To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG).
We performed a 12-month multicenter, randomized, double-blind, ...placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody-positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living.
Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4-12 prednisone AUDTC when compared to placebo (difference MTX - placebo: -488.0 mg, 95% confidence interval -2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%).
We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials.
This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.
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.
This is a retrospective review of pulmonary function tests, respiratory symptoms, and muscle strength testing.
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).
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.
Entrapment neuropathies Arnold, William David; Elsheikh, Bakri H
Neurologic clinics,
05/2013, Volume:
31, Issue:
2
Journal Article
Peer reviewed
Compression neuropathy includes a heterogeneous group of focal neuropathy syndromes related to peripheral nerve compression. Although acute or chronic compression-related injury may occur in ...essentially any peripheral nerve, certain anatomic considerations may predispose certain nerves to intrinsic or extrinsic compression-related injury. The clinical presentations of specific compression or entrapment syndromes depend on factors such as chronicity, location, severity, and mechanism of involvement of a particular nerve. In this article the diagnosis and management strategies of the more common and well-established entrapment and compression-related neuropathy syndromes are addressed.
Objective:
To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical ...function, and motor unit physiology.
Methods:
Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment.
Results:
Six women, seven men (mean age: 37 ± 11, range: 18–59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable.
Conclusions:
Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring
via
improved motor unit reinnervation capacity.
Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA).
Non-ambulatory individuals, aged 18 years or older ...with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1-C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology compound muscle action potential (CMAP), single motor unit size, and motor unit number were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded.
Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21-64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable.
Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.
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).
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).
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 (
< 0.0001).
HyperCKemia can occur in patients with peripheral neuropathy and appears to associate with cramping.
Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of ...therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly.
While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects.
ClinicalTrials.gov.
Horner's syndrome is an established clinical finding unique to neoplastic brachial plexopathy.
We present the case of a patient who developed Horner's syndrome as the first manifestation of ...neurolymphomatosis (NL) of the brachial plexus that did not have the usually associated bulky adenopathy/Pancoast syndrome phenotype.
We discuss the clinical utility of Horner's syndrome with regards to brachial plexopathy of indeterminate etiology, as well as the utility of other diagnostic modalities in NL.
NL, particularly of the brachial plexus, is particularly challenging to diagnose. MRI and CSF studies are often inconclusive. FDG-PET imaging can be difficult to get insurance to approve. The presence of Horner's syndrome in brachial plexopathy of indeterminate etiology, even in the absence of bulky adenopathy, should raise clinical suspicion of NL, possibly prompting such interventions as fascicular nerve biopsy.
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.
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.
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