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Introduction: Though eye movements are relatively spared in motor neuron disease (MND), recent literature suggests patients may exhibit oculomotor dysfunction (OD). Frontal lobe involvement has been postulated based on oculomotor pathway anatomy and clinical overlap of amyotrophic lateral sclerosis (ALS) with frontotemporal dementia. We examined oculomotor characteristics in patients with MND presenting to an ALS Center, hypothesizing that patients with prominent upper motor neuron involvement or pseudobulbar affect (PBA) may demonstrate greater OD., Methods: This was a single-center prospective observational study. Patients with diagnosis of MND were examined at bedside. Center for Neurologic Study-Liability Scale (CNS-LS) was administered to screen for pseudobulbar affect. Primary outcome was OD and the secondary outcome was the association between presence of OD in patients with MND experiencing symptoms of PBA or upper motor neuron dysfunction. Wilcoxon rank-sum scores and Fisher's exact tests were used to perform statistical analyses., Results: 53 patients with MND underwent the clinical ophthalmic evaluation. On bedside examination, 34 patients (64.2%) presented with OD. There were no significant associations between locations of MND at presentation and the presence or type of OD. OD was associated with increased disease severity as measured by reduced FVC (p = 0.02). There was no significant association between OD and CNS-LS (p = 0.2)., Discussion: Though our study did not find a significant association between OD and upper versus lower MND at presentation, OD may be useful as an additional clinical marker for advanced disease.

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.

Introduction: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG)., Methods: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected., Results: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years., Discussion: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status., (© 2020 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

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., (© 2019 Wiley Periodicals, Inc.)

We studied 25-hydroxyvitamin D (vitamin D) levels in patients with amyotrophic lateral sclerosis (ALS) and the effect of vitamin D supplementation. Vitamin D levels were checked in 37 consecutive patients with ALS. Demographic data, vitamin D supplementation, change in Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score, and side effects from vitamin D were noted over a 9 month follow-up period. ALSFRS-R scores were compared between patients who took vitamin D and those who did not. The median age was 55 years and median time since symptom onset was 61 months. The mean vitamin D level was 22.3 ng/mL (normal range, 30-80 ng/mL). Eighty-one percent of patients had a vitamin D level lower than 30 ng/mL and 43% had a vitamin D level lower than 20 ng/mL. Twenty patients took 2000 international units of vitamin D daily. After adjustment for age and baseline vitamin D levels in a linear regression model, the ALSFRS-R score decline was smaller in patients taking vitamin D at 9 months (p=0.02) but was not significantly different at 3 or 6 months. Median vitamin D levels rose from 18.5 to 31.0 ng/mL at 6 months in the group taking vitamin D. No side effects secondary to vitamin D supplementation were reported. Vitamin D supplementation at 2000 international units daily was safe over a period of 9 months and may have a beneficial effect on ALSFRS-R scores. Further studies are warranted to determine whether there is a benefit in vitamin D supplementation for all ALS patients., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In an amyotrophic lateral sclerosis (ALS) patient who also had an IgA gammopathy, autopsy studies identified the IgA in the surviving motor neurons. Further, the IgA bound the surface of isolated bovine motor neurons and inhibited neuronal proliferation in culture. To determine the pathologic basis of this IgA interaction with motor neurons, a neuroblastoma cDNA library was generated and screened with the IgA monoclonal antibody. Reactive clones were identified as flavin adenine dinucleotide (FAD) synthetase. To extend this finding to ALS in general, quantitative RT-PCRs were performed on blood samples from 26 ALS and 30 control blood samples to determine mRNA expression levels of FAD synthetase and other electron transport chain proteins, specifically riboflavin kinase (RFK), cytochrome C1 (CYC1), and succinate dehydrogenase complex subunit B (SDHB). All expression levels were measured against a control enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Expression levels for a non-respiratory chain protein (beta-actin) were also measured. We found that FAD synthetase expression levels were decreased in ALS samples compared to expression levels in controls (P = 0.0151). Expression levels for RFK, CYC1, and SDHB were also significantly decreased in the ALS group (P = 0.0025, P = 0.0002, and P < 0.0001, respectively). As control, expression levels for beta-actin did not show a significant difference between ALS and control groups (P = 0.2118). Our data show that a reduction in electron transport proteins, namely FAD synthetase, RFK, CYC1, and SDHB, is seen in patients with ALS. It is possible that this may have an effect on oxygen-dependent metabolic pathways. Human motor neurons may be particularly susceptible to injury if there is sub-optimal oxidative metabolism.

Introduction: Management of patients with radiculopathy involves estimating the degree of physiologic and anatomic injury, and weighing that to predict the likely clinical course., Objective: To determine whether low distal peroneal and tibial CMAP amplitudes correlate with weakness and fibrillations of functionally relevant muscles in L5/S1 radiculopathy (LSR)., Methods: We reviewed clinical and electrophysiologic data in 66 consecutive patients with LSR., Results: A significantly greater number of patients with low peroneal CMAP amplitudes had weakness of L5 (p = 0.025) and S1 innervated leg muscles (p < 0.001). Low tibial CMAP amplitudes were also associated with weakness of S1 innervated muscles (p < 0.038). The association of low peroneal CMAP amplitudes with weakness persisted when weakness of at least 3 muscles was considered in the analysis for L5 (p < 0.0001) and S1 (p = 0.014) innervated muscles., Conclusions: Low peroneal and tibial CMAP amplitudes may serve as surrogate measures for segmental weakness of functionally relevant muscles in LSR.

Controversy exists concerning whether Miller Fisher syndrome (MFS) is the result of a predominantly axonal or demyelinating polyneuropathy and whether the Guillain-Barré syndrome variant of acute ataxia and areflexia without ophthalmoplegia, ataxic Guillain-Barré syndrome (atxGBS), has a distinct pathophysiology. We explored these issues by reviewing the electrophysiologic features of 6 patients with MFS and 2 patients with atxGBS. EMG laboratory records were reviewed and electrophysiologic findings were categorized as axonal or demyelinating neuropathy using previously defined criteria. Of the 6 patients with MFS, 5 had electrophysiologic evidence suggestive of an axonal, predominantly sensory polyneuropathy; only 1 patient met criteria for demyelinating polyneuropathy. Both patients with atxGBS had demyelinating sensorimotor polyneuropathy. Electrophysiologic abnormalities in MFS typically suggest a predominantly axonal, sensory polyneuropathy, though demyelinating forms occur and may be under-diagnosed using current criteria. AtxGBS, in our experience, is a predominantly demyelinating polyneuropathy.

Reports of an ulnar-median anastomosis in the forearm (UMAF) are rare and its existence has been questioned. A patient with clinical and electrophysiologic evidence of ulnar neuropathy at the elbow (UNE) had unexpected fibrillations in the abductor pollicis brevis muscle (APB). Additional nerve conduction studies suggested both ulnar-median and median-ulnar anastomoses in the forearm. The unexpected finding of APB fibrillations in a patient with UNE should raise the possibility of the rare UMAF.

Objectives: Proximal myotonic myopathy (PROMM) is a multisystem disorder that may mimic myotonic dystrophy (MD). Previously we demonstrated that the 60 s exercise test was normal in two siblings with PROMM. The test enabled distinction of PROMM from MD, as there is a well documented immediate post-exercise compound muscle action potential (CMAP) amplitude decline in MD., Methods: We now performed exercise testing using several exercise durations in 8 PROMM patients from 6 kinships, and one MD patient, extending our previous observations. Repetitive stimulation and needle electromyography findings were also recorded., Results: The 10 (n = 8), 30 (n = 5), and 60 (n = 5) s, and the 5 min (n = 1) exercise tests were normal in all PROMM patients. Specifically, the maximum post-exercise CMAP amplitude decline was 8%. In contrast, the MD patient had CMAP amplitude declines of 48% (10 s exercise test) and 26% (30 s exercise test). The distribution of repetitive stimulation and motor unit duration abnormalities were variable and less diagnostically useful., Conclusions: The 10, 30, and 60 s exercise tests help distinguish PROMM from MD. As the 10 s exercise test is rapid and easily tolerated, we recommend this test for clinical testing.

Objective: To determine whether riluzole is associated with blood pressure elevations in patients with amyotrophic lateral sclerosis (ALS)., Background: Though previously reported, hypertension is not considered a frequent adverse effect of riluzole., Methods: We reviewed data from 35 consecutive ALS patients on riluzole, and 88 randomly selected controls without and 20 patients with ALS who were not on riluzole., Results: A significantly greater number of ALS patients on riluzole had blood pressure elevations (28 of 35 patients) compared to controls (26 of 88, p<0.001; 8 of 20, p = 0. 007). Median systolic and diastolic blood pressures were both significantly higher in riluzole-treated (140/86 mm Hg) than in control patients without ALS (120/70 mm Hg, p<0.001). Systolic, but not diastolic, blood pressures were significantly higher in riluzole-treated patients than in controls with ALS (126 mm Hg, p = 0.002)., Conclusions: Riluzole treatment may be associated with mild blood pressure elevations. Future prospective trials of riluzole should closely assess hypertension., (Copyright 2000 S. Karger AG, Basel.)

Objective: To assess the sensitivities and specificities of velocity differences between median mixed nerve conduction across the wrist (Medmxpw) and (I) median mixed nerve conduction in the forearm (Medmxf) and (II) palm to D2 sensory conduction (MedpD2)., Design and Methods: We prospectively studied 67 limbs of patients with clinically definite carpal tunnel syndrome (CTS). Medmxf and Medmxpw were performed by stimulating the median nerve at the elbow and palm respectively and recording at the proximal wrist crease. We also compared conventional median sensory (D2-wrist) and mixed (palm-wrist) tests in all patients. Thirty limbs of asymptomatic subjects served as normal controls and 21 limbs of subjects with other neuropathies served as diseased controls; control data was collected prospectively., Results: The sensitivity of the MedpD2-Medmxpw difference (0.87) was significantly greater than that of the Medmxf-Medmxpw difference (0.61, P < 0.001). Both tests were similar and highly specific (0.98 and 0.96, respectively)., Conclusions: The MedpD2-Medmxpw study is among the most sensitive and specific electrophysiologic tests for CTS.

We reviewed 49 patients consecutively hospitalized for neurologic Lyme disease to determine the frequency and characteristics of recent onset headaches in this group. All patients had positive serum Lyme ELISAs and other neurologic illness excluded. Recent-onset headache occurred in 26 of 49 patients (53%). Patients with headaches more commonly had central nervous system involvement (54% vs 19%, P < .05) and flu-like illness (58% vs 19%, P < .0005). Eight of 26 (31%) met criteria for meningitis or encephalitis with abnormal CSF examinations. All 8 had focal findings (6), cognitive dysfunction (1), or both (1). The remaining 18 patients had recent-onset headaches resembling migraine (9), tension-type headache (5), or neither (4). Antibiotic treatment resulted in complete headache resolution in 11 of 14 patients with available follow-up data. Based on these findings, we conclude that recent-onset headaches are common in patients hospitalized with Lyme disease. Of those with meningitis or encephalitis requiring intravenous antibiotics, all had focal neurologic findings or cognitive abnormalities, not just headaches.

Twenty-two rabbits received Torpedo californica acetylcholine receptor (AChR) subcutaneously. Six rabbits were treated with 0.5 ml/kg/day of anti-rabbit thymocyte serum (ARTS), and four were treated with 5.0 mg/kg/day of anti-rabbit thymocyte gammaglobulin (ARTG) subcutaneously beginning concomitantly 1, 2 and 3 weeks after the initial AChR immunization. All 12 control animals died of experimental autoimmune myasthenia gravis (EAMG) within 52 days. None of the 10 treated rabbits developed clinical EAMG. ARTS- and ARTG-treated animals had significantly lower anti-AChR antibody titers than control animals at 3 weeks (pre-AChR booster, p < 0.01). At 6 weeks (post-AChR booster), only ARTS-treated animals had significantly lower titers than controls (p < 0.01). ARTS-treated animals developed sterile abscesses at injection sites, which were minimal in the ARTG-treated group. ARTS and ARTG prevent EAMG.