Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.

Challenging Neuromuscular Disease Cases.

The diagnosis of neuromuscular disorders requires a thorough history including family history and examination, with the next steps broadened now beyond electromyography and neuropathology to include genetic testing. The challenge in diagnosis can often be putting all the information together. With advances in genetic testing, some diagnoses that adult patients may have received as children deserve a second look and may result in diagnoses better defined or alternative diagnoses made. Clearly defining or redefining a diagnosis can result in understanding of potential other systems involved, prognosis, or potential treatments. This article presents several cases and approach to diagnosis as well as potential treatment and prognostic concerns, including seipinopathy, congenital myasthenic syndrome, central core myopathy, and myotonic dystrophy type 2.

Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome: New Developments in Diagnosis and Treatment.

"Myasthenia Gravis is, like it or not, the neurologist's disease!" (Thomas Richards Johns II, MD Seminars in Neurology 1982). The most common disorders in clinical practice involving defective neuromuscular transmission are myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). The hallmark of weakness related to malfunction of the neuromuscular junction (NMJ) is variability in severity of symptoms from minute to minute and hour to hour. Fatigable weakness and fluctuation in symptoms are common in patients whether the etiology is autoimmune, paraneoplastic, genetic, or toxic. Autoimmune MG is the most common disorder of neuromuscular transmission affecting adults with an estimated prevalence of 1 in 10,000. While LEMS is comparatively rare, the unique clinical presentation, the association with cancer, and evolving treatment strategies require the neurologist to be familiar with its presentation, diagnosis, and management. In this paper we provide a summary of the meaningful recent clinical developments in the diagnosis and treatment of both MG and LEMS.

Survival and CTG repeat expansion in adults with myotonic dystrophy type 1.

INTRODUCTION: An association is observed between the severity of myotonic dystrophy type 1 (DM1) and the genetic abnormality of cytosine-thymine-guanine (CTG) repeat expansion. It is unknown whether an association exists between survival and CTG repeat expansion. METHODS: In an adult 406-patient DM1 cohort, the phenotype, including survival age, was evaluated in relation to CTG repeat expansion. RESULTS: At study entry, age was 42 ± 12 (range 18-78) years, with a CTG repeat length of 629 ± 386 (range 54-1965). An inverse correlation was observed between CTG repeat length and the age at onset and younger DM1 phenotype. Over a follow-up of 9.2 ± 3.1 years, 118 (29.1%) patients died, including 60 of neuromuscular respiratory failure, 41 of cardiac causes, and 17 of non-neuromuscular, non-cardiac causes. There was an inverse relationship between all-cause survival and CTG length (relative risk 5.4 per log repeat, 95% confidence interval 2.9-10.2, P < 0.001). CONCLUSION: The data demonstrate a genotype-mortality association in DM1.

Office evaluation of the "tired" or "sleepy" patient.

In an outpatient neurologic practice, the patient complaint of being "tired" is frequently encountered yet often not specifically addressed. Clarifying the symptoms and determining whether the tiredness is the result of excessive daytime sleepiness versus fatigue or weakness is the first step in diagnosing and treating the patient. A detailed neurologic and sleep history and exam can often distinguish among these different symptoms, establish the potential causes of excessive sleepiness, and decide on the additional ancillary tests that may be helpful to determine the underlying etiology. Understanding the etiology of patient's symptoms is necessary to initiate appropriate treatment.

Update in the Management of Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome.

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are the most common disorders of neuromuscular transmission in clinical practice. Disorders of the neuromuscular junction (NMJ) are characterized by fluctuating and fatigable weakness and include autoimmune, toxic, and genetic conditions. Adults with NMJ disorders are most often antibody mediated, with MG being the most common, having a prevalence of approximately 1 in 10,000, and with women being affected about twice as often as men. This article focuses on advances in management of autoimmune MG and LEMS.

MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with motor neuron loss as a defining feature. Despite significant effort, therapeutic breakthroughs have been modest. MN-166 (ibudilast) has demonstrated neuroprotective action by various mechanisms: inhibition of proinflammatory cytokines and macrophage migration inhibitory factor, phosphodiesterase inhibition, and attenuation of glial cell activation in models of ALS. Early-phase studies suggest that MN-166 may improve survival outcomes and slow disease progression in patients with ALS. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study in ALS. This study is designed to evaluate the pharmacokinetics, safety and tolerability and assess the efficacy of MN-166 on function, muscle strength, quality of life and survival in ALS.

Lay abstract Amyotrophic lateral sclerosis (ALS) is a neurological disease defined by the loss of the nerve cells going to the muscles. Despite significant effort, we still do not have good treatments for ALS. MN-166 (ibudilast) can protect nerve cells by calming inflammation in several ways in models of ALS. Early human studies suggest that MN-166 may extend life and slow disease progression in ALS patients. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study. This study will show the drug's safety and tolerability and its effects on physical function, muscle strength, quality of life and survival in people living with ALS. Trial registration number: NCT04057898 (ClinicalTrial.gov).

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS.

OBJECTIVE: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

Genetics of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder, although under-diagnosed, with a prevalence of up to 15% depending on the population sampled. Familial aggregation has been widely shown since Ekbom formerly described the condition in 1960; twin studies support a genetic contribution in the development of this disorder. Molecular genetic approaches have identified three genomic regions in RLS susceptibility, however no specific mutations have yet been identified. Herein, we review the current status of genetics in RLS, providing some methodological guidelines to help future research.

GABA and glutamate levels in occlusal splint-wearing males with possible bruxism.

OBJECTIVE: The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the pathophysiology of anxiety behavioural disorders such as panic disorder and post-traumatic stress disorder and is also implicated in the manifestation of tooth-grinding and clenching behaviours generally known as bruxism. In order to test whether the stress-related behaviours of tooth-grinding and clenching share similar underlying mechanisms involving GABA and other metabolites as do anxiety-related behavioural disorders, we performed a Magnetic Resonance Spectroscopy (MRS) study for accurate, in vivo metabolite quantification in anxiety-related brain regions. DESIGN: MRS was performed in the right hippocampus and right thalamus involved in the hypothalamic-pituitary-adrenal axis system, together with a motor planning region (dorsal anterior cingulate cortex/pre-supplementary motor area) and right dorsolateral prefrontal cortex (DLPFC). Eight occlusal splint-wearing men (OCS) with possible tooth-grinding and clenching behaviours and nine male controls (CON) with no such behaviour were studied. RESULTS: Repeated-measures ANOVA showed significant Group×Region interaction for GABA+ (p = 0.001) and glutamate (Glu) (p = 0.031). Between-group post hoc ANOVA showed significantly lower levels of GABA+ (p = 0.003) and higher levels of Glu (p = 0.002) in DLPFC of OCS subjects. These GABA+ and Glu group differences remained significant (GABA+, p = 0.049; Glu, p = 0.039) after the inclusion of anxiety as a covariate. Additionally, GABA and Glu levels in the DLPFC of all subjects were negatively related (Pearson's r = -0.75, p = 0.003). CONCLUSIONS: These findings indicate that the oral behaviours of tooth-grinding and clenching, generally known as bruxism, may be associated with disturbances in brain GABAergic and glutamatergic systems.

Rapid eye movement sleep behavior disorder in women: relevance to general and specialty medical practice.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a treatable parasomnia involving dream-enacting behaviors that is considered to be a male-predominant disorder. However, it is speculated that underrecognition of RBD among female patients in part contributes to the male predominance, probably because women have less aggressive and violent RBD behaviors. We conducted a literature review focused primarily on women with RBD, in which the age of onset of RBD, types of nocturnal behaviors, presence of dream enactment, polysomnographic findings, clinical course, treatment response, male/female ratio, comorbid diagnoses, and medications were tabulated and discussed. RBD was found to primarily affect middle-aged and older women and those with a broad range of neurological disorders. As the link between RBD and neurodegenerative disorders, such as Parkinson's disease, becomes increasingly apparent, including the delayed emergence of parkinsonism in patients initially diagnosed with idiopathic RBD, primary care and specialty physicians should be aware of RBD in women, its potential complications, its excellent response to clonazepam, and its association with neurological disorders and older age groups.

Defining normal duration for afterdischarges with repetitive nerve stimulation: a pilot study.

The presence of afterdischarges on repetitive nerve stimulation may be useful to diagnose cramp fasciculation syndrome, however, the presence and normal duration of afterdischarges has not been well-defined in the normal population and individuals with other neuromuscular diseases. The aim of this pilot study was to describe the distribution of afterdischarge durations in normal controls and patients with peripheral neuropathy. The estimated seventy-fifth percentiles of the afterdischarge durations following tibial nerve repetitive nerve stimulation at 2, 5, 10, and 20 Hz were 315, 688, 745, and 928 milliseconds for 18 normal patients, and 143, 31, 323, and 542 milliseconds for 18 peripheral neuropathy patients respectively. Afterdischarge durations were similar in peripheral neuropathy patients and controls. These findings suggest that afterdischarge durations of more than 500 milliseconds are common in normal controls without subjective cramps and patients with peripheral neuropathy, with some durations beyond 1,000 milliseconds. Therefore, the presence of afterdischarges on repetitive nerve stimulation should be interpreted with caution when evaluating patients for hyperexcitable nerve syndromes.