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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...

Objective To assess the intraepidermal nerve fiber density in patients diagnosed with fibromyalgia (FM) and to evaluate the role of IgM binding to trisulfated heparin disaccharide (TS-HDS) in these patients. Methods FM is a poorly understood pain disorder with several proposed pathophysiologic mechanisms. It is characterized by widespread pain, fatigue, and sleep abnormalities. Small fiber neuropathy (SFN) has been proposed as an underlying mechanism, and patients with FM have been shown to have a reduction in the intraepidermal nerve fiber density. An underlying inflammatory process that could be a result of autoimmune phenomena has also been suggested. Non-length-dependent SFN (NLDSFN) has been shown to have a higher incidence of autoimmune disease. Twenty-two patients with established diagnosis of FM underwent skin biopsy at 2 sites; 10 cm above the lateral malleolus and 10 cm above the patella. Serum IgM binding to TS-HDS was assayed using an ELISA method. Results A total of 5/22 patients had positive TS-HDS antibodies; of these, 4 had NLDSFN (P = 0.0393). Comparison with a control group at Washington University showed no significant difference in percentage with TS-HDS antibodies (P = 0.41). When compared with Washington University database of skin biopsy, there was a trend for an increased percentage of NLDSFN in patients with FM (P = 0.06). Conclusions This study further supports the hypothesis that a subgroup of patients with FM has SFN. We suggest a correlation between the presence of NLDSFN and TS-HDS antibodies.

Amyotrophic lateral sclerosis is a neurodegenerative illness that causes gradual loss of muscle function. Patients eventually develop bulbar impairment, requiring extensive respiratory support. Noninvasive ventilation (NIV) has gained attention as an easily accessible method with promising benefits. We conducted this systematic review to outline the therapeutic effects of NIV, add to previous publications discussing this topic by providing updates on newly completed and ongoing studies, and identify limitations that must be addressed in future trials. A search of PubMed and Cochran for relevant primary studies yielded 26 publications. Studies indicate NIV use is associated with improvements in quality of life, regardless of the severity of bulbar impairment. However, NIV’s benefits on survival were limited to patients with less bulbar impairment. In addition, our review found several limitations that undermine the efforts to establish a definitive treatment regimen. Future studies will need to address these problems in order to provide patients with better respiratory care.

Introduction Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). Methods We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting. Results There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. Discussion Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.

Primary lateral sclerosis (PLS) is a condition that most neurologists will never personally diagnose. For the estimated several thousand people living with PLS globally, while it may not be life-sh...

Introduction Our research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS). Methods A prototype of the PLS Functional Rating Scale (PLSFRS) was generated. Seventy-seven participants with PLS were enrolled and evaluated at 21 sites that comprised the PLSFRS study group. Participants were assessed using the PLSFRS, Neuro-Quality of Life (QoL), Schwab-England Activities of Daily Living (ADL), and the Clinical Global Impression of Change scales. Participants completed telephone assessments at 12, 24, and 48 weeks after enrollment. Results The PLSFRS demonstrated internal consistency as well as intrarater, interrater, telephone test-retest reliability, and construct validity. Significant changes in disease progression were detected at 6 and 12 months; changes measured by the PLSFRS vs the ALSFRS-R were significantly higher. Discussion The PLSFRS is a valid tool to assess the natural history of PLS in a shorter study period.

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.

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

Chronic herpes simplex virus type-1 encephalitis (HSE-1) is uncommon. Past reports focused on its association with prior documented acute infection. Here, we describe a patient with increasingly intractable epilepsy from chronic HSE-1 reactivation without history of acute central nervous system infection. A 49-year-old liver transplant patient with 4-year history of epilepsy after initiation of cyclosporine developed increasingly frequent seizures over 3 months. Serial brain magnetic resonance imaging showed left temporoparietal cortical edema that gradually improved despite clinical decline. Herpes simplex virus type-1 (HSV-1) DNA was detected in cerebrospinal fluid by polymerase chain reaction. Cerebrospinal fluid HSV-1&2 IgM was negative. Seizures were controlled after acyclovir treatment, and the patient remained seizure free at 1-year follow-up. Chronic HSE is a cause of intractable epilepsy, can occur without a recognized preceding acute phase, and the clinical course of infection may not directly correlate with neuroimaging changes.

Background Creutzfeldt–Jakob disease (CJD) is a rare, rapidly progressive neurodegenerative disease that almost always results in death in under a year from onset of symptoms. Here, we report four cases of CJD with different clinical presentations diagnosed at our institution over a 2-year period. Cases The first patient is an 82-year-old woman who presented with depression, cognitive decline, and word-finding difficulty over 4 weeks. The patient deteriorated neurologically to akinetic mutism and death within 6 weeks of presentation. The second patient is a 54-year-old woman with liver cirrhosis who presented with confusion, ataxia, and multiple falls over 4 weeks. She was treated initially for hepatic encephalopathy but continued to progress to mutism, startle myoclonus, and obtundation. Death occurred within 4 weeks of presentation. The third patient is a 58-year-old woman who presented with an 8-week history of confusion, urinary incontinence, Parkinsonism, ataxia, and myoclonus. Death occurred within 2 months from presentation. The fourth patient is a 67-year-old man who presented with a 6-week history of headache, blurred vision, ataxia, and personality change and progressed to confusion, myoclonus, akinetic mutism, and obtundation. Death occurred within 3 weeks from presentation. Conclusion These four cases highlight the varied possible clinical presentations of CJD and demonstrate the importance of considering CJD in patients with atypical presentations of rapidly progressive cognitive decline. To diagnose CJD, brain biopsy remains the gold standard. However, the presence of CSF protein 14-3-3, typical MRI findings and suggestive EEG abnormalities, all support the diagnosis.

Idiopathic inflammatory myopathies (IIM) are a group of chronic, autoimmune conditions affecting primarily the proximal muscles. The most common types are dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myopathy (NAM), and sporadic inclusion body myositis (sIBM). Patients typically present with sub-acute to chronic onset of proximal weakness manifested by difficulty with rising from a chair, climbing stairs, lifting objects, and combing hair. They are uniquely identified by their clinical presentation consisting of muscular and extramuscular manifestations. Laboratory investigations, including increased serum creatine kinase (CK) and myositis specific antibodies (MSA) may help in differentiating clinical phenotype and to confirm the diagnosis. However, muscle biopsy remains the gold standard for diagnosis. These disorders are potentially treatable with proper diagnosis and initiation of therapy. Goals of treatment are to eliminate inflammation, restore muscle performance, reduce morbidity, and improve quality of life. This review aims to provide a basic diagnostic approach to patients with suspected IIM, summarize current therapeutic strategies, and provide an insight into future prospective therapies.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.