Randomized Double-Blind Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis.

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. METHODS: In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. RESULTS: The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. DISCUSSION: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson's disease.

BACKGROUND: Mutations in the F-box protein 7 (FBXO7) gene result in autosomal recessive parkinsonism. This usually manifests as early-onset parkinsonian-pyramidal syndrome but patients exhibit high phenotypic variability. Here we describe the findings of a Yemeni family with two novel FBXO7 mutations. METHODS: Clinical data and DNA were available for three siblings with early-onset parkinsonism together with their parents and three unaffected siblings. A targeted next generation sequencing panel was used to screen the proband for mutations in 14 genes known to cause a parkinsonian disorder. In addition, SNCA, PARK2, PINK1, and PARK7 were screened for copy number variants. RESULTS: The proband carried two novel compound heterozygous FBXO7 mutations: a missense mutation in exon 1 (p.G39R; c.115G > A) and a frameshift mutation in exon 5 (p.L280fs; c.838del). The mutations segregated with disease in the family with the exception of a potentially pre-symptomatic individual whose age was below the age of onset in two of their three affected siblings. P.G39R occurred at a highly conserved amino acid residue and both mutations were predicted to be deleterious in silico. In contrast to most reported families, the phenotype in this pedigree was consistent with clinically typical Parkinson's disease (PD) with a lack of pyramidal signs and good response to dopaminergic therapy. CONCLUSIONS: Our study expands the phenotype associated with FBXO7 to include early-onset PD and broadens the list of causative mutations. These data suggest that FBXO7 should be included in clinical genetic testing panels for PD, particularly in patients with early onset or a recessive inheritance pattern.

Clinical and electrodiagnostic features of sciatic neuropathies.

Sciatic neuropathy is the second most common neuropathy of the lower extremity and a common cause of foot drop. This article reviews the anatomy, clinical features, pathophysiology, and electrodiagnostic assessment of sciatic neuropathies. There are multiple potential sites of pathology, determined in part by the mechanism of insult, including trauma, compression, masses, inflammation, and vascular lesions. Diagnosis is augmented by careful electrodiagnostic studies and imaging to help distinguish sciatic neuropathy from other sources of pathology. Electrodiagnostic studies may also help in assessing for early recovery and in determining prognosis.

Inflammatory myopathies.

OPINION STATEMENT: The mainstay of treatment for the idiopathic inflammatory myopathies currently and traditionally has been therapeutics aimed at suppressing or modifying the immune system. Most therapies being used are directed towards polymyositis (PM) and dermatomyositis (DM), as there is yet to be efficacious treatment of any kind for inclusion body myositis (IBM), However, there are few randomized controlled studies supporting the use of such therapies even in PM and DM. Even in the absence of controlled studies, oral corticosteroids (in particular high-dose prednisone) continue to be the first-line medications used to manage these conditions. Second-line therapies include the addition of chronic, steroid-sparing immunosuppressive drugs such as azathioprine, methotrexate, cyclosporine, cyclophosphamide, and mycophenolate mofetil. These drugs are typically added when patients are on corticosteroids for an extended period or when the disease is refractory. Such medications often allow corticosteroid dosages to be reduced, but monitoring is required for their own side effects, such as bone marrow suppression, kidney dysfunction, and respiratory concerns. Small controlled studies also support the role of intravenous immunoglobulin therapy as an alternative therapy, particularly for DM, though the cost of this treatment is sometimes prohibitive. Rituximab, a monoclonal antibody that depletes B cells, has also shown efficacy in uncontrolled studies in DM and holds promise for the treatment of this disease. Other promising immunotherapies currently under study are inhibitors of interferon-α and tumor necrosis factor-α. Unfortunately, though a number of immunomodulatory treatments have been investigated in IBM, none has convincingly demonstrated benefit.

Paraneoplastic motor neuron disease associated with Purkinje cell autoantibody type 1.

Motor neuron disease has been reported as a rare result of systemic cancers, likely related to an autoimmune effecter mechanism. These patients have been described as having a more rapid onset of symptoms than typical motor neuron disease. Few of these reports demonstrate an association of a cancer-related autoantibody and with motor neuron disease. We present a 54-year-old woman with infiltrating ductal carcinoma of the breast who later developed lower motor neuron disease and was found to have Purkinje cell autoantibodies type 1. The association of lower motor neuron disease as a consequence of breast cancer with this autoantibody profile has not been described previously. This report emphasizes the importance of considering a paraneoplastic syndrome in a patient with an uncommon presentation of motor neuron disease.

The amyotrophic lateral sclerosis center: a model of multidisciplinary management.

Amyotrophic lateral sclerosis (ALS) is a devastating, progressive motor neuron disorder that poses a myriad of clinical problems. Patients who have ALS are best cared for in a multidisciplinary fashion, with involvement of clinicians from various specialties, including neurology, physical medicine and rehabilitation, pulmonary medicine, clinical nurse specialists or nurse practitioners, physical and occupational therapists, speech language pathologists, dietitians, psychologists, social workers, and case managers. This article provides a summary of the current research into the rehabilitation of ALS, including the role of exercise, spasticity management, mood disorders, pain, and palliative care.

Drug therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating condition characterized by progressive muscle wasting, inanition, respiratory failure, and death within approximately 2 to 5 years of onset. ALS is among the most common neuromuscular conditions, with an overall prevalence in the world of approximately 5 to 7 cases/100,000 population. Epidemiologic studies have identified some potential risk factors for developing ALS, including a high-fat, low-fiber diet; cigarette smoking; slimness and athleticism; and living in urban areas. Between 5% and 10% of ALS is genetic, with up to 11 genetic loci identified. Although understanding of the pathophysiology of this disease has advanced over the past 60 years, scant progress has been made regarding effective treatment. The authors review the current understanding of the pathogenic mechanisms of ALS and approaches to treating the disease.

Bilateral isolated phrenic neuropathy causing painless bilateral diaphragmatic paralysis.

The authors report four patients with a syndrome of painless bilateral isolated phrenic neuropathy. Electrophysiologic testing demonstrated active denervation restricted to the diaphragm. Long-term recovery was poor. The authors conclude that bilateral isolated phrenic neuropathy is a cause of painless diaphragmatic paralysis distinguishable from immune brachial plexus neuropathy and other neuromuscular disorders with similar clinical presentation.

Multiple Myeloma and Peripheral Neuropathy in Myotonic Dystrophy Type 2 (DM2).

Myotonic dystrophy type 2 (DM2) is a phenotypically heterogeneous multisystem disorder, most dramatically involving the nervous system. Although multisystem involvement is common in this disease, we present a genetically proven DM2 patient with both peripheral neuropathy and blood dyscrasia, previously unreported in the literature, suggesting a distinct phenotype in this population. Routine electrophoresis in DM2 patients with neuropathy is recommended, and implications surrounding the etiology of peripheral neuropathy and paraproteinemia in DM2 are discussed.

Neuromuscular transmission in amyotrophic lateral sclerosis.

The functional and structural characteristics of the neuromuscular junction were studied in anconeus muscle biopsies of 10 patients with amyotrophic lateral sclerosis (ALS). Intracellular recordings revealed decreased amplitudes of miniature endplate potentials (MEPPs). The MEPP frequencies were highly variable in ALS patients but the average MEPP frequency was not different from that of control patients. The mean quantal content of endplate potentials (m), the mean quanta available for immediate release (n), and the mean quantal stores (N) were all decreased. In contrast, the mean probability of quantal release (p) was normal and the mean probability of quantal store release (P) was surprisingly high at the majority of ALS endplates. Histologic evidence of denervation and small or absent nerve terminals were observed in all ALS patients. These functional and structural abnormalities of the neuromuscular junction may explain the fatigability and the electromyographic evidence of impaired neuromuscular transmission often encountered in ALS patients.

Anconeus muscle: a human muscle preparation suitable for in-vitro microelectrode studies.

We performed in-vitro microelectrode studies on the anconeus muscle of 14 patients with diseases of neuromuscular transmission. The procedure detected marked abnormalities in all patients studied, and may therefore be a valuable technique for the study of human disorders of neuromuscular transmission.