodies against membrane proteins of the peripheral nerve axons or the myelin sheath have been reported recently, and an improved understanding of antibody responses in CIDP may enable the development of future targeted therapeutic interventions.

Multifocal motor neuropathy (MMN) is a disorder of peripheral nerve often associated with a high monosialoganglioside (GM1) antibody and multifocal conduction block. It has a chronic, indolent course with involvement of predominantly peripheral motor nerves, usually in an asymmetric fashion. There have been few reported cases of progression to frank quadriplegia. Secondary amyloidosis refers to the deposition of amyloid in various tissues due to an underlying chronic inflammatory state. We report the first case, to our knowledge, of a patient with MMN associated with high titer of GM1 antibody who developed acute paraplegia with both cranial nerve and worsening sensory involvement associated with multiorgan compromise due to a secondary amyloidosis involving the myocardium.

Diaphragmatic paralysis has previously been reported as a result of diverse pathologic processes involving the peripheral nervous system. We report the clinical history, physical findings, and antibody profile of an atypical case of multifocal motor neuropathy with conduction block initially presenting with respiratory failure secondary to bilateral phrenic neuropathy.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited autosomal dominant disorder that causes a polyneuropathy with predisposition for involvement at sites of compression and is often underdiagnosed or misdiagnosed due to its heterogeneity in clinical and electrophysiological presentation. We report 2 cases of HNPP, which were initially diagnosed and treated as either an acquired demyelinating disorder or alternative inherited demyelinating disorder. Thorough evaluation of repeat electrodiagnostic studies and genetic testing confirmed the diagnosis of HNPP in both cases. One case showed the classic peripheral myelin protein 22 (PMP22) deletion and the other case showed a previously reported single base pair deletion at Leu145 causing a frameshift mutation at the PMP22 gene. These cases underscore the difficulty of diagnosing HNPP, because of the variations in clinical and electrophysiological findings and reinforce the importance of a combination high index of clinical suspicion, electrodiagnostic testing, and genetic testing to make the diagnosis.

The objective of this chapter is to review the pathophysiology and treatment approach in various chronic pain conditions, such as neuropathic pain and other chronic musculoskeletal pain conditions. Postherpetic neuralgia will be used as a model of neuropathic pain. Discussion on fibromyalgia as a model of pain amplification and other musculoskeletal conditions will be included. Pharmacologic management will include an overview of approved medications and other agents proven to be effective based on consensus expert opinion and validated clinical trials.

Intravenous immunoglobulin (IVIG) has become the standard treatment for multifocal motor neuropathy (MMN) based on limited data. To critically assess the efficacy, safety, and tolerability of 10% liquid IVIG (IVIG), 44 adults with MMN were randomized 1 : 1 to either double-blind treatment of IVIG followed by placebo for 12 weeks each or the reverse. Open-label IVIG was administered for 12 weeks at the beginning and end of the study for clinical stabilization, and between double-blinded periods to prevent a carry-over effect. To avoid potential worsening, switching to open-label IVIG was permitted if deterioration occurred during blinded treatment. Mean maximal grip strength of the more affected hand declined 31.38% during placebo and increased 3.75% during IVIG (p = 0.005). In 35.7% of participants, Guy's Neurological Disability scores for upper limbs worsened during placebo and not during IVIG, whereas the converse was true in 11.9% (p = 0.021). Sixty-nine percent (69.0%) switched prematurely from placebo to open-label IVIG and 2.4% switched from blinded to open-label IVIG (p

Multifocal motor neuropathy (MMN) is a rare, treatable neuropathy, but good long-term outcomes are dependent on early treatment. Appropriate diagnostic criteria exist for MMN, but it has a heterogeneous clinical presentation, and, when confined to a small group of nerves, its clinical presentation can overlap with entrapment neuropathies. Electrodiagnosis is a useful diagnostic technique but occasionally MMN can be misdiagnosed as entrapment neuropathies. Misdiagnosis should rarely occur since the nerve involvement in MMN is usually not at sites of common nerve entrapment, and the impact of misdiagnosis can be substantial. The treatments of these conditions differ significantly: intravenous immunoglobulin is the standard therapy for MMN, while treatment options for entrapment neuropathies include conservative treatment, such as splinting, corticosteroids, or surgery. Such treatment in MMN may worsen symptoms, potentially leading to progressive motor symptoms, including muscle weakness, atrophy, and significant motor disability. Two exemplary cases are presented, which highlight the importance of differential diagnosis of these conditions. Emerging technologies, such as high-resolution sonography and magnetic resonance neurography, will aid in defining future diagnostic criteria of MMN.

Myelopathy is a common neurologic finding and presentations may vary widely. Depending on the etiology underlying the myelopathy, treatment may be surgical, medical, or supportive. In this paper, we present three cases of myelopathy due to three different etiologies and pathogeneses. All three cases initially presented with gait disturbance, and the ensuing workup revealed rare diagnoses in two out of the three cases. These three diagnoses differ in etiology and highlight the need for a close and thorough examination and workup to arrive at the correct diagnosis, which in turn leads to appropriate treatment.

A 39-year-old woman with nasopharyngeal carcinoma underwent partial resection along with head and neck radiation therapy. Approximately 10 months later she developed …

Objectives – Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited disorder resulting in a polyneuropathy with particular involvement at sites of entrapment, and is often underdiagnosed or misdiagnosed. We report findings on seven patients referred for evaluation of focal mononeuropathies or polyneuropathies of undetermined etiology, in whom we established a diagnosis of HNPP. Materials and methods – We retrospectively reviewed clinical, electrophysiological and laboratory data for patients diagnosed with HNPP over a 4-year period at our institution. Results – All patients had transient or recurrent neurological symptoms, some with residual deficits. No patients had a family history of any neuropathy. Electrodiagnostic studies revealed abnormal conduction findings at symptomatic and asymptomatic sites. Testing for the Peripheral Myelin Protein (PMP22) deletion was positive in all patients. Conclusions – A high index of clinical suspicion and thorough electrodiagnostic evaluation can lead to correct diagnosis of HNPP, despite the absence of a positive family history.

We describe a 58-year-old male with a few years history of multifocal weakness in the upper limbs with minimal to absent sensory complaints. He was diagnosed as having multiple compressive neuropathies, which required repeated decompressive surgeries. Electrodiagnostic studies prior to diagnosis were limited to a few nerves, evaluating only distal segments. Because of delay in making the diagnosis, his condition progressed, and possibly because of the unnecessary surgeries, he developed atrophy in some muscles, which resulted in significant motor disability. He was later diagnosed as having multifocal motor neuropathy with conduction block and has partially responded to intravenous immunoglobulin therapy.

tube irritation during daily activities such as suction, transfer. Patient 2 showed reflex cough and abnormal posturing due to tube irritation. They underwent granulation removal and stomaplasty for making permanent tracheostoma after 60, 22, 12 months of the first conventional tracheostomy. Setting: Tertiary care hospital Results or Clinical Course: For all three patients, no early and late complications occurred, and airway patency was well maintained. Frequency of suction, sudden spasticity increase, reflex cough were reduced, and airway hygiene was improved after the permanent tracheostoma. All three caregivers reported the reduced difficulty and anxiety and also their satisfaction after the procedure. Discussion: Permanent tracheostoma establishes a short, skinlined, noncollapsing, nonstenosing, self-sustaining passage between the trachea and the external environment, and is not supported by a tube, vent, or stent. The benefit of this tube-free, permanent tracheostoma is that the patients are free of risk for complication caused by tracheostomy tube itself, such as tube displacement, tube obstruction, granuloma, tracheal stenosis. This method is a useful alternative way to make long-term ventilatory bypass without tuberelated complications in the chronic disease such as obstructive sleep apnea, bilateral vocal cord paralysis, laryngotracheal stenosis, chronic pulmonary disease, laryngeal cancer. It is the first report of successful permanent tracheostoma in chronic brain injured patients with long-term tracheostomy, who had cognitive deficit, and weakness of four extremities, and poor head and neck control due to their quadriplegic status. Conclusions: Permanent tracheostoma can be considered a useful alternative way for chronic brain injured patients with long-term tracheostomy.

Abstract 4964 POEMS syndrome is characterized by chronic progressive polyneuropathy (P), organomegaly (O), endocrinopathy (E), serum monoclonal protein (M), and skin changes (S). The bone lesions are typically sclerotic and may be minor in number or aymptomatic. Autologous peripheral blood stem cell transplant (APBSCT) has been reported to reverse major clinical manifestations of this disease. The peripheral neuropathy is often motor and sensory, painful in many cases, and asymmetric in distribution, and is often the major disease manifestation that affects patient performance status, and requires treatment. We report a patient case of POEMS where polyneuropathy was debilitating, confirmed by nerve conduction studies (NCS) with rapid clinical improvement on lenolidomide treatment and objective reversal of findings on NCS. The patient is a 54 year old man who developed slight leg weakness while exercising, and progressive severe lower back pain radiating down his right leg more than left. Plain X-ray showed an abnormality of the T4 and L3 vertebrae, and MRI showed a hypodense abnormality of the T3 vertebra and sclerotic area at the L2-3 vertebra. CT guided biopsy of these lesions showed plasma cells staining positive for CD 138 ; karyotype on the biopsy lesion was negative. The skeletal X-ray series was negative other than T4 and L3. Bone marrow biopsy showed no increase in plasma cells. Body CT showed multiple sclerotic lesions at the bodies of the pubis bones, left ischial tuberosity, femoral heads (left more than right), right sacrum, L3 and T12 vertebral body. PET scan showed uptake in these areas, SUV 3-4.6 The next MRI suggested 2 new sacral lesions and a new T7 lesion. At presentation, he had very remarkable motor and sensory changes in the right leg greater than the left with sensory neuropathy, proprioception and parasthesias. He had dysesthesias, parasthesias and loss of sensation. Nerve conduction studies showed complete loss of motor potentials in the right peroneal and right posterior tibial area and sensory abnormalities in the right sural nerve. He had bilateral foot drop with poor of balance and used a rolling walker, and subjective sensory loss and numbness of the distal extremities with dysthesias and parasthesias. Motor exam of lower extremities notable for 5/5 in the proximal muscles, foot and toe flexion 4/5 bilaterally. Upper extremities and cranial nerves intact except for poor hand grip strength. Laboratory Data SPEP showed small monoclonal IgG lambda band of 0.3 g/dl, immunofixation (urine) showed monoclonal free lambda light chains. Serum free light chains showed a ratio reversal of Lambda 44 to kappa 28. Quantitative immunoglobulins UPEP, CBC and ESR were within normal range. Patient's bone marrow was negative for multiple myeloma and amyloidosis. Lenalidomide was started at 15 mg/day for 21 days of a 28 day cycle with once weekly dexamethasone 40mg. By the second month patient was on therapy, his performance status improved to ECOG 1, with resolution of pain within the first cycle. Repeat nerve conduction studies after 4 cycles of Len/Dex confirmed marked improvement of motor and sensory nerve potentials. Patient underwent APBSCT and had a continued clinical improvement for two years, and was able to return to full time work. Conclusion Lenalidomide is an effective treatment for POEMS syndrome, with rapid and objectively documented improvement in polyneuropathy. As POEMS may be a cytokine-mediated disorder, the immunomodulatory effects of lenolidomide may explain its benefit in these patients. Disclosures Mohrbacher: Celgene: Speakers Bureau. Off Label Use: lenolidomide.

In this multicentre, placebo-controlled, 16-week trial, the efficacy and safety of oxcarbazepine monotherapy in patients with neuropathic pain of diabetic origin was evaluated. Eligible patients had a 6-month to 5-year history of neuropathic pain symptoms of diabetic origin and a pain rating ofor =50 units on the visual analogue scale (VAS). Oxcarbazepine was initiated at a dose of 300 mg/day and titrated to a maximum dose of 1800 mg/day. In total, 146 patients (oxcarbazepine, n=69; placebo, n=77) were randomized. After 16 weeks, oxcarbazepine-treated patients experienced a significantly larger decrease in the average change in VAS score from baseline compared with placebo (-24.3 vs. -14.7 units, respectively; p=0.01). The reduction from baseline in mean VAS score for oxcarbazepine-treated patients was of a greater magnitude than placebo as early as week 2 (-8.0 vs. -4.7; p0.05). A significantly greater proportion of oxcarbazepine-treated patients experienced a50% reduction from baseline in VAS score at the end of treatment compared with placebo (35.2% vs. 18.4%, respectively; p=0.0156; number needed to treat=6.0). Global assessment of therapeutic effect rating was improved in more oxcarbazepine patients than placebo patients (48% vs. 22%, respectively; p=0.0025). Patients on oxcarbazepine were awakened less frequently due to pain than patients on placebo. Most adverse events were mild to moderate in severity, transient, and in line with the known tolerability profile of oxcarbazepine. These observations suggest that oxcarbazepine monotherapy, pending additional trials, may be efficacious and may provide clinically meaningful pain relief in patients with neuropathic pain of diabetic origin.