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Assess how baseline polyneuropathy severity impacts response to patisiran regarding neurologic impairment and quality of life (QOL) in patients with hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis). This post hoc analysis grouped patients from the Phase 3 APOLLO study (n = 225) by baseline Neuropathy Impairment Score (NIS) into quartiles: 6–

Motor neuron diseases involve degeneration of motor neurons in the brain (upper motor neurons), brain stem, and spinal cord (lower motor neurons). Symptoms vary depending on the degree of upper and lower neuron involvement, but progressive painless weakness is the predominant complaint. Motor neuron disease includes numerous specific disorders, including amyotrophic lateral sclerosis, spinal muscular atrophy, spinal bulbar muscular atrophy, and other inherited and acquired conditions. Abnormalities on nerve conduction studies, repetitive nerve stimulation, needle electromyography, and other electrodiagnostic techniques help to distinguish these disorders from each other, and from other disorders with progressive weakness.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...

ObjectiveTo evaluate the relationship between clinical improvement in Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores and the pharmacodynamic effects of IgG autoantibody lowering induced by nipocalimab in the Vivacity MG Phase 2 study.BackgroundNipocalimab is a fully human, aglycosylated, effectorless IgG1 anti-FcRn monoclonal antibody that targets the neonatal Fc receptor (FcRn) with high affinity, thereby lowering IgG pathogenic antibodies in autoimmune disease.Design/MethodsThe relationship between the reduction in acetylcholine-receptor (AChR)- and Muscle-Specific-Tyrosine-Kinase (MuSK)- autoantibodies with improvement in MG-ADL scores were explored across the four nipocalimab dose arms in the Vivacity MG Phase 2 Study in generalized myasthenia gravis (gMG) patients.ResultsOf the 68 patients enrolled, 54 were randomized to one of the four nipocalimab dosing arms. 51 (94%) were seropositive for anti-AChR, 3 (6%) for anti-MuSK. Nipocalimab was well-tolerated and achieved substantial, dose-dependent and rapid reductions in serum total IgG, including all IgG subtypes and anti-AChR autoantibodies. These reductions were associated with dose-dependent, durable and rapid MG-ADL responses in all nipocalimab-treated groups. A similar trend in IgG4 reduction was noted, though the sample size of MuSK positive patients was small.ConclusionsThe results support the rapid, dose-dependent and predictable effect of nipocalimab in lowering pathogenic autoantibodies and inducing clinical improvement in patients with gMG. In addition, the close correlation between serum IgG, anti-AChR and clinical response suggest the potential of using serial serum IgG levels as a biomarker in management of gMG patients treated with nipocalimab; this will be tested in the ongoing Phase 3 gMG trial.

Background Transthyretin amyloid cardiomyopathy results from the accumulation of wild-type (ATTRwt) or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. THAOS (Transthyretin Amyloidosis Outcomes Survey) is a global, longitudinal, observational survey of patients with ATTRv and ATTRwt amyloidosis and asymptomatic patients with transthyretin mutations. Objectives This study explored temporal trends in ATTRwt amyloidosis diagnoses using data from THAOS. Methods Using THAOS data from December 2007 to January 2020, the following comparisons were made according to year: ATTRwt amyloidosis diagnoses in the United States versus rest of the world, ATTRwt versus ATTRv amyloidosis with cardiac-associated mutations diagnoses, and ATTRwt amyloidosis diagnoses by tissue biopsy versus bone scintigraphy. Results There were 1,069 patients with ATTRwt amyloidosis and 525 with ATTRv amyloidosis with cardiac mutations enrolled in THAOS. The median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015–2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011. ATTRv amyloidosis with cardiac mutation diagnoses increased from 3 in 2005 to 37 in 2011, then plateaued. The proportion of patients with ATTRwt amyloidosis diagnosed with New York Heart Association functional class III/IV heart failure decreased from 2012 (46.4%) to 2019 (16.0%). Conclusions In the past decade, ATTRwt amyloidosis diagnoses increased worldwide. Despite the growing utilization of bone scintigraphy, patients are diagnosed several years after symptom onset. (Transthyretin Amyloidosis Outcomes Survey [THAOS]; NCT00628745), Central Illustration

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment. The study was funded by Alnylam Pharmaceuticals, Inc. Medical writing services provided by Kristen Brown (PhD) of Adelphi Communications Ltd, Macclesfeld, UK were funded by Alnylam Pharmaceuticals, Inc. in accordance with Good Publication Practice (GPP3) guidelines. We would like to thank Anastasia McManus (Alnylam Pharmaceuticals, Inc.) for her assistance during preparation of this manuscript. info:eu-repo/semantics/publishedVersion

Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength megascore, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

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INTRODUCTION The utility of repeat muscle biopsy has not been adequately evaluated. METHODS A retrospective review was undertaken of 144 repeat muscle biopsies performed from 1980 to 2017. Repeat biopsy was considered clinically relevant if it provided a new diagnosis, changed the existing diagnosis, or led to treatment changes or further investigations. RESULTS Repeat biopsy was abnormal in 118 cases, different from the initial biopsy in 67 cases, and specific in 40 cases. Factors with a significant effect on clinical relevance of the repeat biopsy (P < 0.05) were an abnormal, specific, or inflammatory initial biopsy, proximal muscle weakness, absence of myalgia, and a repeat biopsy that is different, specific, or consistent with polymyositis or inclusion body myositis. CONCLUSIONS Utility of repeat biopsy was limited to weak patients whose initial biopsy showed inflammatory myositis. Ongoing advances in the diagnosis of immune inflammatory myopathies have led to evolution of the role of repeat biopsy. Muscle Nerve, 2019.

Importance Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment’s sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration ClinicalTrials.gov Identifier:NCT02260388

We present a patient with congenital spinal muscular atrophy associated with pain, subjective sensory loss, right talipes equinovarus, delayed walking, and progressive gait impairment. A sister and niece reportedly had Charcot–Marie–Tooth 1A, but the patient's electromyogram showed an axonal motor neuropathy or neuronopathy. We identified a c.806G>A TRPV4 gene mutation causing an Arg269His amino acid substitution. TRPV4 mutations cause variable phenotypes including axonal sensorimotor neuropathy and motor neuropathy or neuronopathy. Associated features may include arthrogryposis, skeletal dysplasia, vocal cord paresis, sensorineural hearing loss and respiratory weakness. Skeletal X-rays can identify orthopedic causes of pain in patients with TRPV4 mutations, and imaging evidence of bone deformities in patients with suspected hereditary axonal neuropathy, pain and an unknown genetic diagnosis may help lead to a diagnosis of a TRPV4 mutation. Even when a patient's genetic diagnosis is presumed to be known, electrodiagnostic testing is warranted to verify the diagnosis.

Up to 50% of persons with amyotrophic lateral sclerosis (ALS) develop cognitive impairments, particularly of executive function (EF). The Frontal Assessment Battery (FAB) provides a method for rapid assessment of EF. We investigated the FAB as an assessment of cognitive impairment among 16 subjects with ALS, and evaluated their performance on the FAB and the Mini-Mental State Examination (MMSE). Raw FAB and MMSE scores were Z-transformed using published age- and education-based norms. FAB Z-scores were significantly lower than MMSE Z-scores (p

West Nile virus (WNV) is a flavivirus that has been an important cause of neuroinvasive disease during the late summer and early fall in the United States since 1999. In the immunocompetent population, meningoencephalitis occurs in 1:150 individuals infected with WNV. However, in immunocompromised patients, particularly transplant recipients, the incidence of central nervous system disease has been estimated to be as high as 40%, although these calculations are based on relatively small numbers of cases (1). Multiple case reports describing poor outcome in most, but not all, WNV-infected transplant recipients have been published (2–4), likely due to immunosuppressive agents. These drugs act primarily by inhibiting T-lymphocyte function (5, 6). While mechanisms to block cellular rejection have focused on T-cell pathways, B-cell-mediated transplant rejection has more recently been identified (7). Use of rituximab, a monoclonal antibody directed against the B-cell-specific antigen B1 (CD20) (8, 9) is thought to have antihumoral rejection activity and has been employed as a therapeutic in humoral transplant rejection (7). We report a case of a lung transplant recipient who received two courses of rituximab for acute humoral rejection (capillaritis), followed by a rapidly progressive and fatal WNV meningoencephalitis. Furthermore, she was unable to mount serum WNV IgM or IgG antibody responses against WNV two wk following the onset of her symptoms. The diagnosis of WNV neuroinvasive disease was confirmed by positive WNV polymerase chain reaction identification in the cerebrospinal fluid (CSF). Meningoencephalomyelitis at autopsy was extremely extensive, involving all levels of spinal cord sampled, as well as cerebral subcortical gray matter, cerebellum, brainstem, hippocampi, cerebral white matter, and proximal ventral nerve roots. Our concern is that the use of both T-cell and B-cell immunosuppression may have significantly contributed to her rapid decline, as indicated by the rapidity of her course, lack of WNV antibody production, and the severity of tissue damage on histopathologic examination of the brain and spinal cord tissue.

May 2005. Combined demyelination of the central and peripheral nervous system is an uncommon disorder and has been referred to by many appellations. We present the case of a 71-year-old man with a progressive nervous system disorder beginning in his 30s. The diagnosis in life was unclear, but had over the years been variously considered to be Guillain-Barrè Syndrome (GBS), Friedreich ataxia, or multiple sclerosis (MS). At autopsy old CNS demyelination consistent with MS was found as well as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with onion bulb formation in hypertrophic nerves. Microscopic examination showed some onion bulb formation in the CNS as well as in peripheral nerves. The nosology of these disorders is discussed and relevant animal models briefly reviewed.

(2004). Western ALS Study Group. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders: Vol. 5, No. sup1, pp. 121-124.

This report describes the clinical and electrophysiological features of an 8-year-old boy with autoimmune neuromuscular hyperexcitability. He presented with features of lower extremity pain, stiffness, and rippling muscles. The diagnosis was made by electromyography and supported by the presence of an antibody directed against nicotinic acetylcholine receptors. His symptoms responded to immunomodulatory treatment with intravenous immunoglobulin. Response to immunomodulatory therapy has not previously been described in the pediatric population with autoimmune neuromuscular hyperexcitability. This case highlights that this is a treatable condition.

Patients admitted to the intensive care unit (ICU) can develop a condition referred to as “ICU-acquired weakness.” This condition is characterized by profound weakness that is greater than might be expected to result from prolonged bed rest. Intensive care unit–acquired weakness often is accompanied by dysfunction of multiple organ systems. Individuals with ICU-acquired weakness typically have significant activity limitations, often requiring physical assistance for even the most basic activities associated with bed mobility. Many of these individuals have activity limitations months to years after hospitalization. The purpose of this article is to review evidence that guides physical rehabilitation of people with ICU-acquired weakness. Included are diagnostic criteria, medical management, and prognostic indicators, as well as criteria for beginning physical rehabilitation, with an emphasis on patient safety. Data are presented indicating that rehabilitation can be implemented with very few adverse effects. Evidence is provided for appropriate measurement approaches and for physical intervention strategies. Finally, some of the key issues are summarized that should be investigated to determine the best intervention guidelines for individuals with ICU-acquired weakness.

Chronic muscle weakness is a common complaint among patients seen in rheumatology and neuromuscular specialty clinics. This article focuses on adult-onset muscular dystrophies, select hereditary myopathies, and other neuromuscular conditions that must be distinguished from acquired causes of inflammatory muscle disease such as polymyositis. A few organizing principles help to focus the evaluation and narrow the differential diagnosis.

Evidence suggests that West Nile virus (WNV) neuroinvasive disease occurs more frequently in both solid organ and human stem cell transplant recipients. The effect of concomitant anti-B-cell therapy with rituximab, a CD20(+) monoclonal antibody, on WNV infection in this population, however, has not been reported. We describe a case of a patient with alpha-1-antitrypsin deficiency who underwent single lung transplantation in 2005 and was maintained on tacrolimus, cytoxan and prednisone. More recently, she had received two courses of rituximab for recurrent A2-A3 grade rejection with concomitant capillaritis and presented six months later with rapid, fulminant WNV meningoencephalitis. Her diagnosis was made by cerebrospinal fluid (CSF) PCR but serum and CSF WNV IgM and IgG remained negative. She received WNV-specific hyperimmune globulin (Omr-Ig-Am) through a compassionate protocol. She experienced a rapidly progressive and devastating neurological course despite treatment and died three wk after onset of her symptoms. Autopsy revealed extensive meningoencephalomyelitis.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA.

Neuromuscular medicine fellowship training, like neurology training, is undergoing important changes. The widespread effort to standardize educational practices and assessment methods across programs is exemplified by the Next Accreditation System. The lasting effects of this framework are largely unknown and will require study. In order truly to meet the goals of improving patient and population outcomes and improving the educational experience for trainees, more changes will likely be needed.

X-linked dilated cardiomyopathy (XLCM) was first described in 1987 and associated with dystrophin gene (DMD) mutations a decade later in one of the original two families. Here we report long-term follow-up of the second family (XLCM-2), for which a DMD mutation was never found. Analysis of the lysosome-associated membrane protein-2 (LAMP-2) gene detected a novel mutation, confirming a diagnosis of Danon disease. The broad phenotype in this family included dilated and hypertrophic cardiomyopathy, cardiac pre-excitation, skeletal myopathy with high serum creatine kinase, cognitive impairment (in males), and a pigmentary retinopathy in affected females. Cardiac biopsy specimens showed extensive vacuolar changes in an affected adult male. Remarkably, the skeletal muscle biopsy in a 13-month-old mutation-carrying male showed no vacuolization by standard histology. We conclude that XLCM may be the presenting sign of Danon disease and, in the presence of a familial history of HCM, pre-excitation, skeletal muscle involvement and retinal pigmentary dystrophy should prompt LAMP-2 clinical testing. Furthermore, the absence of vacuolar myopathy in biopsies from young patients may not exclude Danon disease.

Two patients with multiple sclerosis developed symptomatic chronic inflammatory demyelinating polyneuropathy with massive spinal or cranial nerve hypertrophy revealed by neuroimaging. Sural nerve biopsy in one showed only moderate demyelination, axonal loss, and onion-bulb formation, illustrating dichotomy between severe proximal and milder distal nerve involvement. Patients with coexistent central and peripheral demyelination usually are symptomatic from dysfunction at one site or the other, but not from both. Our patients showed minimal response to steroids, intravenous immunoglobulin, or azathioprine. These cases suggest that the mechanism of disease in symptomatic central and peripheral demyelination may differ from that of disease in only one region, and that optimal therapy in this situation must be explored further.

Hereditary amyloidosis with early and prominent peripheral nerve involvement is often designated familial amyloid polyneuropathy (FAP). The abnormality usually lies in the transthyretin (TTR) gene. We describe a patient with a tyr77 TTR gene mutation who presented with sensorimotor polyneuropathy but no other systemic symptoms of amyloidosis. This is one of a few documented cases of the tyr77 mutation in North America. The clinical and electrophysiologic features of this unusual cause of sensorimotor polyneuropathy are discussed.

Acute idiopathic dysautonomia is an uncommon syndrome consisting of varying degrees of sympathetic and parasympathetic dysfunction. The etiology and potential treatments for the disorder are uncertain.1 Treatment with IV immunoglobulin (IVIg) has been reported in only two patients.2,3 We describe the results of electrophysiologic and autonomic testing and response to IVIg of a patient with acute idiopathic dysautonomia. A 61-year-old man was evaluated for severe lightheadedness and syncope with standing. Two weeks earlier, he had developed acute, lancinating pains in his arms and legs, difficulty urinating, erectile dysfunction, constipation, fever, and orthostatic hypotension with syncope. He had no visual blurring, changes in sweating, or weakness. He received IV fluid at that time without benefit. The limb pain disappeared spontaneously over several days. On initial evaluation, he was afebrile. Supine blood pressure was 150/90 mmHg with a heart rate of 60 beats/minute. Blood pressure seated was 130/85 mmHg; blood pressure standing fell to 85/50 mmHg with an associated heart rate of 68 beats/minute. He was severely symptomatic when standing. Neurologic examination showed no evidence of …

Article abstract A 35-year-old man presented with partial seizures 10 years after resection of a left-sided glioblastoma multiforme. At the old operative site MRI demonstrated extensive cortical and white matter gadolinium enhancement, and PET showed hypermetabolism. Biopsy of the area was postponed when MRS showed a normal biochemical spectrum. MRI and PET abnormalities resolved after control of the seizures. MRS is noninvasive and can provide essential information in the management of patients with seizures and previously treated cerebral neoplasms.

The most common complication of herpes zoster (shingles) is postherpetic neuralgia (PHN), a severe, deep, burning, or jabbing pain that persists for months and often years after resolution of zoster rash. Although gabapentin1 and topical lidocaine2 are the only federally approved drugs to manage PHN, the many other agents being prescribed for PHN indicate that better symptomatic therapies are needed. Ketamine hydrochloride is an NMDA receptor antagonist that has been useful IV for neuropathic pain in patients with various conditions, including PHN.3 A topical form reduced sympathetically mediated pain in five patients,4 but it has not been used for PHN. We examined the effectiveness of topical ketamine in 23 PHN patients. ### Ketamine preparation. Soybean lecithin granules (250 g; Spectrum LE 102) were mixed with 150 mL isopropyl palmitate (Aldrich Chemical #29–178–1, Milwaukee, WI). The mixture was stirred at least 12 hours until a uniformly dark, amber-colored solution was obtained. Ketamine (10 mL; Ketalar N0071–4582–10, 50 mg/mL) …

Objective: To describe the variable presentation of TTR Thr 60 Ala Transthyretin Familial Amyloidotic Polyneuropathy (FAP) within a family and determine if the mutation is de novo or related to the previously described Donegal kindred. Background Transthyretin FAP is an autosomal dominant disorder characterized by sensory and autonomic polyneuropathy and variable cardiac, renal, liver, and other organ system involvement. Over 100 known mutations exist. The Thr 60 Ala mutation has been reported by several groups and felt to be the result of a founder mutation from Donegal, Ireland. Design/Methods: We describe the clinical and available electrodiagnostic presentations of six mutation positive individuals in a family with Thr 60 Ala Transthyretin FAP. Haplotype analysis on two affected family members was performed using PCR and compared to the previously described haplotype of the Donegal kindred. Results: The proband developed a painful sensory polyneuropathy at age 48. Muscle weakness rapidly followed. Autonomic symptoms of erectile dysfunction, orthostasis, and postprandial nausea and vomiting were prominent and early features. Cardiomyopathy was also identified. Electrodiagnostic evaluation showed severe sensorimotor axonal polyneuropathy. Death occurred within 7 years of diagnosis. The other five family members with the mutation were less severely affected, ranging from asymptomatic to mild polyneuropathy and cardiac involvement. Haplotype analysis strongly suggested that this family is related to the previously described Donegal kindred. Conclusions: The Thr 60 Ala Transthyretin FAP phenotype is characterized by variable penetrance with sensory > motor polyneuropathy and cardiac involvement. Haplotype analysis suggests this mutation arose primarily from a single founder and is not a common spontaneous mutation. Supported by: In part by the Transthyretin Amyloidosis Outcomes Survey, FoldRx, and Pfizer. Disclosure: Dr. Graham has nothing to disclose. Dr. Slavov has nothing to disclose. Dr. Taylor has received personal compensation for activities with Guidepoint Global as a consultant. Dr. Quan has nothing to disclose.

Background Postherpetic neuralgia (PHN) is a complication of shingles (herpes zoster), a painful rash due to varicella-zoster virus reactivation. Studies of patients with PHN and zoster sine herpete (radicular pain without rash) support the notion that low-grade viral ganglionitis contributes to pain. If chronic pain reflects active infection, then antiviral therapy may help patients with PHN. Objective To determine whether antiviral treatment helps reduce PHN-associated pain. Design Prospective, open-label phase I/II clinical trial. Setting Tertiary care university hospital. Patients Fifteen patients with moderate to severe PHN. Interventions Intravenous acyclovir at a dosage of 10 mg/kg every 8 hours for 14 days followed by oral valacyclovir at a dosage of 1000 mg 3 times per day for 1 month. Main Outcome Measure Numeric Rating Scale for Pain score. Results As defined by a decrease of 2 or more points on the Numeric Rating Scale for Pain, 8 (53%) of 15 patients reported improvement. Conclusion Clinical improvement reported by most of our patients warrants further investigation in a larger, randomized, double-blind, placebo-controlled trial. Published online May 8, 2006 (doi:10.1001/archneur.63.7.noc60049).

The extent of human T-cell leukemia/lymphoma virus type II (HTLV-II) infection and its rate of spread have been difficult to determine owing to the serological cross-reactivity between HTLV-I and HTLV-II. The present study overcame this problem by directly detecting type-specific proviral sequences by means of the polymerase chain reaction (PCR) and liquid hybridization. Screening was performed on a cohort of primarily white intravenous drug abusers (IVDAs), and individuals of other behaviorally defined risk groups from the New York City area. Eleven percent (19 of 169) of the individuals in these high-risk groups were determined by PCR to have HTLV-II proviral infections. One of these patients displayed an exfoliative erythrodermatitis. Thirteen of the 19 subjects were positive in an HTLV-II enzyme-linked immunosorbent assay (ELISA). The remaining six individuals, although negative in the HTLV- II ELISA, were confirmed as HTLV-II positive by analyzing their DNA with a second HTLV-II-specific primer detector system. Four additional individuals were reactive in the HTLV-II ELISA but were PCR-negative for HTLV-II. PCR analysis for HTLV-I revealed that all four were positive for that virus. Thirty-seven percent (seven of 19) of the HTLV- II PCR-positive subjects were also PCR-positive for HTLV-I, and 84% (16 of 19) of the HTLV-II positive individuals were infected with human immunodeficiency virus (HIV-1). Six individuals were triply infected with HTLV-I, HTLV-II, and HIV-1.