Safety and Efficacy of Topiramate in Individuals With Cryptogenic Sensory Peripheral Neuropathy With Metabolic Syndrome: The TopCSPN Randomized Clinical Trial.

Importance: Cryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase neuropathy risk. Diet and exercise have shown promise but are limited by poor adherence. Objective: To determine whether topiramate can slow decline in intraepidermal nerve fiber density (IENFD) and/or neuropathy-specific quality of life measured using the Norfolk Quality of Life-Diabetic Neuropathy (NQOL-DN) scale. Design, Setting, and Participants: Topiramate as a Disease-Modifying Therapy for CSPN (TopCSPN) was a double-blind, placebo-controlled, randomized clinical trial conducted between February 2018 and October 2021. TopCSPN was performed at 20 sites in the National Institutes of Health-funded Network for Excellence in Neurosciences Clinical Trials (NeuroNEXT). Individuals with CSPN and metabolic syndrome aged 18 to 80 years were screened and randomly assigned by body mass index (<30 vs ≥30), which is calculated as weight in kilograms divided by height in meters squared. Patients were excluded if they had poorly controlled diabetes, prior topiramate treatment, recurrent nephrolithiasis, type 1 diabetes, use of insulin within 3 months before screening, history of foot ulceration, planned bariatric surgery, history of alcohol or drug overuse in the 2 years before screening, family history of a hereditary neuropathy, or an alternative neuropathy cause. Interventions: Participants received topiramate or matched placebo titrated to a maximum-tolerated dose of 100 mg per day. Main Outcomes and Measures: IENFD and NQOL-DN score were co-primary outcome measures. A positive study was defined as efficacy in both or efficacy in one and noninferiority in the other. Results: A total of 211 individuals were screened, and 132 were randomly assigned to treatment groups: 66 in the topiramate group and 66 in the placebo group. Age and sex were similar between groups (topiramate: mean [SD] age, 61 (10) years; 38 male [58%]; placebo: mean [SD] age, 62 (11) years; 44 male [67%]). The difference in change in IENFD and NQOL-DN score was noninferior but not superior in the intention-to-treat (ITT) analysis (IENFD, 0.21 fibers/mm per year; 95% CI, -0.43 to ∞ fibers/mm per year and NQOL-DN score, -1.52 points per year; 95% CI, -∞ to 1.19 points per year). A per-protocol analysis excluding noncompliant participants based on serum topiramate levels and those with major protocol deviations demonstrated superiority in NQOL-DN score (-3.69 points per year; 95% CI, -∞ to -0.73 points per year). Patients treated with topiramate had a mean (SD) annual change in IENFD of 0.56 fibers/mm per year relative to placebo (95% CI, -0.21 to ∞ fibers/mm per year). Although IENFD was stable in the topiramate group compared with a decline consistent with expected natural history, this difference did not demonstrate superiority. Conclusion and Relevance: Topiramate did not slow IENFD decline or affect NQOL-DN score in the primary ITT analysis. Some participants were intolerant of topiramate. NQOL-DN score was superior among those compliant based on serum levels and without major protocol deviations. Trial Registration: ClinicalTrials.gov Identifier: NCT02878798.

Choroid plexus mis-splicing and altered cerebrospinal fluid composition in myotonic dystrophy type 1.

Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knock-in model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knock-in mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from neurologically unaffected (two females, three males; ages 50-70 years) and myotonic dystrophy type 1 (one female, three males; ages 50-70 years) donors. To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55 years) and non-myotonic dystrophy patients (three females, four males; ages 26-51 years), and western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knock-in mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knock-in mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.

Remote assessment of myotonic dystrophy type 1: A feasibility study.

INTRODUCTION/AIMS: Remote study visits (RSVs) are emerging as important tools for clinical research. We tested the feasibility of using RSVs to evaluate patients with myotonic dystrophy type 1 (DM1), including remote quantitative assessment of muscle function, and we assessed correlations of remote assessments with patient-reported function. METHODS: Twenty three subjects with DM1 were consented remotely. Toolkits containing a tablet computer, grip dynamometer, and spirometer were shipped to participants. The tablets were loaded with software for video-conferencing and questionnaires about functional impairment, patient experience with technology, and willingness to participate in future remote studies. Grip strength, forced vital capacity, peak cough flow, timed-up-and-go (TUG), and grip myotonia (hand opening time) were determined during RSVs. We assessed correlations of remote assessments with patient-reported outcomes of muscle function and with CTG repeat size. RESULTS: All 23 subjects completed RSVs. 95% of participants were able to complete all components of the remote study. All toolkit components were returned upon completion. Grip strength and TUG demonstrated moderate to strong correlations with self-reported inventories of upper and lower extremity impairment, respectively (ρ = 0.7 and ρ = -0.52). A total of 91% of subjects expressed interest in participating in future RSVs. DISCUSSION: Results of this study support the feasibility of using portable devices and video-conferencing for remote collection of patient-reported outcomes and quantitative assessment of muscle function in DM1.

In Vivo Reflectance Microscopy of Meissner Corpuscles and Bedside Measures of Large Fiber Sensory Function: A Normative Data Cohort.

BACKGROUND AND OBJECTIVES: The goal of this work was to establish age-, sex-, and body dimension-adjusted normal cutoff values for Meissner corpuscle (MC) densities via in vivo reflectance confocal microscopy (RCM), timed vibration sensory thresholds with a 128-Hz tuning fork, and touch-pressure sensory thresholds with standardized monofilaments for clinical and research application. METHODS: Seventy-seven prospectively recruited individuals without signs or symptoms of peripheral neuropathy or a condition or neurotoxin exposure that can alter sensory function underwent cross-sectional evaluation of MC densities via in vivo RCM, monofilament touch-pressure sensory thresholds, and timed vibration sensory thresholds in nondominant upper and lower extremities. Age-, sex-, and body dimension (e.g., height)-adjusted normal values were developed. The fifth percentile for MC densities and timed vibration thresholds and 95th percentile for MF touch-pressure thresholds were selected as normal cutoff points. RESULTS: Participants were 9 to 89 years of age. Age and sex were uniformly distributed. Timed vibration and touch-pressure thresholds were less sensitive with increasing age and were more sensitive in the hand than in the leg or foot within individuals. Timed vibration thresholds did not differ by sex or body dimensions. Touch-pressure thresholds were lower (more sensitive) at the thenar eminence and digit V in the hand in women compared to men but otherwise did not differ by sex at other measurement locations. Body dimensions did not affect touch-pressure thresholds. There were no apparent age-related floor effects for the 5th and 95th percentile normal cutoff values for timed vibration or touch-pressure thresholds, respectively. MC densities also declined with age and were highest at digit V and lowest at the arch within individuals. MC densities were affected by sex or body dimensions at all imaging sites, with lower densities seen in male participants or larger individuals. MC densities were quantifiable in the hand of all participants and were associated with touch-pressure thresholds at all locations. DISCUSSION: This study establishes age-, sex-, and body dimension-adjusted normal cutoff values for 2 easily applied measures of large fiber sensory function and RCM assessment of MC densities for multiple limb locations. These results will aid in the detection and monitoring of peripheral sensory nerve disorders.

Practicing in a Pandemic: A Clinician's Guide to Remote Neurologic Care.

Neurologists around the country and the world are rapidly transitioning from traditional in-person visits to remote neurologic care because of the coronavirus disease 2019 pandemic. Given calls and mandates for social distancing, most clinics have shuttered or are only conducting urgent and emergent visits. As a result, many neurologists are turning to teleneurology with real-time remote video-based visits with patients to provide ongoing care. Although telemedicine utilization and comfort has grown for many acute and ambulatory neurologic conditions in the past decade, remote visits and workflows remain foreign to many patients and neurologists. Here, we provide a practical framework for clinicians to orient themselves to the remote neurologic assessment, offering suggestions for clinician and patient preparation before the visit; recommendations to manage common challenges with remote neurologic care; modifications to the neurologic examination for remote performance, including subspecialty-specific considerations for a variety of neurologic conditions; and a discussion of the key limitations of remote visits. These recommendations are intended to serve as a guide for immediate implementation as neurologists transition to remote care. These will be relevant not only for practice today but also for the likely sustained expansion of teleneurology following the pandemic.

Measuring peripheral nerve involvement in Friedreich's ataxia.

OBJECTIVE: Experimental therapies under development for Friedreich's Ataxia (FRDA) require validated biomarkers. In-vivo reflectance confocal microscopy (RCM) of skin is a noninvasive way to quantify Meissner's corpuscle (MC) density and has emerged as a sensitive measure of sensory polyneuropathies. We conducted a prospective, cross-sectional study evaluating RCM of MCs and conventional peripheral nerve measures as candidate peripheral nerve markers in FRDA. METHODS: Sixteen individuals with FRDA and 16 age- and gender-matched controls underwent RCM of MC density and morphology, skin biopsies for epidermal nerve fiber density (ENFD), nerve conduction studies (NCS), and quantitative sensory testing (QST) including touch, vibration, and cooling thresholds. RESULTS: MC densities were measurable in all participants with FRDA, and were lower at digit V (hand), thenar eminence, and arch (foot) compared to controls. By contrast, sensory NCS showed floor effects and were obtainable in only 13% of FRDA participants. QST thresholds for touch, vibration, and cooling were higher at the hand and foot in FRDA than controls. Reductions in ENFDs were present in more severely affected individuals with FRDA (Friedreich's Ataxia Rating Scale (FARS) >60) compared to matched controls, although skin biopsies were not well tolerated in children. MC densities, ENFDs, and touch and vibration thresholds were associated with clinical disease severity (FARS and modified FARS) and duration since symptom onset. INTERPRETATION: MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.

The Charcot-Marie-Tooth Health Index: Evaluation of a Patient-Reported Outcome.

OBJECTIVE: The development of a disease-specific patient-reported outcome for Charcot-Marie-Tooth disease is an important step in the preparation for therapeutic trials. This study describes the development of the Charcot-Marie-Tooth Health Index (CMTHI). METHODS: Inherited Neuropathy Consortium Contact Registry participants were queried on the symptoms that most impacted their lives. The CMTHI was developed based on these responses. Factor analysis, assessment of test-retest reliability, known group validity, and patient interviews were utilized to refine the instrument. RESULTS: The final CMTHI contains 18 themes that capture Charcot-Marie-Tooth disease (CMT) burden. The CMTHI has a high internal consistency and test-retest reliability. The CMTHI was able to discriminate between patient groups expected to have different disease burden. The CMTHI was able to discriminate levels of disability as measured by the CMT examination score and the mobility-Disability Severity Index. INTERPRETATION: The CMTHI represents a valid and reliable outcome to assess patient-reported disease burden in CMT. Ann Neurol 2018;84:225-233.

In-vivo reflectance confocal microscopy of Meissner's corpuscles in diabetic distal symmetric polyneuropathy.

OBJECTIVE: To evaluate in-vivo reflectance confocal microscopy (RCM) of Meissner's corpuscles (MC) in diabetic distal symmetric polyneuropathy (DSP). METHODS: Forty-three adults with diabetes and 21 control subjects underwent RCM of MC density at the fingertip of digit V, thenar eminence (TE), and arch of the foot, ankle skin biopsy for epidermal nerve fiber density (ENFD), electrophysiological studies, monofilament threshold testing, and timed vibration at the toe. Subjects with diabetes were subdivided into groups with and without clinical DSP using the American Academy of Neurology (AAN) case definition and neuropathy outcomes were compared across groups. RESULTS: Both diabetic groups (with and without AAN clinical DSP criteria) had objective evidence of peripheral sensory involvement using conventional sensory measures, although those with clinical DSP criteria had greater abnormalities. MC densities were lower in the entire diabetic group at the TE and digit V relative to controls. MC densities at all imaging sites were associated with corresponding conventional sensory measures. MC densities were reduced in subjects without AAN clinical DSP criteria at the TE and digit V compared to controls whereas conventional upper limb sensory measures did not differ between these groups. CONCLUSIONS: In-vivo RCM of MC density at digit V is a non-invasive, painless, objective marker in diabetes that offers a window into early large fiber sensory nerve terminal loss. Further studies are needed to determine whether RCM of MCs can identify quantitative changes in DSP associated with disease progression or treatment.

International service and public health learning objectives for medical students.

OBJECTIVE: We aimed to improve the education of medical students involved in a longitudinal perinatal health improvement project in Gowa, Malawi. DESIGN: We conducted qualitative interviews with students who participated in the project, reviewed their quantitative reports, and assessed the application of methodologies consonant with the learning objectives of a novel community health improvement course within their experience. SETTING: The Gowa Health Promotions Project, designed to improve perinatal care for women and their families within the Gowa Health Clinic, used community participatory research strategies. METHOD: Medical students partnered with clinic workers and the local residents, evaluated, and revised an existing perinatal educational program. Qualitative and quantitative health and program data were collected, and program revisions were implemented. The value of the student experiences as a public health educational tool was evaluated by the authors. RESULTS: Project sustainability was enhanced by a fellowship and planning for sequential students. The community health course structure and goals enhanced learning in the project. Engagement of investigators as early as possible in an international public health enhancement project improves student learning and ongoing commitment. CONCLUSION: Service learning objectives aimed at providing valuable medical learning to student learners immersed in other cultures are consistent with evidence-based learning objectives in the field of public health. Proactively structuring this experience to explicate these goals can enhance student learning. This dual strategy may improve the sustainability of international health programs by educating medical students while leading them into careers where these skills will be leveraged.

Integrating speech and iconic gestures in a Stroop-like task: evidence for automatic processing.

Previous research has demonstrated a link between language and action in the brain. The present study investigates the strength of this neural relationship by focusing on a potential interface between the two systems: cospeech iconic gesture. Participants performed a Stroop-like task in which they watched videos of a man and a woman speaking and gesturing about common actions. The videos differed as to whether the gender of the speaker and gesturer was the same or different and whether the content of the speech and gesture was congruent or incongruent. The task was to identify whether a man or a woman produced the spoken portion of the videos while accuracy rates, RTs, and ERPs were recorded to the words. Although not relevant to the task, participants paid attention to the semantic relationship between the speech and the gesture, producing a larger N400 to words accompanied by incongruent versus congruent gestures. In addition, RTs were slower to incongruent versus congruent gesture-speech stimuli, but this effect was greater when the gender of the gesturer and speaker was the same versus different. These results suggest that the integration of gesture and speech during language comprehension is automatic but also under some degree of neurocognitive control.

An intentional stance modulates the integration of gesture and speech during comprehension.

The present study investigates whether knowledge about the intentional relationship between gesture and speech influences controlled processes when integrating the two modalities at comprehension. Thirty-five adults watched short videos of gesture and speech that conveyed semantically congruous and incongruous information. In half of the videos, participants were told that the two modalities were intentionally coupled (i.e., produced by the same communicator), and in the other half, they were told that the two modalities were not intentionally coupled (i.e., produced by different communicators). When participants knew that the same communicator produced the speech and gesture, there was a larger bi-lateral frontal and central N400 effect to words that were semantically incongruous versus congruous with gesture. However, when participants knew that different communicators produced the speech and gesture--that is, when gesture and speech were not intentionally meant to go together--the N400 effect was present only in right-hemisphere frontal regions. The results demonstrate that pragmatic knowledge about the intentional relationship between gesture and speech modulates controlled neural processes during the integration of the two modalities.