Guidelines on clinical presentation and management of nondystrophic myotonias.

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.

Hereditary and acquired polyneuropathy conditions of the peripheral nerves: clinical considerations and MR neurography imaging.

Polyneuropathies can be classified as either primarily demyelinating or axonal, and further as hereditary or acquired. It is important to recognize acquired neuropathies because some are amenable to treatment. Clinical findings and electrophysiology are used in the routine diagnosis of these conditions. Magnetic resonance neurography (MRN) is a helpful supplementary diagnostic tool. This article discusses the typical clinical findings, electrophysiology findings, and MRN appearances of common hereditary or acquired neuropathies such as chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, and postsurgical neuropathy.

Non-dystrophic myotonia: prospective study of objective and patient reported outcomes.

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.

An Unusual Presentation of Dermatomyositis With Muscle Hypertrophy.

Peripheral nerve hyperexcitability is a rare disorder characterized by spontaneous motor unit activity. Although peripheral nerve hyperexcitability is seen in multiple immune-mediated neurological conditions, an association with dermatomyositis has rarely been reported. We present a 65-year-old woman with serological and muscle biopsy features of dermatomyositis who also developed marked muscle hypertrophy, stiffness, and delayed relaxation along with electrodiagnostic features of peripheral nerve hyperexcitability such as that seen in Isaacs syndrome.

A quantitative measure of handgrip myotonia in non-dystrophic myotonia.

INTRODUCTION: Non-dystrophic myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials. METHODS: Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared with historical normal controls studied with identical methods. RESULTS: Thirty subjects had chloride channel mutations, 31 had sodium channel mutations, 6 had DM2 mutations, and 24 had no identified mutation. Chloride channel mutations were associated with prolonged first handgrip relaxation times and warm-up on subsequent handgrips. Sodium channel mutations were associated with prolonged first handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning. CONCLUSION: QMA is an automated, non-invasive technique for evaluating myotonia in NDM.

Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial.

CONTEXT: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. OBJECTIVE: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network. INTERVENTION: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. MAIN OUTCOME MEASURES: Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact). RESULTS: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. CONCLUSION: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00832000.

Muscle Channelopathies.

PURPOSE OF REVIEW: This article describes the clinical features, diagnosis, pathophysiology, and management of nondystrophic myotonia and periodic paralysis. RECENT FINDINGS: An increasing awareness exists about the genotype-phenotype overlap in skeletal muscle channelopathies, and thus genetic testing is needed to make a definitive diagnosis. Electrodiagnostic testing in channelopathies is highly specialized with significant overlap in various mutation subtypes. Randomized clinical trials have now been conducted in these disorders with expanded treatment options for patients with muscle channelopathies. SUMMARY: Skeletal muscle channelopathies are rare heterogeneous conditions characterized by lifelong symptoms that require a comprehensive management plan that includes pharmacologic and nonpharmacologic interventions. The significant variability in biophysical features of various mutations, coupled with the difficulties of performing clinical trials in rare diseases, makes it challenging to design and implement treatment trials for muscle channelopathies.

New patient access via telehealth in neuromuscular medicine during COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has changed the face of health care delivery. Health care institutions rapidly transitioned to telehealth to provide care to patients. Prior to the pandemic, telehealth services extended mostly to patients with established diagnoses. Driven by a necessity to provide care to all patients during the pandemic, neurologists started evaluating new patients also via telehealth. OBJECTIVE: To explore opportunities, challenges, and feasibility of telehealth for new patients with neuromuscular disorders. METHODS: New patient visits performed in our neuromuscular clinic were analyzed from March 18, 2020 - July 31, 2020. Data collected included visit volume, demographics, geographic distance of patient's residence from our institution, and no-show and cancellation rates. RESULTS: Total number of patients seen was 1,471; 472 (32%) were new patients. No-show and cancellation rates for telehealth visits were lower than historical in-person visits. There was a wide range of ages (35-74 years) with representation of new patients from a large geographical territory. CONCLUSION: This study advances our understanding regarding the adoption and implementation of telehealth for new patients. Our clinic was able to provide timely access and care to a significant number of patients who could not travel to our institution during COVID-19.

Skeletal Muscle Channelopathies.

Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. These disorders cause lifetime disability and impact quality of life. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis, therapeutic, genetic counseling, and research planning. Electrodiagnostic testing is useful in directing the diagnosis, but has several limitations: patient discomfort, time consuming, and significant overlap of findings in muscle channelopathies. Although genetic testing is the gold standard in making a definitive diagnosis, a mutation might not be identified in many patients with a well-supported clinical diagnosis of periodic paralysis. In the recent past, there have been landmark clinical trials in non-dystrophic myotonia and periodic paralysis which are encouraging as they demonstrate the ability of robust clinical research consortia to conduct well-controlled trials of rare diseases.

Transverse myelitis in systemic sclerosis.

BACKGROUND: Neurological involvement occurs rarely with systemic sclerosis (SSc). Only a few cases of transverse myelopathy have been reported in the setting of SSc. OBJECTIVE: To describe a patient with SSc who developed transverse myelitis that improved during a course of immunosuppression. RESULTS: A 30-year-old woman with SSc presented with subacute onset of bilateral lower extremity weakness and numbness. Results of magnetic resonance imaging and cerebrospinal fluid studies supported a diagnosis of transverse myelitis. The patient responded favorably to a course of corticosteroids and cyclophosphamide. No overlapping autoimmune disorders were evident. Clinical follow-up showed significant recovery, with resolution of radiological abnormalities. CONCLUSION: Transverse myelitis can occur as a rare manifestation of SSc and may respond favorably to immunosuppressive therapy.

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.

Treatment and management of neuromuscular channelopathies.

OPINION STATEMENT: Neuromuscular channelopathies are heterogeneous disorders with marked phenotypic and genotypic variability. These include non-dystrophic myotonia (NDM), periodic paralysis (PP), and congenital myasthenic syndrome (CMS). Their diverse clinical manifestations remain a challenge in diagnosis and management to this date. These disorders impact quality of life and cause lifelong disabling symptoms. Treatment options are few and not FDA-approved. This is largely due to a paucity of large, randomized clinical trials in these rare diseases. Challenges of conducting such trials include the rarity of these disorders and the genetic heterogeneity. Physicians rely on off-label use of drugs to treat muscle channelopathies to reduce morbidity and improve quality of life. Besides pharmacological treatment, dietary modifications, lifestyle changes, awareness of triggers, and genetic counseling also play an important role in long-term disease management. This article reviews the current management strategies for neuromuscular channelopathies.

Muscle channelopathies.

Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis and therapeutics. These disorders can cause lifetime disability and affect quality of life. There is no treatment of these disorders approved by the US Food and Drug Administration at this time. Recognition and treatment of symptoms might reduce morbidity and improve quality of life. This article summarizes the clinical manifestations, diagnostic studies, pathophysiology, and treatment options in nondystrophic myotonia, congenital myasthenic syndrome, and periodic paralyses.

Nondystrophic myotonia: challenges and future directions.

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Common symptoms include muscle stiffness, transitory weakness, fatigue, and pain. Although seldom life-shortening, these myotonias cause life-time disability and affected individuals cannot perform many daily activities. A notable feature of the recessive form of chloride channelopathies is the presence of transient weakness. While there has been considerable progress in skeletal muscle channelopathies with regards to identifying biophysical abnormalities, the mechanism of transient weakness remains unclear. A recent study published in Experimental Neurology (Desaphy et al., 2013) explored this question further by comparing the biophysical properties of 3 chloride channel mutations associated with recessive myotonia congenita, with varying susceptibility to transient weakness. The authors identified a variety of functional defects in channel behavior among the 3 mutations, suggesting that this variability contributes to the differing phenotypes among chloride channelopathies. This commentary discusses nondystrophic myotonias, the results of Desaphy et al., and the treatment challenges in this rare disease.

Treatment of painful peripheral neuropathy.

Neuropathic pain management is an important aspect in the management of painful peripheral neuropathy. Anticonvulsants and antidepressants have been studied extensively and are often used as first-line agents in the management of neuropathic pain. In this article, data from multiple randomized controlled studies on painful peripheral neuropathies are summarized to guide physicians in treating neuropathic pain. Treatment is a challenge given the diverse mechanisms of pain and variable responses in individuals. However, most patients derive pain relief from a well-chosen monotherapy or well-designed polypharmacy that combines agents with different mechanisms of action.

Huntington chorea presenting with motor neuron disease.

BACKGROUND: There have been a few case reports of motor neuron disease in association with Huntington disease (HD). OBJECTIVE: To describe a patient presenting with prominent fasciculations, chorea, and possible amyotrophic lateral sclerosis (ALS) in whom genetic testing revealed HD mutation. DESIGN: Case report. SETTING: University of Texas Southwestern Medical Center, Dallas. Patient  A 69-year-old man with chorea and fasciculations. INTERVENTIONS: Genetic and electrophysiologic testing. MAIN OUTCOME MEASURES: Genetic test result, electrophysiologic test result, and physical examination. RESULTS: A 69-year-old man with long-standing depression and failing memory presented with muscle twitches of 8 months' duration. He was found to have choreoathetoid movements and distal weakness on neurological examination. Electrophysiologic studies revealed evidence of motor neuron disease. Genetic test showed CAG repeat of 40 on chromosome 4, confirming the diagnosis of HD. CONCLUSION: Motor neuron disease can rarely occur in patients with HD and could be one of its presenting features.

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.

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.