Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose.

BACKGROUND: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. METHODS: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. RESULTS: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12. CONCLUSIONS: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. TRIAL REGISTRATION: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

Anti-myelin-associated glycoprotein neuropathy: Where do we stand?

Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves as an antigen for immunoglobulin M (IgM) monoclonal antibodies. Individuals who harbor anti-MAG antibodies classically develop a progressive autoimmune peripheral neuropathy characterized clinically by ataxia, distal sensory loss, and gait instability, and electrophysiologically by distally accentuated conduction velocity slowing. Although off-label immunotherapy is common, there are currently no proven effective disease-modifying therapeutics, and most patients experience slow accumulation of disability over years and decades. The typically slowly progressive nature of this neuropathy presents unique challenges when trying to find effective anti-MAG therapeutic agents. Drug development has also been hampered by the lack of validated outcome measures that can detect clinically meaningful changes in a reasonable amount of time as well as by the lack of disease activity biomarkers. In this invited review, we provide an update on the state of clinicometric outcome measures and disease activity biomarkers in anti-MAG neuropathy. We highlight the insensitivity of widely used existing clinicometric outcome measures such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score as well as the INCAT sensory subscore in anti-MAG neuropathy, referencing the two previous negative randomized controlled clinical trials evaluating rituximab. We then discuss newly emerging candidate therapeutic agents, including tyrosine kinase inhibitors and enhanced B-cell-depleting agents, among others. We conclude with a practical approach to the evaluation and management of anti-MAG neuropathy patients.

Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy.

INTRODUCTION: With the advent of disease-altering therapies for spinal muscular atrophy (SMA), there is a requirement to better characterize outcome measures, particularly in milder forms of disease. METHODS: Maximal voluntary isometric contraction testing and 6-minute walk test (6MWT) performed in ambulatory SMA adults as part of the SMA-VALIANT trial were analyzed. Test-retest reliability and correlation with other candidate biomarkers and outcomes were investigated. RESULTS: Maximal voluntary isometric contraction testing and 6MWT showed good test-retest reliability (intraclass correlation coefficient = 0.98 and 0.85, respectively). Maximal voluntary isometric contraction testing and 6MWT demonstrated very strong correlation (r = 0.83, P <. 0001), and each correlated with the SMA Functional Rating Scale (r = 0.7, P < .0001 and r = 0.65, P = .0001, respectively), lean muscle mass (r = 0.68, P < .0001 and r = 0.56, P = .001, respectively), and ulnar compound muscle action potential (r = 0.57, P = .0008 and r = 0.47, P = .008, respectively). DISCUSSION: Maximal voluntary isometric contraction testing and 6MWT are suitable outcomes for use in ambulatory adults with SMA. Maximal voluntary isometric contraction testing may be preferable because of superior test-retest reliability and closer associations with other outcomes and biomarkers of neuromuscular function.

Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

Pregnancy and delivery in women with spinal muscular atrophy.

OBJECTIVES: To expand the limited available knowledge about pregnancy and delivery in women with spinal muscular atrophy (SMA) using a cohort of genetically proven SMA patients from USA. METHODS: This was a cross-sectional questionnaire-based study. We mailed questionnaires to 58 women with confirmed SMA. RESULTS: Thirty-two women responded, reporting 35 pregnancies, including 19 women with at least one pregnancy. In this cohort, preterm labor and delivery by cesarean section were more common in mothers with SMA particularly SMA type 2. Seventy-four percent of mothers reported increased weakness during pregnancy that persisted after delivery in 42%. SMA mothers generally had a positive experience and good outcomes and elected to have more than one pregnancy. CONCLUSION: This information regarding pregnancy in women with genetically confirmed 5q SMA will prove useful in guiding future research and in providing counseling to women with SMA.

Correlation of single-breath count test and neck flexor muscle strength with spirometry in myasthenia gravis.

INTRODUCTION: Although formal spirometry is the gold standard for monitoring respiratory function in patients with myasthenia gravis (MG), such testing is often delayed or unavailable. There is a need for a simple bedside test that can accurately measure respiratory function. METHODS: We conducted a prospective, cross-sectional, single-blind study in adults with acetylcholine receptor antibody positive MG. Participants performed the single breath count test (SBCT) and underwent manual muscle strength testing, and a respiratory therapist performed spirometry blinded to SBCT and strength results. RESULTS: Thirty-one patients, aged 57 ± 19 years participated. SBCT showed significant correlations with forced vital capacity (FVC), negative inspiratory force, and neck flexor strength (P < 0.01). FVC showed significant correlation with neck flexor strength (P = 0.02) but no correlation with shoulder abductor strength. CONCLUSIONS: These data suggest that the SBCT and neck flexor strength testing are valuable tools for bedside assessment of respiratory function in MG patients.

The clinical spectrum of isolated peripheral motor dysfunction.

INTRODUCTION: Isolated peripheral motor dysfunction due to lower motor neuron or peripheral nerve disorders presents an interesting challenge to clinicians because of the diverse differential diagnosis with a broad range of prognoses. METHODS: We retrospectively reviewed clinical data of adults who presented over 12 years with muscle weakness, atrophy, or fasciculations, but without hyperreflexia or sensory involvement. RESULTS: In 119 patients, 52% had a motor neuron disease (MND), 13% had immune neuropathies, 11% had genetic neuronopathies, 10% had residual or post-polio syndrome, 5% had benign fasciculation, 1% had an infectious etiology, and 8% were not given a final diagnosis. Only MND patients had cognitive dysfunction or frontal release signs. Bulbar and respiratory symptoms virtually excluded consideration of immune neuropathy. CONCLUSIONS: Only half of the patients were diagnosed with MND. A significant minority have treatable conditions. Cognitive involvement, frontal release signs, and bulbar or respiratory symptoms are strongly suggestive of MND.

Neuromuscular junction disorders mimicking myopathy.

INTRODUCTION: Small-amplitude, short-duration motor unit action potentials are non-specific findings seen in myopathies and neuromuscular junction (NMJ) disorders. NMJ studies (repetitive nerve stimulation and single-fiber electromyography) can determine if such findings are related to NMJ abnormalities but are not considered routinely in atypical cases. METHODS: Medical records of 338 patients with confirmed NMJ disorders were reviewed to identify cases with a clinical or electrodiagnostic impression of myopathy during initial evaluation. A history of muscle biopsy with findings that did not support a myopathic process was required for inclusion. RESULTS: Four patients met the inclusion criteria. NMJ studies were abnormal in all cases. One patient had elevated acetylcholine receptor antibodies. Three patients were antibody negative: 2 demonstrated immunotherapy responsiveness, and 1 had a Rapsyn mutation. CONCLUSIONS: NMJ disorders may mimic myopathies, and NMJ studies should be performed to clarify so-called "myopathic" electromyographic findings to avoid unnecessary testing and delayed diagnosis.

SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy.

INTRODUCTION: An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults. METHODS: There were 33 subjects, aged 20­55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10­20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. RESULTS: Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. CONCLUSIONS: VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.

Rasch analysis of clinical outcome measures in spinal muscular atrophy.

INTRODUCTION: Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). METHODS: Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. RESULTS: Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. CONCLUSIONS: The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges.

Male Reproduction in Spinal Muscular Atrophy (SMA) and the Potential Impact of Oral Survival of Motor Neuron 2 (SMN2) Pre-mRNA Splicing Modifiers.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene resulting in reduced levels of SMN protein. SMN protein is produced by cells throughout the body, and evidence suggests that low SMN protein can have systemic implications, including in male reproductive organs. However, a paucity of research exists on this important topic. This article will discuss findings from non-clinical studies on the role of SMN in the male reproductive system; additionally, real-world observational reports of individuals with SMA will be examined. Furthermore, we will review the non-clinical reproductive findings of risdiplam, a small-molecule SMN2 splicing modifier approved for the treatment of SMA, which has widespread distribution in both the central nervous system and peripheral organs. Specifically, the available non-clinical evidence of the effect of risdiplam on male reproductive organs and spermatogenesis is examined. Lastly, the article will highlight available capabilities to assess male fertility as well as the advanced reproductive technologies utilized to treat male infertility. This article demonstrates the need for further research to better understand the impacts of SMA on male fertility and reproduction.

Characterizing Ventilatory Muscle Dysfunction in Inclusion Body Myositis.

OBJECTIVE: Investigation of the frequency and progression of ventilatory muscle dysfunction in patients with inclusion body myositis, the most common myopathy after age of 50 yrs. Prior research is limited to case series and cross-section studies. DESIGN: This is a retrospective review of pulmonary function tests, respiratory symptoms, and muscle strength testing. RESULTS: Of the 54 patients reviewed (mean age: 65 ± 9 yrs and disease duration: 7 ± 7 yrs), the majority ( n = 32, 59%) had restrictive forced vital capacity deficits at initial visit. Patients with reduced forced vital capacity showed higher prevalence of respiratory symptoms; but age, body mass index, and limb strength were similar when compared with patients without restrictive forced vital capacity. Mean rate of forced vital capacity decline of 0.108 l/yr in inclusion body myositis patients. Lower baseline limb strength correlated with longer disease duration and future forced vital capacity decline (eg, weaker patients experienced faster decline). CONCLUSIONS: Based on forced vital capacity, there is a high frequency of ventilatory pump muscle weakness in inclusion body myositis, which is associated with a higher burden of respiratory symptoms. Baseline strength may indicate risk of respiratory decline and need for vigilant screening. Importantly, ventilatory and limb muscle decline may not progress in a corresponding manner, highlighting the importance of pulmonary function surveillance.

Differential impact on motor unit characteristics across severities of adult spinal muscular atrophy.

OBJECTIVE: To test the hypotheses that decomposition electromyography (dEMG) motor unit action potential (MUAP) amplitude and firing rate are altered in SMA; dEMG parameters are associated with strength and function; dEMG parameters are correlated with traditional electrophysiological assessments. METHODS: Ambulatory and non-ambulatory adults with SMA on nusinersen and healthy controls were enrolled. MUAPs were decomposed from multielectrode surface recordings during 30-s maximum contraction of the abductor digiti minimi (ADM). Isometric strength, upper limb function, patient-reported function, and standard electrophysiologic measures of the ADM (compound muscle action potential [CMAP], single motor unit potential [SMUP], motor unit number estimation [MUNE]) were collected. RESULTS: dEMG MUAP amplitudes were higher in ambulatory versus control and non-ambulatory groups and were higher in controls versus non-ambulatory SMA. In contrast, dEMG firing rates were higher in ambulatory versus non-ambulatory and control groups but similar between non-ambulatory and control. dEMG parameters showed moderate to strong positive correlation with strength and function whereas CMAP and MUNE better correlated with function than strength. SMUP did not correlate with strength, function, or dEMG MUAP amplitude. dEMG parameters show overall good test-retest reliability. INTERPRETATION: dEMG provided reliable, noninvasive measure of MUAP amplitude size and firing rate and revealed divergent patterns across disease severity in adults with SMA. Firing rate enhancement, as seen in milder SMA, may provide a therapeutic avenue for improving function in more severe SMA, where firing rates appear preserved. MUAP amplitude size and firing rate, quantified with dEMG, may be promising monitoring biomarker candidates for noninvasive assessment of SMA.

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1) gene and reduced expression levels of the survival motor neuron (SMN) protein. Degeneration of alpha motor neurons in the spinal cord causes progressive skeletal muscle weakness. The wide range of disease severities, variable rates of decline, and heterogenous clinical responses to approved disease-modifying treatment remain poorly understood and limit the ability to optimize treatment for patients. Validation of a reliable biomarker(s) with the potential to support early diagnosis, inform disease prognosis and therapeutic suitability, and/or confirm response to treatment(s) represents a significant unmet need in SMA. OBJECTIVES: The SMA Multidisciplinary Biomarkers Working Group, comprising 11 experts in a variety of relevant fields, sought to determine the most promising candidate biomarker currently available, determine key knowledge gaps, and recommend next steps toward validating that biomarker for SMA. METHODS: The Working Group engaged in a modified Delphi process to answer questions about candidate SMA biomarkers. Members participated in six rounds of reiterative surveys that were designed to build upon previous discussions. RESULTS: The Working Group reached a consensus that neurofilament (NF) is the candidate biomarker best poised for further development. Several important knowledge gaps were identified, and the next steps toward filling these gaps were proposed. CONCLUSIONS: NF is a promising SMA biomarker with the potential for prognostic, predictive, and pharmacodynamic capabilities. The Working Group has identified needed information to continue efforts toward the validation of NF as a biomarker for SMA.

Lean tissue mass measurements by dual-energy X-ray absorptiometry and associations with strength and functional outcome measures in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive disease of skeletal muscle. Dual energy X-ray absorptiometry (DEXA) is a widely available, cost-effective and sensitive technique for measuring whole body and regional lean tissue mass and has been used in prior clinical trials in neuromuscular diseases. The Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study is a prospective, longitudinal, observational multisite study. We obtained concurrent DEXA scans and functional outcome measurements in 185 patients with FSHD at the baseline visit. We determined the associations between lean tissue mass in the upper and lower extremities and corresponding clinical outcome measures. There were moderate correlations between upper and lower extremity lean tissue mass and their corresponding strengths and function. Lean tissue mass obtained by DEXA scan may be useful as a biomarker in future clinical trials in FSHD.

Prognosis of acute compressive radial neuropathy.

INTRODUCTION: Small published case series suggest that compressive radial neuropathy is often a self-limited phenomenon with a favorable prognosis. Due to paucity of data, we sought to clearly define prognosis. METHODS: To define clinical and electrodiagnostic features in this condition, we retrospectively reviewed consecutive cases of compressive radial neuropathy confirmed using electrodiagnostic studies at a large tertiary center over a 10-year period. RESULTS: A total of 51 patients (26 men, 25 women, mean age 46 years ± 15; range, 19-83 years) with compressive radial neuropathy were identified and reviewed. All patients in whom clinical follow-up was available (23 [45%] of the 51 patients identified) experienced complete recovery. Mean duration from onset to resolution of symptoms was 3.4 months. CONCLUSIONS: Our results support a good prognosis in essentially all patients with acute compressive radial neuropathies. This report provides valuable information to assist in counseling patients who may present with profound clinical deficits.

Neurofilament Levels in CSF and Serum in an Adult SMA Cohort Treated with Nusinersen.

OBJECTIVE: To retrospectively evaluate the utility of serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) as biomarkers for spinal muscular atrophy (SMA) progression and response to nusinersen treatment. METHODS: NfL and pNfH levels were quantified using single molecular array (SIMOA) in CSF of 33 adult SMA patients (SMN copy number 3-5) before and in response to nusinersen treatment. In 11 of the patients, blood serum samples were also collected. CSF NfL and pNfH from patients were compared to CSF Nfs from age-matched controls without neurological disease (n = 6). For patients, pearson correlation coefficients (r) were calculated to investigate associations between Nf levels and other functional outcome measures. RESULTS: Nf levels were similar between SMA and control adults and showed no change in response to nusinersen treatment in CSF or serum. Cross-sectional analyses showed an increase in CSF NfL and pNfH with age in patients (NfL p = 0.0013; pNfH p = 0.0035) and an increase in CSF NfL in controls (p = 0.002). In non-ambulatory patients, baseline serum pNfH showed a negative correlation with multiple strength and functional assessment metrics including Revised Upper Limb Module (r = -0.822, p = 0.04), upper extremity strength (r = -0.828, p = 0.042), lower extremity strength (r = -0.860, p = 0.028), and total strength (r = -0.870, p = 0.024). CONCLUSIONS: Nf levels did not change in response to nusinersen in adults with SMA and were not different from controls. In patients and controls, we detected an age-related increase in baseline CSF NfL and pNfH levels. Though some associations were identified, our results suggest Nf levels are not preditive or prognostic biomarkers in this population.

Recurrent Miller Fisher: A Case Report Along With a Literature and an EMG/NCS Review.

MFS has been reported to recur in 10-12% of patients. There may be a genetic component related to HLA-DR2. Anti-GAD antibodies can be present in MFS along with anti-GQ1b. Common EMG/NCS associations consist of a predominantly axonal, sensory polyneuropathy and absent H reflexes. A 32-year-old female with a history of hypothyroidism presented to our institution twice with symptoms of diplopia, lower extremity weakness and distal paresthesias occurring a year apart. She had ophthalmoplegia, reduced reflexes, and ataxia on exam. CSF showed a borderline elevated protein of 47 and white blood cells <3. She was positive for anti-GQ1b both times. Her anti-GAD65 antibody was elevated during both admissions. EMG/NCS on her first admission revealed comparatively reduced sensory nerve action potentials (SNAPs) and a normal blink reflex. Her SNAPs improved on the second admission, however, the EMG was performed only 2 days after the onset of her symptoms, limiting some early findings that may have not matured electrophysiologically. She was treated with IVIG on both occasions with rapid recovery within 5 days. This case highlights the fact that MFS can be recurrent. It also provides further evidence that anti-GAD antibodies may be associated with MFS. Reported findings of the blink reflex in MFS are diverse and further data is needed to determine if certain findings are more predominant than others. Treatment typically consists of IVIG, though steroids may also be considered for recurrence. Prognosis is generally favorable, regardless of treatment.

Cerebrospinal Fluid Protein Level and Mechanical Ventilation in Guillain-Barré Syndrome patients.

The prognostic value of cerebrospinal fluid (CSF) protein in Guillain Barré Syndrome (GBS) is unclear. We aimed to explore the potential association between CSF protein level and mechanical ventilation in GBS. We undertook a retrospective study of GBS patients from January 2000 to November 2019 at the University of Michigan. 94 patients were ultimately included for evaluation. After adjusting for the Erasmus GBS Respiratory Insufficiency Scale (EGRIS), we did not find a significant difference in CSF protein between ventilated and non-ventilated patients. Elevated CSF protein level does not appear to portend an increased likelihood of mechanical ventilation in GBS patients.

Elevated Creatinine Kinase in Peripheral Neuropathy Is Associated With Muscle Cramping.

Introduction: Serum Creatinine Kinase (CK) is a non-specific marker of muscle damage. There has been limited investigation of the association between peripheral neuropathy and CK elevation (hyperCKemia). Methods: We performed a chart review to investigate the CK level in peripheral neuropathies. Demographics, clinical history, physical exam, electrodiagnostic data, CK level, statin use, etiology of neuropathy, and concomitant neuromuscular disorders were recorded. HyperCKemia was defined using our laboratory cutoff values of >180 U/L (women) and >220 U/L (men). Results: We identified 450 patients with peripheral neuropathy who had CK testing, 92 (20.4%) of whom had hyperCKemia. Sixty-one of those patients (13.5% of the total figure) had a concomitant etiology that could explain the CK elevation. Thirty-one patients (6.9%) had no other identifiable etiology for their hyperCKemia beyond the neuropathy. The average CK level in the latter cohort with hyperCKemia was 376 U/L (women: 312 U/L; men: 444 U/L). The frequency of cramping was greater in patients with elevated vs. normal CK (p < 0.0001). Discussion: HyperCKemia can occur in patients with peripheral neuropathy and appears to associate with cramping.