Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis.

Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355).Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival.Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time.Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial.

INTRODUCTION: Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). METHODS: We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting. RESULTS: There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. DISCUSSION: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.

Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort.

OBJECTIVES: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). METHODS: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. RESULTS: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. CONCLUSIONS: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.

Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome.

Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD.

ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): study methodology, recruitment, and baseline demographic and disease characteristics.

Abstract In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3-6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer 'definite ALS' diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

Isolated neck extensor myopathy: is it responsive to immunotherapy?

OBJECTIVE: To determine if isolated neck extensor myopathy (INEM) is responsive to immunosuppressive treatment. METHODS: We retrospectively reviewed charts of patients with INEM from 2002 to 2008 to identify patients and determine the response to immunomodulatory therapy. Clinical, electrodiagnostic, histologic, and radiographic data were reviewed. RESULTS: Four patients were identified during the study period. Three were women. The age of onset of neck extensor weakness ranged from 58 to 78 years. Serum creatine kinase levels were within normal limits in all patients. None had clinical, laboratory, or electrophysiological findings to suggest a generalized neuromuscular disorder. On electrodiagnostic studies, all patients had myopathic changes with or without irritative features in cervical paraspinal muscles. No inflammation was present on muscle biopsy from three of the patients. All patients received one or more immunosuppressive agents. Neck strength improved by 1 point or greater on the Medical Research Council scale in all subjects with a peak response observed between 3 and 6 months after treatment initiation. CONCLUSIONS: A trial of immunosuppressive agents should be offered to patients with INEM because a subset will improve. Rigorously defined, INEM is a noninflammatory myopathy. However, a focal myositis could be missed on muscle biopsy and may explain the favorable response to treatment.

Reversible nitrous oxide-induced myeloneuropathy with pernicious anemia: case report and literature review.

A previously healthy 27-year-old woman developed a subacute myeloneuropathy after receiving nitrous oxide anesthesia for dental procedures. Neurologic evaluation revealed that she was vitamin B(12) deficient due to underlying pernicious anemia. Discontinuation of nitrous oxide and supplementation with vitamin B(12) resulted in dramatic clinical improvement, with near-complete normalization of her neurologic examination. This case and published reports reviewed here emphasize that favorable outcomes are possible following prompt recognition and treatment of vitamin B(12) deficiency.

Repetitive nerve stimulation of facial muscles in MuSK antibody-positive myasthenia gravis.

To better define electrophysiological abnormalities in myasthenia gravis (MG) patients with muscle-specific tyrosine kinase (MuSK) antibodies (Ab), we compared electrophysiological features of 14 MuSK Ab-positive, 73 acetylcholine receptor antibody (AChR Ab)-positive, and 22 MuSK and AChR Ab-negative (seronegative) patients with generalized disease. Repetitive nerve stimulation (RNS) abnormalities were observed in 86% of MuSK Ab-positive and 82% of AChR Ab-positive patients but in only 55% of seronegative patients. RNS decrements in the orbicularis oculi were more common and severe in the MuSK Ab-positive patients than the other two groups. Single-fiber electromyography (SFEMG) of the extensor digitorum communis was abnormal in 90% of MuSK Ab-positive patients. The high frequency of RNS abnormalities in facial muscles in the MuSK Ab-positive population reflects the propensity for facial muscle involvement in this form of MG and emphasizes the importance of including facial muscles in RNS protocols when evaluating these patients.

Primary lateral sclerosis: clinical and laboratory features in 25 patients.

OBJECTIVE: : The objective of this study was to characterize the clinical features and natural history of primary lateral sclerosis (PLS). BACKGROUND: : PLS is a motor neuron disorder defined by corticospinal and corticobulbar tract dysfunction without clinically significant lower motor neuron involvement. METHODS: : We collected data from 25 patients with PLS seen in 2 academic neurology departments over a 5-year period. RESULTS: : The PLS population represented approximately 3% of acquired motor neuron disease cases seen during that period. Twenty-three patients (92%) presented with lower limb weakness, spasticity, or difficulty with ambulation. None presented with upper limb symptoms. Eleven patients (44%) developed bulbar symptoms. All patients had hyperreflexia and increased muscle tone. Muscle weakness was observed in 15 patients (60%) and tended to be mild and asymmetric. Needle electromyography (EMG) was normal or showed only fasciculations in 15 patients (60%); 10 patients had features of mild active denervation, consisting of fibrillation or positive sharp wave potentials, but the extent of these findings did not satisfy World Federation of Neurology electrophysiological criteria for the diagnosis of amyotrophic lateral sclerosis. Fourteen patients (52%) continued independent ambulation. Of the 10 patients with active denervation on EMG, 6 (60%) required a walker, scooter, or wheelchair at a mean follow up of 6.2 years. There were no fatalities over the 5-year period. CONCLUSIONS: : Our experience supports the observation that PLS progresses more slowly than other forms of acquired motor neuron disease, particularly amyotrophic lateral sclerosis. Follow-up data suggest that patients with active denervation changes develop greater disability.

Von hippel-lindau disease associated with thymoma and myasthenia gravis.

Von Hippel-Lindau (VHL) disease is an autosomal-dominant disorder characterized by central nervous system hemangioblastomas, retinal angioma, and renal cell carcinoma. Thymoma and autoimmune neurologic disorders have not been reported in association with VHL disease. We report a unique concurrence of antibody-positive myasthenia gravis and thymoma in a patient with VHL disease. Although this may be coincidental, a possible genetic link between thymoma and VHL is described.

Challenges in the identification of cobalamin-deficiency polyneuropathy.

BACKGROUND: Diagnosing cobalamin (Cbl) deficiency as a cause of polyneuropathy (PN) is problematic, as the frequency of both disorders increases with age, and serum Cbl levels can be difficult to interpret. OBJECTIVES: To identify unique clinical or laboratory features among PN patients with Cbl deficiency and to examine the role of testing of serum metabolite levels in the identification of Cbl deficiency. DESIGN: Cohort survey comparing patients with Cbl deficiency and cryptogenic PN identified during a 2-year period. Cobalamin deficiency was diagnosed using low serum Cbl levels or elevated serum methylmalonic acid or homocysteine levels. SETTING: Academic neuromuscular clinic. RESULTS: Of 324 PN patients, 27 were diagnosed as having Cbl deficiency. Twelve had Cbl levels within the normal range, but elevated serum metabolite levels. Compared with patients with cryptogenic sensory/sensorimotor PN, those with Cbl deficiency were more likely to have concomitant involvement of the upper and lower extremities and experience symptom onset in the hands and a sudden onset of symptoms (P<.005). These differences were seen regardless of whether Cbl deficiency was defined using low Cbl levels or elevated serum metabolite levels. Autoimmune pernicious anemia was identified in 6 (50%) of 12 Cbl-deficient patients with normal serum Cbl levels. The patients with PN and Cbl deficiency showed little objective improvement after parenteral replacement therapy; however, progression occurred less often in these patients compared with those with cryptogenic sensory/sensorimotor PN (P =.02). CONCLUSIONS: This study highlights the challenges of proving that Cbl deficiency is the cause for PN and identifies clinical features that suggest Cbl-deficiency PN. Testing of serum metabolite levels may identify Cbl deficiency in some patients with normal serum Cbl levels.

Adult polyglucosan body disease associated with lewy bodies and tremor.

BACKGROUND: Adult polyglucosan body disease (PGBD) is rare and typically presents with upper and lower motor neuron involvement and neurogenic bladder. Extrapyramidal features are unusual in PGBD and are presumed secondary to widespread pathology that includes the basal ganglia. There are no prior reports of Lewy bodies in PGBD. OBJECTIVE: To report a unique finding of Lewy bodies in a patient with PGBD. REPORT OF A CASE A 46-year-old woman initially presented with a 4-year history of resting tremor. The tremor responded to levodopa therapy. Several months later, she developed upper and lower motor neuron involvement and other clinical features of PGBD. A sural nerve biopsy specimen revealed intra-axonal polyglucosan bodies that confirmed the clinical diagnosis. Bulbar and limb weakness progressed, and she developed dementia. She died 6 years after onset. At autopsy, extensive polyglucosan body formation was found in many regions of the central nervous system. In addition, numerous alpha-synuclein staining Lewy bodies were observed in the substantia nigra, accompanied by marked neuron depopulation. CONCLUSIONS: To our knowledge, this is the first report of adult PGBD associated with Lewy bodies and levodopa-responsive tremor. Although polyglucosan bodies were seen in substantia nigra, it is most likely that our patient had coexisting Parkinson disease.

Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis.

We initiated a randomized, double-blinded, placebo-controlled trial of intravenous immunoglobulin (IVIG) treatment in myasthenia gravis (MG). Patients received IVIG 2 gm/kg at induction and 1 gm/kg after 3 weeks vs. 5% albumin placebo. The primary efficacy measurement was the change in the quantitative MG Score (QMG) at day 42. Fifteen patients were enrolled (6 to IVIG; 9 to placebo) before the study was terminated because of insufficient IVIG inventories. At day 42, there was no significant difference in primary or secondary outcome measurements between the two groups. In a subsequent 6-week open-label study of IVIG, positive trends were observed.

Peripheral Neuropathy Due to Leprosy.

Leprosy, also known as Hansen's disease, remains a significant cause of disability worldwide. After the introduction of treatment regimens using a combination of dapsone, rifampin, and clofazimine, the prevalence of the disease declined from 5.4 million registered cases in 1985 to less than a million in 1999. However, the incidence of new cases has remained stable due at least in part to a population of asymptomatic carriers. Immune-mediated nerve damage can occur during treatment or after treatment is completed and mandates continued careful follow-up of patients. Patient education and rehabilitation are crucial aspects of disease management and prevention of disability. In the US, patient care and medications are available through regional clinics sponsored by the Department of Health and Human Services. Patients should contact the National Hansen's Disease Program at 1770 Physician's Park Drive, Baton Rouge, Louisiana 70816; 1-800-642-2477.