Pushpa Narayanaswami

Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine

OBJECTIVE To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs). METHODS Systematic review and practice recommendation development using the American Academy of Neurology guideline development process. RESULTS Most LGMDs are rare, with estimated prevalences ranging from 0.07 per 100,000 to 0.43 per 100,000. The frequency of some muscular dystrophies varies based on the ethnic background of the population studied. Some LGMD subtypes have distinguishing features, including pattern of muscle involvement, cardiac abnormalities, extramuscular involvement, and muscle biopsy findings. The few published therapeutic trials were not designed to establish clinical efficacy of any treatment. PRINCIPAL RECOMMENDATIONS For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on clinical phenotype, inheritance pattern, and associated manifestations (Level B). Clinicians should refer newly diagnosed patients with an LGMD subtype and high risk of cardiac complications for cardiology evaluation even if they are asymptomatic from a cardiac standpoint (Level B). In patients with LGMD with a known high risk of respiratory failure, clinicians should obtain periodic pulmonary function testing (Level B). Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties designed specifically to care for patients with neuromuscular disorders (Level B). Clinicians should not offer patients with LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment (Level R). Detailed results and recommendations are available on the Neurology® Web site at Neurology.org.Objective: To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs). Methods: Systematic review and practice recommendation development using the American Academy of Neurology guideline development process. Results: Most LGMDs are rare, with estimated prevalences ranging from 0.07 per 100,000 to 0.43 per 100,000. The frequency of some muscular dystrophies varies based on the ethnic background of the population studied. Some LGMD subtypes have distinguishing features, including pattern of muscle involvement, cardiac abnormalities, extramuscular involvement, and muscle biopsy findings. The few published therapeutic trials were not designed to establish clinical efficacy of any treatment. Principal recommendations: For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on clinical phenotype, inheritance pattern, and associated manifestations (Level B). Clinicians should refer newly diagnosed patients with an LGMD subtype and high risk of cardiac complications for cardiology evaluation even if they are asymptomatic from a cardiac standpoint (Level B). In patients with LGMD with a known high risk of respiratory failure, clinicians should obtain periodic pulmonary function testing (Level B). Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties designed specifically to care for patients with neuromuscular disorders (Level B). Clinicians should not offer patients with LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment (Level R). Detailed results and recommendations are available on the Neurology® Web site at Neurology.org.

International consensus guidance for management of myasthenia gravis Executive summary

Objective: To develop formal consensus-based guidance for the management of myasthenia gravis (MG). Methods: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. Results: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. Conclusion: This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide.

Electrical impedance myography as a biomarker to assess ALS progression

Abstract Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM’s potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique’s correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.

Summary of evidence-based guideline: Complementary and alternative medicine in multiple sclerosis: Report of the Guideline Development Subcommittee of the American Academy of Neurology

Objective: To develop evidence-based recommendations for complementary and alternative medicine (CAM) in multiple sclerosis (MS). Methods: We searched the literature (1970–March 2011; March 2011−September 2013 MEDLINE search), classified articles, and linked recommendations to evidence. Results and recommendations: Clinicians might offer oral cannabis extract for spasticity symptoms and pain (excluding central neuropathic pain) (Level A). Clinicians might offer tetrahydrocannabinol for spasticity symptoms and pain (excluding central neuropathic pain) (Level B). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity (short-term)/tremor (Level B) and possibly effective for spasticity and pain (long-term) (Level C). Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols) for spasticity symptoms, pain, and urinary frequency (Level B). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity/urinary incontinence (Level B). Clinicians might choose not to offer these agents for tremor (Level C). Clinicians might counsel patients that magnetic therapy is probably effective for fatigue and probably ineffective for depression (Level B); fish oil is probably ineffective for relapses, disability, fatigue, MRI lesions, and quality of life (QOL) (Level B); ginkgo biloba is ineffective for cognition (Level A) and possibly effective for fatigue (Level C); reflexology is possibly effective for paresthesia (Level C); Cari Loder regimen is possibly ineffective for disability, symptoms, depression, and fatigue (Level C); and bee sting therapy is possibly ineffective for relapses, disability, fatigue, lesion burden/volume, and health-related QOL (Level C). Cannabinoids may cause adverse effects. Clinicians should exercise caution regarding standardized vs nonstandardized cannabis extracts and overall CAM quality control/nonregulation. Safety/efficacy of other CAM/CAM interaction with MS disease-modifying therapies is unknown.

Electrical impedance myography correlates with standard measures of ALS severity.

Introduction: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. Methods: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale‐Revised (ALSFRS‐R) score, and motor unit number estimation (MUNE). Results: Moderate strength correlations between EIM parameters and HHD were observed for both whole‐body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS‐R upper and lower extremity subscores, but not total ALSFRS‐R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. Conclusions: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS. Muscle Nerve 49:441–443, 2014

Electrical characteristics of rat skeletal muscle in immaturity, adulthood and after sciatic nerve injury, and their relation to muscle fiber size

Localized impedance methods can provide useful approaches for assessing neuromuscular disease. The mechanism of these impedance changes remains, however, uncertain. In order to begin to understand the relation of muscle pathology to surface impedance values, 8 immature rats, 12 mature rats and 8 mature rats that had undergone sciatic crush were killed. Measurement was made on tissue from the gastrocnemius muscle from each animal in an impedance cell, and the conductivity and relative permittivity of the tissue were calculated in both the longitudinal and transverse directions for frequencies of 2 kHz to 1 MHz. In addition, quantitative histological analysis was performed on the tissue. Significant elevations in transverse conductivity and transverse relative permittivity were found with animal growth, but longitudinal values showed no difference. After sciatic crush, both transverse and longitudinal conductivity increased significantly, with no change in the relative permittivity in either direction. The frequency dependence of the values also changed after nerve injury. In the healthy animals, there was a strong linear relation between measured conductivity and relative permittivity with cell area, but not for the sciatic crush animals. These results provide a first step toward developing a comprehensive understanding of how the electrical properties of muscle alter in neuromuscular disease states.

Charcot-Marie-Tooth disease (hereditary motor sensory neuropathies) and hereditary sensory and autonomic neuropathies.

Background:Since the description of Charcot-Marie-Tooth disease over a century ago, it is now been recognized that these conditions are not caused by generalized metabolic defects but rather have various discrete genetic origins. These disorders can also have variable phenotypes due to dysfunction of peripheral nerve axons or their myelin due to the genetic defects that affect the formation of specific nerve proteins. Review Summary:This article summarizes the clinical presentation of various phenotypes of the hereditary motor sensory neuropathies and the hereditary sensory and autonomic neuropathies, genetic mutations, and their relevant protein products. Proper identification of the genetic defects provides the opportunity for better genetic counseling and hopefully therapies in the future.

Utilizing a handheld electrode array for localized muscle impedance measurements

Electrical impedance myography (EIM) is a noninvasive technique used for assessment of muscle health in which a high‐frequency, low‐amplitude electric current is applied to the skin overlying a muscle, and the resulting surface voltage is measured. We have previously used adhesive electrodes, application of which is inconvenient. We present data using a handheld electrode array (HEA) that we devised to expedite the EIM procedure in a clinical setting.

The effect of subcutaneous fat on electrical impedance myography when using a handheld electrode array: The case for measuring reactance

OBJECTIVE Recent developments in electrical impedance myography (EIM) have led to the use of handheld electrode arrays (HEAs) for data acquisition. Although preferable for several reasons, this approach tends to be more affected by subcutaneous fat (SF) than the original approach in which the impedance-measuring electrodes are widely spaced. In this study, we seek to identify the EIM parameter least impacted by subcutaneous fat (SF) when using an HEA. METHODS 18 normal subjects underwent 50 kHz EIM and ultrasound of the medial gastrocnemius muscles on the dominant side. Coefficients of determination (R(2) values) were calculated for each of the three major EIM variables (reactance, resistance, and phase) and SF thickness. RESULTS For both resistance and phase, a strong relationship to SF thickness was observed (R(2) = 0.64 and R(2) = 0.70, respectively, p < 0.001 for both). In contrast, for reactance, the relationship was non-significant, with R(2) = 0.07, p = 0.30. CONCLUSIONS Unlike resistance and phase, both of which are highly impacted by SF thickness, the reactance shows no significant relationship. SIGNIFICANCE Future clinical studies employing HEAs to perform EIM should evaluate alterations in reactance in addition to those in resistance and phase.

The effect of subacute denervation on the electrical anisotropy of skeletal muscle: Implications for clinical diagnostic testing

OBJECTIVE Applied electrical current flows preferentially along rather than across muscle fibers, a characteristic called anisotropy. In this study, we investigate the alteration in muscle anisotropy after denervation. METHODS Eight adult male rats underwent sciatic nerve crush and the gastrocnemius was harvested from 1 to 2.5 weeks later. Muscle from 12 additional healthy rats was also obtained. Multifrequency electrical impedance measurements were made on the tissue and its conductivity and relative permittivity (i.e., its polarizability) calculated. Anisotropy of the tissue was determined by calculating conductivity and permittivity differences, subtracting transverse from longitudinal values. Muscle fiber and blood vessel quantification were also performed. RESULTS The mean conductivity difference for sciatic crush animals was higher (p<0.05) than for the healthy animals across the frequency spectrum, due to a greater increase in longitudinal conductivity than in transverse conductivity. For example, at 10 kHz, the conductivity difference was 0.15S/m for healthy animals and 0.29 S/m for post-crush animals. Relative permittivity difference values, however, were similar between groups. There was a strong correlation of conductivity anisotropy to muscle fiber size but not to blood vessel area. CONCLUSIONS Anisotropy of muscle conductivity increases markedly after subacute denervation injury. SIGNIFICANCE This alteration in anisotropy has direct relevance to the clinical application of electrical impedance myography. We also speculate that it may impact other forms of diagnostic testing, including needle electromyography and magnetic resonance imaging.