Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study.

OBJECTIVE: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium. METHODS: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined. RESULTS: The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD] = 6.0, range = 0-28) and 14.60 (SD = 7.56, range = 0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p = 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p = 0.016] vs 0.06 points [p = 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p = 0.025] vs -0.03 for baseline CMTES 0-7 [p = 0.958] and 0.25 for baseline CMTES ≥ 15 [p = 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable. INTERPRETATION: CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576.

Challenging Neuromuscular Disease Cases.

The diagnosis of neuromuscular disorders requires a thorough history including family history and examination, with the next steps broadened now beyond electromyography and neuropathology to include genetic testing. The challenge in diagnosis can often be putting all the information together. With advances in genetic testing, some diagnoses that adult patients may have received as children deserve a second look and may result in diagnoses better defined or alternative diagnoses made. Clearly defining or redefining a diagnosis can result in understanding of potential other systems involved, prognosis, or potential treatments. This article presents several cases and approach to diagnosis as well as potential treatment and prognostic concerns, including seipinopathy, congenital myasthenic syndrome, central core myopathy, and myotonic dystrophy type 2.

Cognitive function and its relationship with brain structure in myotonic dystrophy type 1.

Studies have shown relationships between white matter abnormalities and cognitive dysfunction in myotonic dystrophy type 1 (DM1), but comprehensive analysis of potential structure-function relationships are lacking. Fifty adult-onset DM1 individuals (33 female) and 68 unaffected adults (45 female) completed the Wechsler Adult Intelligence Scale-IV (WAIS-IV) to determine the levels and patterns of intellectual functioning. Neuroimages were acquired with a 3T scanner and were processed with BrainsTools. Regional brain volumes (regions of interest, ROIs) were adjusted for inter-scanner variation and intracranial volume. Linear regression models were conducted to assess if group by ROI interaction terms significantly predicted WAIS-IV composite scores. Models were adjusted for age and sex. The DM1 group had lower Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores than the unaffected group (PRI t(113)  = -3.28, p = 0.0014; WMI t(114)  = -3.49, p = 0.0007; PSI t(114)  = -2.98, p = 0.0035). The group by hippocampus interaction term was significant for both PRI and PSI (PRI (t(111)  = -2.82, p = 0.0057; PSI (t(112)  = -2.87, p = 0.0049)). There was an inverse association between hippocampal volume and both PRI and PSI in the DM1 group (the higher the volume, the lower the intelligence quotient scores), but no such association was observed in the unaffected group. Enlarged hippocampal volume may underlie some aspects of cognitive dysfunction in adult-onset DM1, suggesting that increased volume of the hippocampus may be pathological.

Quantitative muscle MRI as a sensitive marker of early muscle pathology in myotonic dystrophy type 1.

BACKGROUND: Quantitative muscle MRI as a sensitive marker of early muscle pathology and disease progression in adult-onset myotonic dystrophy type 1. The utility of muscle MRI as a marker of muscle pathology and disease progression in adult-onset myotonic dystrophy type 1 (DM1) was evaluated. METHODS: This prospective, longitudinal study included 67 observations from 36 DM1 patients (50% female), and 92 observations from 49 healthy adults (49% female). Lower-leg 3T magnetic resonance imaging (MRI) scans were acquired. Volume and fat fraction (FF) were estimated using a three-point Dixon method, and T2-relaxometry was determined using a multi-echo spin-echo sequence. Muscles were segmented automatically. Mixed linear models were conducted to determine group differences across muscles and image modality, accounting for age, sex, and repeated observations. Differences in rate of change in volume, T2-relaxometry, and FF were also determined with mixed linear regression that included a group by elapsed time interaction. RESULTS: Compared with healthy adults, DM1 patients exhibited reduced volume of the tibialis anterior, soleus, and gastrocnemius (GAS) (all, P < .05). T2-relaxometry and FF were increased across all calf muscles in DM1 compared to controls. (all, P < .01). Signs of muscle pathology, including reduced volume, and increased T2-relaxometry and FF were already noted in DM1 patients who did not exhibit clinical motor symptoms of DM1. As a group, DM1 patients exhibited a more rapid change than did controls in tibialis posterior volume (P = .05) and GAS T2-relaxometry (P = .03) and FF (P = .06). CONCLUSIONS: Muscle MRI renders sensitive, early markers of muscle pathology and disease progression in DM1. T2 relaxometry may be particularly sensitive to early muscle changes related to DM1.

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies.

OBJECTIVE: Charcot-Marie-Tooth (CMT) disease is most commonly caused by duplication of a chromosomal segment surrounding Peripheral Myelin Protein 22, or PMP22 gene, which is classified as CMT1A. Several candidate therapies reduce Pmp22 mRNA levels in CMT1A rodent models, but development of biomarkers for clinical trials in CMT1A is a challenge given its slow progression and difficulty in obtaining nerve samples. Quantitative PCR measurements of PMP22 mRNA in dermal nerves were performed using skin biopsies in human clinical trials for CMT1A, but this approach did not show increased PMP22 mRNA in CMT1A patients compared to controls. One complicating factor is the variable amounts of Schwann cells (SCs) in skin. The objective of the study was to develop a novel method for precise evaluation of PMP22 levels in skin biopsies that can discriminate CMT1A patients from controls. METHODS: We have developed methods to normalize PMP22 transcript levels to SC-specific genes that are not altered by CMT1A status. Several CMT1A-associated genes were assembled into a custom Nanostring panel to enable precise transcript measurements that can be normalized to variable SC content. RESULTS: The digital expression data from Nanostring analysis showed reproducible elevation of PMP22 levels in CMT1A versus control skin biopsies, particularly after normalization to SC-specific genes. INTERPRETATION: This platform should be useful in clinical trials for CMT1A as a biomarker of target engagement that can be used to optimize dosing, and the same normalization framework is applicable to other types of CMT. ANN NEUROL 2019;85:887-898.

Myotonic dystrophy type 1 alters muscle twitch properties, spinal reflexes, and perturbation-induced trans-cortical reflexes.

BACKGROUND: Neurophysiologic biomarkers are needed for clinical trials of therapies for myotonic dystrophy (DM1). We characterized muscle properties, spinal reflexes (H-reflexes), and trans-cortical long-latency reflexes (LLRs) in a cohort with mild/moderate DM1. METHODS: Twenty-four people with DM1 and 25 matched controls underwent assessment of tibial nerve H-reflexes and soleus muscle twitch properties. Quadriceps LLRs were elicited by delivering an unexpected perturbation during a single-limb squat (SLS) visuomotor tracking task. RESULTS: DM1 was associated with decreased H-reflex depression. The efficacy of doublet stimulation was enhanced, yielding an elevated double-single twitch ratio. DM1 participants demonstrated greater error during the SLS task. DM1 individuals with the least-robust LLR responses showed the greatest loss of spinal H-reflex depression. CONCLUSIONS: DM1 is associated with abnormalities of muscle twitch properties. Co-occurring alterations of spinal and trans-cortical reflex properties underscore the central nervous system manifestations of this disorder and may assist in gauging efficacy during clinical trials.

Gender difference in clinical conditions among hospitalized adults with myotonic dystrophy.

INTRODUCTION: In this study we examined gender differences in adult hospitalizations with myotonic dystrophy (DM). METHODS: From the Nationwide Inpatient Sample (NIS) 2010-2014, we identified 1,891 adult hospitalizations with a DM diagnosis and constructed a comparison group of hospitalizations without DM using propensity score matching. We calculated relative risk by gender for 44 clinical diagnoses that each accounted for at least 5% of DM hospitalizations. RESULTS: Hospitalizations with DM were longer (4.8 vs. 4.1 days, P < 0.0001) and more costly ($13,241 vs. $11,458, P < 0.0001) than those without DM. More than half (25 of 44) of the conditions co-occurring with DM hospitalizations did not differ in their relative risks by gender. For those that differed by gender, only 5 were specific to DM, compared with hospitalizations without DM. DISCUSSION: Our findings highlight the importance of comprehensive and coordinated care for DM rather than gender-oriented care in the inpatient setting. Muscle Nerve 59:348-353, 2019.

Charcot-marie-tooth disease type 1X in women: Electrodiagnostic findings.

INTRODUCTION: Symptoms and signs in women with Charcot-Marie-Tooth disease type 1X (CMT1X) are often milder from those in men, but the available electrophysiologic evidence regarding CMT1X in women has been characterized in some patients as non-uniform or asymmetric. METHODS: We retrospectively reviewed electrodiagnostic findings from 45 women and 31 men with CMT1X. RESULTS: Motor nerve conduction parameters in CMT1X women were less abnormal (P < 0.05), and a wider range of motor conduction velocities (CVs) were seen in women (P < 0.001) compared with men. In women, nerve conduction studies showed lack of conduction block without temporal dispersion. Motor CVs were more frequently in the normal range in women compared with men. There was no significant relationship to age of presentation and motor CV or compound muscle action potential in women. CONCLUSION: NCS parameters in CMT1X women did not demonstrate features suggestive of an acquired demyelinating neuropathy. Muscle Nerve, 2016 Muscle Nerve 54: -, 2016 Muscle Nerve 54: 728-732, 2016.

Update on Charcot-Marie-Tooth disease.

PURPOSE OF REVIEW: Charcot-Marie-Tooth disease (CMT) is the common terminology used to describe the hereditary neuropathies. This update reviews advances in the past year in our understanding of these diseases, including some important earlier references. RECENT FINDINGS: In the past year, advances in next-generation sequencing continued to increase the number of genes associated with CMT. The connection between genotype and phenotype has become more complicated. New insights into the pathogenesis of the diseases are reviewed. Treatment and clinical trial updates coming from these new insights, as well as use of high-throughput screening to match potential treatments with targets, are moving the field forward. There is a discussion of potential next steps, including the use of patient-derived induced pluripotent stem cells, to enhance our understanding of individual genotypes and phenotypes. SUMMARY: The use of high-throughput screens, and techniques such as RNAi and induced pluripotent stem cell continue to push forward other therapies for specific genetic forms of CMT and are potentially more generalizable to peripheral neuropathies. These developments, along with the development of improved outcome measures and longitudinal natural history data, advance CMT, making the future for finding treatments and/or cures closer than it has ever been.

The Auxiliary to the American Academy of Neurology.

The American Academy of Neurology (AAN) was founded in 1948, and the Women's Auxiliary to the AAN was founded shortly thereafter. We reviewed historical archives of the AAN and Women's Auxiliary and interviewed past Auxiliary leaders to understand the perception and roles of neurologists' spouses. The Women's Auxiliary to the AAN was originally formed for the wives of neurologist Academy members with the intention of facilitating social and intragroup relationships. The first leaders and members of the organization included some of the spouses of the original Academy founders. With the original scope to provide socialization while the men were at meetings, the male neurologists initially planned much of the Auxiliary's activities. Over time, the Auxiliary's activities shifted and became women-led; engagement in community outreach grew, subcommittees expanded, and the group engaged in supporting the AAN in achieving its goals of improving neurology education and research. The change paralleled the women's movement with educational topics during the Auxiliary's meetings evolving from topics on homemaking to business and understanding neurologic diseases. The Auxiliary was intertwined with the Academy and initiated the S. Weir Mitchell Award and the Founders Award of the AAN in 1955 and 1994 to encourage basic and clinical research in neurology, respectively. In 1982, the Auxiliary requested increased involvement in the scientific programs at the annual meetings. Reflecting societal change, the name was changed to the "Auxiliary to the AAN" in the 1970s, and in the mid-1990s to the "Alliance to the AAN" to accommodate the increasing number of male partners of neurologists. Based on interviews, the Auxiliary provided engagement, empowerment, and connection between women. The Auxiliary's activities tapered in the late 1990s, in part due to changes in women's occupations, and to the rise of women's membership and leadership within the Academy.

Analysis of Faculty Gender and Race in Scholarly Achievements in Academic Neurology.

Background: Intersection of gender and race and/or ethnicity in academic medicine is understudied; we aim to understand these factors in relation to scholarly achievements for neurology faculty. Methods: Faculty from 19 US neurology departments completed a survey (2021-2022) to report rank, leadership positions, publications, funded projects, awards, and speaker invitations. Regression analyses examined effects of gender, race, and their intersectionality on these achievements. Women, Black/Indigenous/People of Color (BIPOC), and BIPOC women were comparator groups. Results: Four hundred sixty-two faculty responded: 55% women, 43% men; 31% BIPOC, 63% White; 21% BIPOC women, 12% BIPOC men, 36% White women, 31% White men. Men and White faculty are more likely to be full professors than women and BIPOC faculty. The number of leadership positions, funded projects, awards, and speaker invitations are significantly greater in White compared to BIPOC faculty. Relative to BIPOC women, the number of leadership positions is significantly higher among BIPOC men, White women, and White men. Publication numbers for BIPOC men are lower, number of funded projects and speaker invitations for White women are higher, and number of awards among White men and White women is higher compared to BIPOC women. Discussion: Our study highlights that inequities in academic rank, award number, funded projects, speakership invitations, and leadership roles disproportionately impacted BIPOC women. More studies are needed to evaluate gender and race and/or ethnicity intersectionality effects on faculty achievements, reasons for inequities, recognition, and potential solutions.

Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial.

BACKGROUND AND PURPOSE: In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial. METHODS: CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression. RESULTS: Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01-1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70-4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51-3.76; P=0.52). CONCLUSIONS: The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00894803.

Longitudinal changes in white matter as measured with diffusion tensor imaging in adult-onset myotonic dystrophy type 1.

Myotonic dystrophy type 1 is characterized by neuromuscular degeneration. Our objective was to compare change in white matter microstructure (fractional anisotropy, radial and axial diffusivity), and functional/clinical measures. Participants underwent yearly neuroimaging and neurocognitive assessments over three-years. Assessments encompassed full-scale intelligence, memory, language, visuospatial skills, attention, processing speed, and executive function, as well as clinical symptoms of muscle/motor function, apathy, and hypersomnolence. Mixed effects models were used to examine differences. 69 healthy adults (66.2% women) and 41 DM1 patients (70.7% women) provided 156 and 90 observations, respectively. There was a group by elapsed time interaction for cerebral white matter, where DM1 patients exhibited declines in white matter (all p<0.05). Likewise, DM1 patients either declined (motor), improved more slowly (intelligence), or remained stable (executive function) for functional outcomes. White matter was associated with functional performance; intelligence was predicted by axial (r = 0.832; p<0.01) and radial diffusivity (r = 0.291, p<0.05), and executive function was associated with anisotropy (r = 0.416, p<0.001), and diffusivity (axial: r = 0.237, p = 0.05 and radial: r = 0.300, p<0.05). Indices of white matter health are sensitive to progression in DM1. These results are important for clinical trial design, which utilize short intervals to establish treatment efficacy.

Discordant thymectomy in identical twins concordant for myasthenia gravis.

BACKGROUND: Thymectomy is standard therapy fornonthymomatousmyasthenia gravis despite the absence of randomized clinical trials (1). Myasthenia gravis is uncommonly reported in monozygous twins; disease concordance occurs in approximately one third of such identical twin pairs; and treatment for myasthenia gravis, when described,is usually concordant in identical twin pairs (2). OBJECTIVE: To report an 11-year clinical course of a pair of identical twins concordant for generalized acetylcholine receptor antibody­positive nonthymomatous myasthenia gravis in whom only 1 was treated with extended transsternal thymectomy. CASE REPORT: Twin A was a 19-year-old white woman who presented with an 8-week history of intermittent leg weakness, causing her to fall during activities, such as climbing stairs. On examination,she had moderately severe fatigable proximal muscle weakness and ptosis. Her weakness improved with intravenous edrophonium administration.Initial binding acetylcholine receptor antibody titer was 1.22 nmol/L (normal value, 0.03 nmol/L). Repetitive 2-Hz nerve(median, ulnar, and facial) stimulation studies demonstrated up to a 16% decremental response. Chest computed tomography showed residual thymic tissue without thymoma. An extended transsternal thymectomy was performed 11 weeks after the onset of symptoms.

Adding more muscle and nerve to clinical trials.

In this review we illustrate both the fundamentals and challenges of randomized clinical trials in neuromuscular disorders and suggest directions for prospective efforts to improve the design, conduct, rigor, and objectivity of these trials. Current research in clinical trials for neuromuscular disorders and key issues affecting these trials are reviewed. This perspective addresses the planning of clinical research, level of preclinical data needed to justify trials, patient recruitment and retention, and opportunities to access federal funding and infrastructure in support of clinical trials. The need for innovation in trial design and conduct, rigorous standards for the preclinical efficacy and safety data that support trial rationale, novel collaborative paradigms, objective interpretations of outcomes, and sharing of the lessons learned from trials in any one disorder among all neuromuscular trialists are imperative to improving the heretofore limited success in delivering novel, safe, and effective therapies to patients burdened by neuromuscular disorders.

Training in Neurology: Feedback from Graduates About the Psychiatry Component of Residency Training.

OBJECTIVE: To obtain feedback from early career adult and pediatric neurologists about the psychiatry component of residency training. METHODS: A survey was developed and administered electronically to 4 cohorts of recently certified American Board of Psychiatry and Neurology diplomates. RESULTS: The response rate was 16% (431/2,677) and included 330 adult neurologists and 101 pediatric neurologists. Fewer than half of the respondents described themselves as extremely or quite satisfied with their psychiatry training whereas 26% of the adult neurologists and 33% of the pediatric neurologists felt slightly or not at all prepared for this component of practice. Four themes were identified in the respondents' suggestions for improving psychiatry training: provide more outpatient experience; provide more time/teaching in psychiatry; provide more experience with both pharmacologic and nonpharmacologic psychiatric treatments; and provide more exposure to patients with conditions likely to be encountered in neurology/child neurology practice. CONCLUSION: These recent graduates of adult and pediatric neurology residency programs felt underprepared for the psychiatric issues they encountered in their patients. They suggested a number of strategies for better alignment of psychiatry training with the likely demands of practice. A model curriculum recently developed by the American Academy of Neurology's Consortium of Neurology Program Directors and the American Association of Directors of Psychiatric Residency Training also provides guidance for both neurology and psychiatry program directors.

Fully automated 3D segmentation of MR-imaged calf muscle compartments: Neighborhood relationship enhanced fully convolutional network.

Automated segmentation of individual calf muscle compartments from 3D magnetic resonance (MR) images is essential for developing quantitative biomarkers for muscular disease progression and its prediction. Achieving clinically acceptable results is a challenging task due to large variations in muscle shape and MR appearance. In this paper, we present a novel fully convolutional network (FCN) that utilizes contextual information in a large neighborhood and embeds edge-aware constraints for individual calf muscle compartment segmentations. An encoder-decoder architecture is used to systematically enlarge convolution receptive field and preserve information at all resolutions. Edge positions derived from the FCN output muscle probability maps are explicitly regularized using kernel-based edge detection in an end-to-end optimization framework. Our method was evaluated on 40 T1-weighted MR images of 10 healthy and 30 diseased subjects by fourfold cross-validation. Mean DICE coefficients of 88.00-91.29% and mean absolute surface positioning errors of 1.04-1.66 mm were achieved for the five 3D muscle compartments.

Neurocognitive Features of Motor Premanifest Individuals With Myotonic Dystrophy Type 1.

OBJECTIVE: The goal of the study was to identify brain and functional features associated with premanifest phases of adult-onset myotonic dystrophy type 1 (i.e., PreDM1). METHODS: This cross-sectional study included 68 healthy adults (mean age = 43.4 years, SD = 12.9), 13 individuals with PreDM1 (mean age: 47.4 years, SD = 16.3), and 37 individuals with manifest DM1 (mean age = 45.2 years, SD = 9.3). The primary outcome measures included fractional anisotropy (FA), motor measures (Muscle Impairment Rating Scale, Grooved Pegboard, Finger-Tapping Test, and grip force), general cognitive abilities (Wechsler Adult Intelligence Scales), sleep quality (Scales for Outcomes in Parkinson's Disease-Sleep), and apathy (Apathy Evaluation Scale). RESULTS: Individuals with PreDM1 exhibited an intermediate level of white matter FA abnormality, where whole-brain FA was lower relative to healthy controls (difference of the estimated marginal mean [EMMdifference] = 0.02, 95% confidence interval (CI) 0.01-0.03, p < 0.001), but the PreDM1 group had significantly higher FA than did individuals with manifest DM1 (EMMdifference = 0.02, 95% CI 0.009-0.03, p < 0.001). Individuals with PreDM1 exhibited reduced performance on the finger-tapping task relative to control peers (EMMdifference = 5.70, 95% CI 0.51-11.00, p = 0.03), but performance of the PreDM1 group was better than that of the manifest DM1 group (EMMdifference = 5.60, 95% CI 0.11-11.00, p = 0.05). Hypersomnolence in PreDM1 was intermediate between controls (EMMdifference = -1.70, 95% CI -3.10-0.35, p = 0.01) and manifest DM1 (EMMdifference = -2.10, 95% CI -3.50-0.60, p = 0.006). CONCLUSIONS: Our findings highlight key CNS and functional deficits associated with PreDM1, offering insight in early disease course.