Key Points For Issue

Muscle and Neuromuscular Junction Disorders p. December 2019, Vol.25, No.6 doi: 10.1212/01.CON.0000617316.35637.9c
KEY POINTS FOR ISSUE
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Muscle and Neuromuscular Junction Disorders

Article 1: Approach to Muscle and Neuromuscular Junction Disorders

Mamatha Pasnoor, MD, FAAN; Mazen M. Dimachkie, MD, FAAN, FANA. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1536–1563.

ABSTRACT

PURPOSE OF REVIEW

Muscle and neuromuscular junction disorders are a diverse group of disorders that can be difficult to diagnose. This article provides a diagnostic approach based on clinical history and neurologic examination leading to a narrow set of diagnostic tests.

RECENT FINDINGS

Numerous discoveries in recent years have facilitated clinician access to more advanced laboratory and genetic testing to pinpoint the exact diagnosis in patients with muscle or neuromuscular junction disorders. Large-scale genetic testing has become much less expensive, and free testing has become available for many of the rare conditions because of increased research and the availability of effective therapies for these rare disorders.

SUMMARY

The approach to muscle and neuromuscular junction disorders depends on the clinical pattern of muscle weakness. By classifying patients into one of 10 muscle patterns, diagnostic testing can be targeted and gene testing yield will be optimized. With the increased accessibility and reduced cost of genetic testing (eg, gene panels, whole-exome sequencing, whole-genome sequencing, and chromosomal microarray), this clinical approach to muscle weakness and targeted gene testing will ensure a cost-effective investigational plan. This clinical approach should also assist clinicians in making a timely and accurate diagnosis.

KEY POINTS

  • Thorough history of onset and progression is fundamentally important for the diagnosis of myopathies and neuromuscular junction disorders.
  • The main features that distinguish neuromuscular junction defects from myopathies are fluctuation in symptoms and signs, as well as ocular manifestations.
  • Identification of triggering factors for weakness or stiffness is useful for diagnosis of muscle and neuromuscular junction disorders.
  • The 10 patterns of muscle involvement are an extremely valuable starting point to formulate the initial diagnoses and guide ordering of confirmatory tests.
  • Family history and pattern of inheritance provide information for the efficient diagnosis of genetic conditions.
  • Examination of children can be challenging in comparison with that of adults with neuromuscular disease. Examination of the parent may provide a valuable clue to the diagnosis (eg, grip myotonia in a mother of a hypotonic infant).
  • Assessment for other organ involvement is important for diagnosis and prognosis of muscle and neuromuscular junction disorders.
  • Muscle biopsies are mostly useful for acquired myopathies and hereditary myopathies with negative genetic testing or with variants of unknown significance.
  • Needle EMG or MRI can be used to identify the most useful muscle site to biopsy.
  • Commercial genetic testing has significantly improved in recent years with increased efficiency and reduced cost.
  • Despite genetic testing becoming more readily available and affordable, the resolution of variants of uncertain significance requires the implementation of a careful and thoughtful pattern approach, support from electrophysiology, and muscle biopsy.

Article 2: Immune-Mediated Myopathies

Namita A. Goyal, MD, FAAN. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1564–1585.

ABSTRACT

PURPOSE OF REVIEW

This article summarizes the clinical features, diagnostic evaluation, and management of the common immune-mediated myopathies: dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy, and overlap myositis.

RECENT FINDINGS

The identification of myositis-specific autoantibodies has improved the characterization of the subtypes of myositis and associated clinical phenotypes, as the severity of muscle involvement, extramuscular manifestations, and risk of malignancy may vary among the subtypes of autoimmune myopathies.

SUMMARY

The understanding and diagnostic accuracy of the subtypes of autoimmune myopathies have been enhanced with careful attention to the key clinical features, the emergence of myositis-specific autoantibodies, the characterization of histopathologic hallmark features, and the aid of muscle imaging. Several immunotherapeutic options now exist that can be selected to target a specific subtype, often with a favorable prognosis, especially when treatment starts early in the disease course.

KEY POINTS

  • Muscle weakness in patients with dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy, overlap myositis, and polymyositis is symmetric and proximal, often involving the proximal shoulder and hip girdle limb muscles; with progression, it may also affect the truncal muscles.
  • Dermatomyositis presents in children and adults with a subacute onset of proximal muscle weakness that is accompanied or preceded by a distinct skin rash, a cardinal feature of dermatomyositis.
  • A pathognomonic heliotrope (violaceous discoloration) rash often involves the upper eyelids with or without periorbital edema.
  • Aside from the cutaneous involvement, other extramuscular manifestations in dermatomyositis include involvement of cardiac, pulmonary, gastrointestinal, and joint systems, as well as malignancy.
  • In dermatomyositis, creatine kinase levels are often increased; however, they may range from normal to up to thousands of international units per liter.
  • Patients with dermatomyositis with a positive anti–Mi-2 antibody are noted to have more classical cutaneous features of dermatomyositis, confer a good prognosis with a favorable response to steroids, and have a relatively low malignancy risk.
  • The anti–TIF-1γ antibody in dermatomyositis is highly associated with malignancy (in adult dermatomyositis but not in juvenile dermatomyositis) and severe skin manifestations, including diffuse photoerythema and “dusky red face” and unique characteristic cutaneous lesions of hypopigmented and telangiectatic (“red on white”) patches.
  • Anti–nuclear matrix protein 2 antibodies are found in up to 25% of patients with juvenile dermatomyositis but are also detected in up to 40% of patients with adult dermatomyositis.
  • Perifascicular muscle fiber atrophy is a specific and pathologic hallmark feature of dermatomyositis.
  • In dermatomyositis, short tau inversion recovery MRI sequences commonly demonstrate hyperintensity or edema in a patchy distribution in the muscle, along with edema of the subcutaneous tissues and fascia (an uncommon finding in other inflammatory myopathies), and may mirror the distribution of skin involvement.
  • Patients with antisynthetase syndrome may present with a constellation of all or some of the following clinical features: inflammatory myopathy, interstitial lung disease, arthritis, Raynaud syndrome, fever, and mechanic’s hands.
  • Of the antisynthetase antibodies, anti–Jo-1 (the first to be discovered and most frequent antisynthetase autoantibody) is associated with the greatest risk of developing a myositis.
  • Up to 90% of patients with Jo-1 antibodies have a myositis; however, the risk of developing interstitial lung disease has been reported in up to 50% of patients with anti–PL-12 antibodies, but they have no muscle involvement.
  • Serum creatine kinase levels in immune-mediated necrotizing myopathy are typically markedly elevated, up to several thousands of international units per liter, with the median peak reported at 4700 U/L.
  • The 2017 European Neuromuscular Centre criteria for immune-mediated necrotizing myopathy describe three subtypes: anti–SRP myopathy, anti–3-hydroxy-3-methylglutaryl coenzyme A reductase myopathy, and antibody-negative immune-mediated necrotizing myopathy.
  • The anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibody associated immune-mediated necrotizing myopathy was first described in patients with a history of statin exposure with weakness that continued to progress despite stopping use of the statin mediation; however, up to one-third may be statin naïve and may have a more resistant treatment response.
  • The muscle histopathology in immune-mediated necrotizing myopathy is characterized by the presence of necrosis of muscle fibers or regeneration with a paucity of (if any) lymphocytic infiltrates.
  • The most common myositis-associated antibodies are anti-Ro52 antibodies, which are nonspecific and have been detected in approximately 25% of patients with all types of myositis.
  • Immunosuppressive therapy is widely accepted as the mainstay of treatment for autoimmune myopathies.
  • Corticosteroids, commonly prednisone, are the first-line therapy in the treatment of inflammatory myopathies, typically prescribed at a dose of 0.5 mg/kg/d to 1 mg/kg/d, with a maximum dose of 60 mg/d to 80 mg/d.
  • Recent evidence has suggested that particular subtypes of autoimmune myopathies (based on autoantibodies) may have a robust response to particular immunotherapies.
  • Several biologic agents are under investigation for the treatment of refractory cases of autoimmune inflammatory myopathies.
  • Although treatment for inflammatory myopathies remains challenging because several therapeutic options are available without consensus guidelines, patients with myositis tend to respond favorably to conventional immunotherapy when started early in the course of the disease.
  • Because the majority of malignancies are identified in the first 3 years of myositis onset, a comprehensive evaluation in search of an underlying malignancy with chest, abdomen, and pelvis CT, as well as age-appropriate cancer screening should be performed, especially in myositis autoantibody subtypes with an increased risk of malignancy.

Article 3: Sporadic Inclusion Body Myositis and Other Rimmed Vacuolar Myopathies

Conrad C. Weihl, MD, PhD. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1586–1598.

ABSTRACT

PURPOSE OF REVIEW

This article reviews the clinical, laboratory, and histopathologic features of sporadic inclusion body myositis (IBM) and explores its pathogenic overlap with inherited myopathies that have IBM-like pathology.

RECENT FINDINGS

Sporadic IBM is the most common acquired muscle disease in patients older than 50 years of age and is becoming more prevalent because of the increasing age of the population, the emerging development of more inclusive diagnostic criteria, and the advent of a diagnostic autoantibody. No effective therapy is known, and the pathogenic mechanism remains unclear. Some pathogenic insight can be gleaned from other myopathies with pathologic similarities or hereditary inclusion body myopathies. Although clinically distinct from sporadic IBM, preclinical models of hereditary inclusion body myopathy have offered an opportunity to move some therapies toward clinical development.

SUMMARY

Patients with sporadic IBM experience significant morbidity, and the disease is associated with a large unmet medical need. As therapies are developed, improved diagnosis will be essential. Early diagnosis relies on awareness, clinical history, physical examination, laboratory features, and appropriate muscle biopsy processing. Future research is needed to understand the natural history, identify genetic risk factors, and validate biomarkers to track disease progression. These steps are essential as we move toward therapeutic interventions.

KEY POINTS

  • The estimated prevalence of sporadic inclusion body myositis varies from 5 per million to 71 per million but is still likely an underestimate. Diagnostic uncertainty or ambiguity, delays in sporadic inclusion body myositis diagnosis, and the aging population support a higher prevalence.
  • Patients with sporadic inclusion body myositis have a slowly progressing preferential pattern of muscle involvement that includes quadriceps, finger flexor, and ankle dorsiflexion weakness.
  • An atypical pattern of weakness, rapid progression, or onset younger than 40 years age should prompt the clinician to consider an alternate diagnosis.
  • Patients with sporadic inclusion body myositis have modestly elevated creatine kinase levels (≤1500 U/L) and electrodiagnostic studies that may be challenging to interpret because they suggest a mixed myopathic/neuropathic process.
  • MRI of the lower extremities can reveal a differential pattern of muscle involvement that selectively affects the anterior thigh muscle. The value of MRI as a diagnostic or prognostic tool in sporadic inclusion body myositis has not been established.
  • At present, muscle histology demonstrating endomysial inflammation, a feature that should be captured when a clinically affected muscle is biopsied, is required for a definitive diagnosis of sporadic inclusion body myositis.
  • Overreliance on skeletal muscle histopathology and rare but specific biopsy features such as rimmed vacuoles or electron microscopic identification of proteinaceous inclusions may lead to an underdiagnosis of patients with sporadic inclusion body myositis.
  • The most sensitive and specific diagnostic features for sporadic inclusion body myositis are the clinical presentation and physical examination findings.
  • Diagnostic criteria that emphasize clinical measures of strength have higher sensitivity and specificity. Specifically, the presence of finger flexor weakness and knee extension strength less than or equal to hip flexion strength has a higher sensitivity for sporadic inclusion body myositis as compared with some pathologic features on muscle biopsy.
  • Anti–5'-nucleotidase, cytosolic IA (NT5C1A) seropositivity is present in approximately 40% to 60% of patients with sporadic inclusion body myositis. A negative anti-NT5C1A antibody test should not be used to rule out sporadic inclusion body myositis. Moreover, anti-NT5C1A seropositivity can occur in other inflammatory myopathies and should be interpreted with caution. It remains to be determined where anti-NT5C1A seropositivity fits within current diagnostic algorithms.
  • Anti–5'-nucleotidase, cytosolic IA seropositivity may predict a more severe sporadic inclusion body myositis phenotype with higher mortality and bulbar symptoms.
  • Although not systematically studied, exercise may correlate with a higher functional status in patients with sporadic inclusion body myositis.
  • Sporadic inclusion body myositis is a slowly progressive chronic muscle disease. Patients decline at an average rate of 4% per year in affected muscle groups. Most patients with sporadic inclusion body myositis lose ambulation after 10 to 20 years of the disease.
  • Of patients with sporadic inclusion body myositis, 98% report falling within the last year. Prevention of falls by patient education is an essential aspect of care of patients with sporadic inclusion body myositis.
  • Although defined as a sporadic disease, patients with sporadic inclusion body myositis may carry genetic risk factors that are associated with autoimmunity and muscle degeneration such as a human leukocyte antigen DRB1*03:01 allele or FYCO1 missense variants.
  • No treatment has been demonstrated to be clinically effective at reversing or slowing weakness in patients with sporadic inclusion body myositis.
  • Patients with hereditary myopathies can be mistaken for sporadic inclusion body myositis because of clinical and biopsy features that overlap.
  • Future therapies aimed at correcting muscle degeneration rather than immune dysfunction may be effective in treating patients with sporadic inclusion body myositis.

Article 4: The Limb-Girdle Muscular Dystrophies

Matthew P. Wicklund, MD, FAAN. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1599–1618.

ABSTRACT

PURPOSE OF REVIEW

As a group, the limb-girdle muscular dystrophies (LGMDs) are the fourth most prevalent genetic muscle disease, yet they are still not well known or understood. This article defines and describes LGMDs, delineates a diagnostic strategy, and discusses treatment of the LGMDs.

RECENT FINDINGS

In 2018, the definition of the LGMDs was further refined, and a new nomenclature was proposed. Diagnosis of the LGMDs was long guided by the distinctive clinical characteristics of each particular subtype but now integrates use of genetics—with next-generation sequencing panels, exomes, and full genome analysis—early in the diagnostic assessment. Appreciation of the phenotypic diversity of each LGMD subtype continues to expand. This emphasizes the need for precision genetic diagnostics to better understand each subtype and formulate appropriate management for individual patients. Of significant relevance, the explosion of research into therapeutic options accentuates the need for accurate diagnosis, comprehensive disease characterization, and description of the natural histories of the LGMDs to move the field forward and to mitigate disease impact on patients with LGMD.

SUMMARY

The LGMDs are genetic muscle diseases that superficially appear similar to one another but have important differences in rates of progression and concomitant comorbidities. Definitive diagnoses are crucial to guide management and treatment now and in the future. As targeted treatments emerge, it will be important for clinicians to understand the nomenclature, diagnosis, clinical manifestations, and treatments of the LGMDs.

KEY POINTS

  • Hundreds of genes can lead to proximal muscle weakness including disorders of the motor neuron (spinal muscular atrophy), neuromuscular junction (congenital myasthenic syndromes), and muscle (genetic myopathies inclusive of limb-girdle muscular dystrophies).
  • Limb-girdle muscular dystrophy is defined as a genetically inherited condition primarily affecting skeletal muscle that leads to progressive, predominantly proximal muscle weakness in individuals who have achieved independent walking and who have elevated creatine kinase levels. Degenerative changes are demonstrated on muscle imaging, and dystrophic changes are demonstrated on muscle histology in the most affected muscles.
  • In 2018, the European Neuromuscular Centre set forth a new nomenclature to better delineate the limb-girdle muscular dystrophies from other genetic muscle diseases.
  • The diagnostic process for the limb-girdle muscular dystrophies has changed, as now broad genetic testing should be performed once a clinical suspicion is present for a genetic muscle disease.
  • Patients previously followed for the diagnosis of myositis, especially if poorly responsive to immunomodulatory therapy, should undergo limb-girdle muscular dystrophy genetic testing. Patients with limb-girdle muscular dystrophy with negative panel, exome or genome genetic analysis should be tested for autoantibodies recognizing 3-hydroxy-3-methylglutaryl coenzyme A reductase (even without exposure to statin drugs and even in children).
  • Calpainopathies are the most common limb-girdle muscular dystrophy subtype, except in some Northern European countries and perhaps in Asia.
  • If someone with limb-girdle muscular dystrophy cannot stand on his or her toes in the first few years after onset of disease, strong consideration should be given to limb-girdle muscular dystrophy type 2B (and type 2L).
  • In the sarcoglycanopathies (limb-girdle muscular dystrophy types 2C through 2F), in leg MRIs, one often finds a predictable proximal to distal gradient of fatty and fibrous replacement in the anterior thigh, with relative sparing of the distal vasti muscles.
  • Exercise-induced muscle pain affects two-thirds and myoglobinuria affects one-third of patients with limb-girdle muscular dystrophy type 2I.
  • Similar to dysferlinopathies (limb-girdle muscular dystrophy type 2B), anecdotal evidence exists for athletic prowess prior to onset of symptoms in anoctaminopathies (limb-girdle muscular dystrophy type 2L).
  • A significant proportion of undiagnosed patients with a limb-girdle muscular dystrophy phenotype harbor RYR1 pathogenic variants.
  • In patients with limb-girdle muscular dystrophy type 1B, early cardiology consultation and proactive intervention with cardiac pacemakers, defibrillators, and transplantation mitigate complications related to malignant arrhythmias and heart failure.
  • Treatment recommendations for patients with limb-girdle muscular dystrophy include (1) medical management through multidisciplinary neuromuscular clinics; (2) access to cardiology, pulmonary, and orthopedic evaluation and treatment; (3) involvement of physical, occupational, and speech therapy along with access to orthotic and durable medical equipment services; (4) availability of genetic testing, interpretation, and counseling; and (5) encouragement for patients to remain active and lead fulfilling lives.

Article 5: The Dystrophinopathies

Mathula Thangarajh, MD, PhD, FAAN. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1619–1639.

ABSTRACT

PURPOSE OF REVIEW

The dystrophinopathies are among the most common neuromuscular conditions, and they include Duchenne and Becker muscular dystrophies. This article reviews the epidemiology, clinical manifestations, genetic cause, management, and new and emerging therapies for this condition.

RECENT FINDINGS

New studies have highlighted how oral corticosteroids have changed the natural history of the disease, prolonging ambulation in boys with Duchenne muscular dystrophy and reducing the risk of developing scoliosis and subsequent surgical correction, improving cardiac health, and increasing long-term survival. Additionally, recent publications have provided insights into how newer and emerging treatment options are becoming more common for this condition. With gene therapy being approved in the United States for the severe form, the dystrophinopathies represent model diseases to understand the personalization of genetic treatment.

SUMMARY

Improvement in the standardization of care and the use of oral corticosteroids have increased the life expectancy of patients with dystrophinopathy and changed the natural history of the disease. This article presents a summary of clinical features, diagnostic testing, and new and emerging treatment strategies for the dystrophinopathies.

KEY POINTS

  • Clinical outcomes in dystrophinopathy have improved, and many individuals with the severe phenotype (Duchenne muscular dystrophy) are surviving into adulthood. Thus, adult neurologists are increasingly providing care for these individuals.
  • Young boys presenting with developmental delay and delayed motor milestones should be tested for dystrophinopathy. Serum creatine kinase is the first diagnostic testing that can help.
  • Genetic testing is readily available and should be actively pursued to establish a diagnosis of dystrophinopathy and guide therapy as more mutation-specific therapies are becoming available.
  • Cardiomyopathy is a frequent complication of dystrophinopathy, especially in those with the milder but variable phenotype (Becker muscular dystrophy) and in female carriers of dystrophinopathy.
  • Corticosteroids begun between the ages 4 and 7 years change the natural history of Duchenne muscular dystrophy.
  • At least two drugs have been approved for treatment in Duchenne muscular dystrophy, and new therapeutic agents are increasingly being tested.
  • A cohesive, interdisciplinary team is integral for the provision of high-quality medical care for individuals with dystrophinopathy.

Article 6: Congenital Muscular Dystrophy and Congenital Myopathy

Russell J. Butterfield, MD, PhD, FAAN. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1640–1661.

ABSTRACT

PURPOSE OF REVIEW

Congenital muscular dystrophies and congenital myopathies are a heterogeneous group of disorders resulting in hypotonia, muscle weakness, and dystrophic or myopathic features on muscle biopsy. This article summarizes the clinical and genetic aspects of these disorders.

RECENT FINDINGS

Historically, diagnoses of congenital muscular dystrophy and congenital myopathy have been made by clinical features and histopathology; however, recent advances in genetics have changed diagnostic practice by relying more heavily on genetic findings. This article reviews the clinical and genetic features of the most common congenital muscular dystrophies including laminin subunit alpha 2 (LAMA2)–related (merosin deficient), collagen VI–related, and α-dystroglycan–related congenital muscular dystrophies and reviews the most common congenital myopathies including nemaline rod, core, and centronuclear myopathies. With the increasing accessibility of genetic testing, the number of genes found to be associated with these disorders has increased dramatically. A wide spectrum of severity and onset (from birth to adulthood) exist across all subtypes. Progression and other features are variable depending on the subtype and severity of the specific genetic mutation.

SUMMARY

Congenital muscular dystrophy and congenital myopathy are increasingly recognized disorders. A growing appreciation for the breadth of phenotypic variability and overlap between established subtypes has challenged long-standing phenotypic and histopathologic classifications of these disorders but has driven a greater understanding of pathogenesis and opened the door to the development of novel treatments.

KEY POINTS

  • Congenital muscular dystrophies are most often distinguished genetically by involvement of proteins important for stabilization of the cytoskeletal matrix to the sarcolemmal membrane and the extracellular matrix.
  • Congenital myopathies most often involve proteins important in the contractile matrix or excitation-contraction coupling.
  • Classic definitions of clinical and histopathologic phenotypes are being challenged by genetic classifications, which have revealed significant overlap between syndromes and the breadth of severity in patients with mutations in most congenital muscular dystrophy and congenital myopathy genes.
  • Creatine kinase is often elevated in patients with congenital muscular dystrophy due to destabilization of the sarcolemmal membrane but is normal in patients with congenital myopathy, where stability of the sarcolemmal membrane is maintained.
  • Genetic testing is rapidly emerging as the first diagnostic test in most patients with suspected congenital muscular dystrophy and congenital myopathy.
  • Treatment for congenital muscular dystrophies and congenital myopathies requires a multidisciplinary team including orthopedic, pulmonary, nutrition, and cardiac surveillance.
  • Juxtaposition of distal joint hyperlaxity and proximal contracture with weakness and skin changes make collagen VI–related muscular dystrophy a recognizable clinical phenotype.
  • Patients with LAMA2-related muscular dystrophies have severe white matter changes on MRI resembling a leukodystrophy but lack upper motor neuron signs and have normal cognitive function.
  • Patients with α-dystroglycanopathies can have severe brain malformations including cobblestone lissencephaly.
  • Congenital myopathies are traditionally classified by histopathologic findings including nemaline rods, cores, and central nuclei.
  • Nemaline myopathies are most frequently caused by mutations in NEB and ACTA1 and can have a very severe neonatal course that is typically not progressive.
  • The majority of core myopathies are caused by mutations in RYR1 and have significant risk for malignant hyperthermia.
  • Patients with collagen VI–related muscular dystrophy and SELENON-related muscular dystrophy have early respiratory compromise and may require noninvasive ventilation while asleep, even while still ambulatory.
  • Variants in the TTN gene encoding titin are seen in many healthy people, complicating the interpretation of TTN variants in patients with suspected congenital myopathy.

Article 7: Facioscapulohumeral Muscular Dystrophies

Kathryn R. Wagner, MD, PhD. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1662–1681.

ABSTRACT

PURPOSE OF REVIEW

Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular dystrophy affecting both pediatric and adult patients. This article reviews the phenotype and pathophysiology of the disease as well as the recent efforts in clinical outcome measures and clinical trials.

RECENT FINDINGS

As the name implies, FSHD involves weakness of facial muscles, muscles that fix the scapula, and muscles overlying the humerus (biceps and triceps). The distinctive phenotype of FSHD occurs secondary to two different genetic mechanisms. FSHD type 1 (FSHD1) is due to a deletion on chromosome 4q, leading to hypomethylation and derepression of DUX4. FSHD type 2 (FSHD2) is due to mutations in SMCHD1 with resulting hypomethylation of the same subtelomeric region of chromosome 4q and derepression of DUX4. Understanding the central role of DUX4 has opened up the possibility of disease-modifying treatments. In preparation for clinical trials of novel agents, researchers are in the process of validating a number of clinical trial outcome measures including MRI, the 6-minute walk test, the FSHD Composite Outcome Measure, reachable workspace, electrical impedance myography, and the FSHD Health Index.

SUMMARY

The treatment of FSHD is currently supportive only. While past clinical trials in FSHD have been largely disappointing, novel agents in development, including antisense oligonucleotides, gene therapy, and small molecules, hold promise for future meaningful therapies.

KEY POINTS

  • The two forms of facioscapulohumeral muscular dystrophy are type 1 (95% of cases) and type 2 (5% of cases). The presentations of both types are identical.
  • Both facioscapulohumeral muscular dystrophy types 1 and 2 are due to hypomethylation of the subteleomeric region of chromosome 4q, leading to aberrant expression of a normally silent transcription factor DUX4.
  • Facioscapulohumeral muscular dystrophy presents with asymmetric weakness of the orbicularis oculi, orbicularis oris, rhomboids, serratus anterior, biceps, triceps, paraspinals, rectus abdominis, and tibialis anterior. Eventually, other muscles of the arms and legs may become involved.
  • Facioscapulohumeral muscular dystrophy has few associated signs and symptoms. In those with large deletions, an increased risk of retinal vasculopathy and hearing loss is present.
  • The diagnosis of facioscapulohumeral muscular dystrophy rests on the recognition of the clinical phenotype and genetic testing. Creatine kinase is normal to mildly elevated, and EMG and muscle biopsy are nonspecific and not indicated.
  • Patients with large deletions in chromosome 4q should be seen by a retina specialist and have a hearing examination.
  • Surgical scapular fixation is an extensive procedure and should be undertaken only in specific patients with preserved deltoid strength and should be carried out by experienced surgeons.
  • Bone health is important to prevent morbidity. Vitamin D3 levels should be checked in all patients with facioscapulohumeral muscular dystrophy and supplemented as needed. For those with significant weakness, bone density should be followed by annual dual energy x-ray absorptiometry scans.
  • The rectus abdominis and semimembranosus are among the most severely affected muscles in patients with facioscapulohumeral muscular dystrophy, as noted on MRI.
  • On imaging, muscle affected by facioscapulohumeral muscular dystrophy may follow a pathologic progression from normal signal intensity to short tau inversion recovery hyperintensity to T1-weighted hyperintensity.
  • β2-Adrenergic agonists have been trialed in patients with facioscapulohumeral muscular dystrophy, and while they show increased muscle mass, they have had mixed results in showing increased strength.
  • Aerobic exercise in the form of cycling has shown mixed results with some improvement in fitness and strength observed in patients with facioscapulohumeral muscular dystrophy.
  • Future therapies for patients with facioscapulohumeral muscular dystrophy include antisense oligonucleotides, gene therapy, and small molecules all targeting DUX4.

Article 8: Myotonic Muscular Dystrophies

Nicholas E. Johnson, MD, MSc, FAAN. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1682–1695.

ABSTRACT

PURPOSE OF REVIEW

This article describes the clinical features, pathogenesis, prevalence, diagnosis, and management of myotonic dystrophy type 1 and myotonic dystrophy type 2.

RECENT FINDINGS

The prevalence of myotonic dystrophy type 1 is better understood than the prevalence of myotonic dystrophy type 2, and new evidence indicates that the risk of cancer is increased in patients with the myotonic dystrophies. In addition, descriptions of the clinical symptoms and relative risks of comorbidities such as cardiac arrhythmias associated with myotonic dystrophy type 1 have been improved.

SUMMARY

Myotonic dystrophy type 1 and myotonic dystrophy type 2 are both characterized by progressive muscle weakness, early-onset cataracts, and myotonia. However, both disorders have multisystem manifestations that require a comprehensive management plan. While no disease-modifying therapies have yet been identified, advances in therapeutic development have a promising future.

KEY POINTS

  • The myotonic muscular dystrophies are autosomal dominant disorders characterized by a clinical triad of progressive weakness, myotonia, and early-onset cataracts.
  • Myotonic dystrophy type 1 is the most common form of muscular dystrophy.
  • Myotonic dystrophy type 1 is caused by a CTG repeat expansion in the 3′ untranslated region of the DMPK gene. Myotonic dystrophy type 2 is caused by an intronic CCTG repeat expansion in the CNBP gene.
  • The clinical triad associated with myotonic dystrophy type 1 is distal muscle weakness, myotonia, and early-onset cataracts.
  • Cardiac arrhythmias, such as atrioventricular block, are the leading cause of death in myotonic dystrophy type 1.
  • The most impactful symptom in myotonic dystrophy type 1 is fatigue, which may be driven by a combination of sleep apnea, respiratory failure, and excessive daytime sleepiness.
  • Patients with myotonic dystrophy type 1 may have a symptom complex similar to irritable bowel syndrome.
  • If the symptoms of myotonic dystrophy type 1 begin at birth, it is called congenital myotonic dystrophy. The neonatal manifestations often include hypotonia, respiratory failure, feeding problems, and talipes equinovarus (clubfoot).
  • Childhood-onset myotonic dystrophy is defined as symptoms after the age of 1 and before the age of 10. These early childhood symptoms often include intellectual impairment and gastrointestinal symptoms.
  • Muscle weakness in myotonic dystrophy type 2 is predominantly proximal rather than distal and includes the neck flexors, hip flexors, and hip extensors.
  • It is possible that pain may be diagnosed as fibromyalgia in the absence of other myotonic dystrophy type 2–associated features.
  • Both patients with myotonic dystrophy type 1 and patients with myotonic dystrophy type 2 benefit from moderate-intensity aerobic exercise.
  • Skeletal muscle myotonia in patients with myotonic dystrophy type 1 or myotonic dystrophy type 2 may be treated with several different agents that target skeletal muscle sodium channels, such as mexiletine.
  • Patients with myotonic dystrophy type 1 or myotonic dystrophy type 2 are at an increased risk of developing life-threatening cardiac arrhythmias. It is recommended that patients have an ECG at diagnosis and annually thereafter.
  • It is important to screen patients with myotonic dystrophy type 1 and patients with myotonic dystrophy type 2 for the presence of central or obstructive sleep apnea.
  • Patients with myotonic dystrophy type 1 or myotonic dystrophy type 2 should be screened with a glucose breath test for a bacterial overgrowth syndrome and treated appropriately if the test is positive. A high-fiber diet is the first-line treatment for patients with diarrhea or constipation.
  • Patients with myotonic dystrophy are at risk of thyroid deficiency, which may exacerbate their fatigue and myotonia without treatment.
  • Patients with myotonic dystrophy type 1 are at increased risk with use of general anesthesia. Complications include a hypersensitivity to opiate medications, a paradoxical reaction to muscle-depolarizing agents, or a prolonged ventilatory wean.

Article 9: Episodic Muscle Disorders

Valeria A. Sansone, MD, PhD. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1696–1711.

ABSTRACT

PURPOSE OF REVIEW

This article reviews the episodic muscle disorders, including benign cramp-fasciculation syndrome, the periodic paralyses, and the nondystrophic myotonias. The core diagnostic criteria for a diagnosis of primary periodic paralysis, including clues to distinguish between the hypokalemic and hyperkalemic forms, and the distinctive elements that characterize Andersen-Tawil syndrome are discussed. Management of patients with these disorders is also discussed.

RECENT FINDINGS

Childhood presentations of periodic paralysis have recently been described, including atypical findings. Carbonic anhydrase inhibitors, such as dichlorphenamide, have recently been approved by the US Food and Drug Administration (FDA) for the treatment of both hypokalemic and hyperkalemic forms of periodic paralysis. Muscle MRI may be a useful outcome measure in pharmacologic trials in periodic paralysis. Genetic research continues to identify additional gene mutations responsible for periodic paralysis.

SUMMARY

This article will help neurologists diagnose and manage episodic muscle disorders and, in particular, the periodic paralyses and the nondystrophic myotonias.

KEY POINTS

  • Cramp-fasciculation syndrome is a rare condition characterized by persistent muscle cramping and twitching (fasciculations), usually in the legs, in otherwise healthy individuals.
  • Abortive attacks of weakness involving one or more limbs may erroneously suggest a psychogenic (functional) neurologic disorder because of the transitory nature of the event and the anxiety patients experience related to the loss of function, no matter how brief.
  • Complete paralysis of all four limbs is the typical presentation that leads to the diagnostic workup for periodic paralysis. The most frequent differential diagnosis is Guillain-Barré syndrome.
  • Children presenting with leg stiffness, cramps, muscle pain, and fluctuating extraocular movements should be examined for myotonia to rule out an underlying sodium channelopathy.
  • Episodes of muscle weakness may also occur in the nondystrophic myotonias (sodium and chloride channelopathies).
  • Cardiac involvement in Andersen-Tawil syndrome warrants close monitoring, even in patients who are asymptomatic.
  • Testing the patient’s serum potassium level during an attack of weakness is crucial to the diagnosis of periodic paralysis.
  • Creatine kinase levels are not diagnostic in periodic paralysis.
  • EMG may contribute to the diagnosis of periodic paralysis in patients in whom family history and potassium levels during an attack are unavailable or not informative.
  • Muscle biopsy is not diagnostic in periodic paralysis; although tubular aggregates may be found in some patients, they are not specific to periodic paralysis.
  • Patients can manage their episodes of periodic paralysis by learning to avoid triggers, following a diet based on the type of periodic paralysis, and stabilizing their serum potassium levels by taking oral potassium or diuretics according to the type of periodic paralysis.
  • When managing patients with periodic paralysis, clinicians should consider more aggressive pharmacologic treatment with carbonic anhydrase inhibitors (preferably dichlorphenamide), if needed, and closely monitor cardiac function in Andersen-Tawil syndrome, even when no symptoms are present.

Article 10: Toxic Myopathies

Christopher T. Doughty, MD; Anthony A. Amato, MD, FAAN. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1712–1731.

ABSTRACT

PURPOSE OF REVIEW

This article reviews the pathogenesis, clinical features, and management of toxic myopathy related to common medications, critical illness, and illicit substances.

RECENT FINDINGS

Muscle symptoms are common among statin users and are usually reversible after discontinuation of the statin; rarely, however, statins trigger an immune-mediated necrotizing myopathy that persists and requires immunomodulatory therapy. Autoantibodies targeting 3-hydroxy-3-methylglutaryl coenzyme A reductase can distinguish the toxic and immune-mediated forms. Immune checkpoint inhibitors, increasingly used in the treatment of advanced cancer, have recently been associated with the development of inflammatory myositis. A reversible mitochondrial myopathy has long been associated with zidovudine, but recent reports elucidate the risk of myopathy with newer antivirals, such as telbivudine and raltegravir.

SUMMARY

The medications most commonly associated with myopathy include statins, amiodarone, chloroquine, hydroxychloroquine, colchicine, certain antivirals, and corticosteroids, and myopathy can occur with chronic alcoholism. Certain clinical, electrodiagnostic, and histologic features can aid in early recognition. Stopping the use of the offending agent reverses symptoms in most cases, but specific and timely treatment may be required in cases related to agents that trigger immune-mediated muscle injury.

KEY POINTS

  • The clinical presentation of toxic myopathy is diverse. Some patients present with severe symptoms soon after initiation of the causative medication, whereas others present with mild symptoms that develop insidiously after months of exposure.
  • In most cases, stopping the offending medication leads to improvement and even resolution of symptoms. Statins and immune checkpoint inhibitors, however, can cause an immune-mediated myopathy that may require immunomodulatory treatment.
  • The spectrum of myopathic symptoms encountered with cholesterol-lowering agents includes myalgia, cramps, asymptomatic creatine kinase level elevation, proximal muscle weakness, and rhabdomyolysis with myoglobinuria.
  • Myalgia and cramps are common among statin users but are not always related to the statin.
  • Rhabdomyolysis in statin-treated patients is a rare event, with an estimated incidence of 2 to 3 per 100,000 patient-years.
  • Many drugs interact with statins and increase the risk of muscle toxicity, including rhabdomyolysis, when used concurrently. Important examples include other cholesterol-lowering agents and cyclosporine.
  • Higher doses, older age, and renal failure all increase the risk of statin myotoxicity.
  • Manifestations of statin-associated toxic necrotizing myopathy resolve within 1 week to 3 months after stopping the statin. Persistent symptoms or creatine kinase level elevations thereafter should prompt consideration of immune-mediated necrotizing myopathy or other underlying disorders.
  • A markedly elevated creatine kinase level and EMG demonstrating irritable myopathy are seen in both toxic necrotizing and immune-mediated forms of statin myopathy, but serum anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies are specific for the immune-mediated form.
  • Fibrates cause a spectrum of muscle symptoms similar to statins. Myopathy has also been reported with niacin and ezetimibe, but mostly when used together with a statin.
  • Although less common than other neurologic immune-related adverse events, inflammatory myositis can complicate treatment with immune checkpoint inhibitors. Symptoms typically begin after one or two treatment cycles.
  • In addition to proximal and axial weakness, oculomotor and bulbar weakness are common with immune checkpoint inhibitor–associated myositis. Myasthenia gravis can develop concurrently.
  • Muscle biopsy has demonstrated histiocytic and lymphocytic inflammatory infiltrates in patients with immune checkpoint inhibitor–associated myositis. The creatine kinase level is typically elevated, and EMG will show fibrillation potentials and positive sharp waves in most patients.
  • When patients on an immune checkpoint inhibitor develop myositis or myasthenia gravis, the immune checkpoint inhibitor should be stopped. Most patients should also be treated with corticosteroids. Patients’ symptoms markedly improve over a period of weeks.
  • Chloroquine, hydroxychloroquine, and amiodarone can all cause clinical neuromyopathy. Vacuolar myopathy is evident on muscle biopsy.
  • Recovery from amiodarone neuromyopathy may be partial and prolonged over months.
  • Colchicine causes a neuromyopathy associated with vacuoles on muscle biopsy. Prolonged exposure is typically required, with weakness developing gradually over months.
  • Zidovudine commonly caused a reversible mitochondrial myopathy but is used less commonly to treat HIV now. Myopathy has been reported with more contemporary antivirals, as well, including telbivudine, lamivudine, entecavir, and raltegravir.
  • Proximal weakness related to steroid myopathy typically occurs after prolonged treatment with the equivalent of prednisone 30 mg daily. Creatine kinase values and EMG are commonly normal.
  • Sepsis, multiorgan system failure, and hyperglycemia are associated with a higher risk of developing critical illness myopathy. The risk associated with corticosteroids or neuromuscular blocking agents is much less clear than previously thought.
  • Recent reports suggest that levetiracetam, febuxostat, and isotretinoin can all rarely cause rhabdomyolysis and/or myopathy. The mechanism is uncertain.
  • Mild proximal myopathy is common among patients with chronic alcoholism. Binge drinking and use of cocaine, amphetamines, and phencyclidine can all result in rhabdomyolysis.

Article 11: Mitochondrial and Metabolic Myopathies

Bruce H. Cohen, MD, FAAN. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1732–1766.

ABSTRACT

PURPOSE OF REVIEW

This article provides an overview of mitochondrial and metabolic biology, the genetic mechanisms causing mitochondrial diseases, the clinical features of mitochondrial diseases, lipid myopathies, and glycogen storage diseases, all with a focus on those syndromes and diseases associated with myopathy. Over the past decade, advances in genetic testing have revolutionized patient evaluation. The main goal of this review is to give the clinician the basic understanding to recognize patients at risk of these diseases using the standard history and physical examination.

RECENT FINDINGS

Primary mitochondrial disease is the current designation for the illnesses resulting from genetic mutations in genes whose protein products are necessary for mitochondrial structure or function. In most circumstances, more than one organ system is involved in mitochondrial disease, and the value of the classic clinical features as originally described early in the history of mitochondrial diseases has reemerged as being important to identifying patients who may have a primary mitochondrial disease. The use of the genetic laboratory has become the most powerful tool for confirming a diagnosis, and nuances of using genetic results will be discussed in this article. Treatment for mitochondrial disease is symptomatic, with less emphasis on vitamin and supplement therapy than in the past. Clinical trials using pharmacologic agents are in progress, with the field attempting to define proper goals of treatment. Several standard accepted therapies exist for many of the metabolic myopathies.

SUMMARY

Mitochondrial, lipid, and glycogen diseases are not uncommon causes of multisystem organ dysfunction, with the neurologic features, especially myopathy, occurring as a predominant feature. Early recognition requires basic knowledge of the varied clinical phenotypes before moving forward with a screening evaluation and possibly a genetic evaluation. Aside from a few specific diseases for which there are recommended interventions, treatment for the majority of these disorders remains symptomatic, with clinical trials currently in progress that will hopefully result in standard treatments.

KEY POINTS

  • Primary mitochondrial disease is the current designation for the illnesses resulting from genetic mutations in genes whose protein products are necessary for mitochondrial structure or function.
  • Most primary mitochondrial diseases, as defined by the illnesses caused by mutations in mitochondrial-targeted genes, are a result of deficient energy production or excessive free radical production.
  • Most patients with primary mitochondrial disease have at least one nervous system or special sensory system tissue involved.
  • For patient care, it is most logical to classify the patient’s mitochondrial illness by both genotype and phenotype, if available. It is recognized that no well-structured nomenclature for classifying all the mitochondrial diseases exists.
  • If it is not certain that mitochondrial disease is the cause of the patient’s illness, it is highly recommended to avoid using the terms possible or probable as adjectives or descriptors of the term mitochondrial disease. Risks of mislabeling include failing to make the correct diagnosis, creating unnecessary worry, initiating unnecessary therapies, and providing incorrect genetic counseling.
  • Treatment for the lipid myopathies depends on the specific enzyme defect; some disorders have no specific therapy and others have treatments, which often involve dietary manipulation or the use of cofactors or vitamins.
  • Glycogen storage diseases result from deficiencies in the enzymes that build glycogen, as well as those that interfere with the degradation of glycogen and subsequent mobilization of glucose.
  • The glycogen storage diseases that affect muscle present either with exercise intolerance and rhabdomyolysis, as seen with McArdle disease (GSD5) or Tarui disease (GSD7), or with myopathy without rhabdomyolysis, as in Pompe disease (GSD2) or debrancher defect (GSD3a).
  • Enzyme replacement with acid maltase can dramatically improve the muscle symptoms of Pompe disease.
  • Patients with McArdle disease can demonstrate a “second wind phenomenon” in which symptoms improve or disappear after a period of exercise.
  • The creatine kinase level is usually chronically elevated in McArdle disease and Pompe disease.
  • Dietary therapy is a mainstay of therapy for the glycogen storage diseases.
  • Pompe disease has a specific therapy involving IV infusion of alglucosidase alfa.

Article 12: Myasthenia Gravis and Congenital Myasthenic Syndromes

Emma Ciafaloni, MD. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1767–1784.

ABSTRACT

PURPOSE OF REVIEW

Myasthenia gravis (MG) is an autoimmune neuromuscular disease that causes fluctuating weakness in ocular, bulbar, and limb muscles and can, in 15% of cases, cause myasthenic crisis, a neurologic emergency characterized by respiratory failure. Although infrequent, MG needs to be promptly recognized and treated because the potential for improvement and remission is very high. The diagnosis of MG can be challenging and delayed because of the fluctuating nature of muscle weakness and the overlap of signs and symptoms with other neuromuscular diseases.

This article reviews the importance of prompt recognition of the typical signs and symptoms, best tests to confirm the diagnosis, currently available acute and chronic treatment modalities, the role of thymectomy, and the natural history of the disease. Special consideration related to the diagnosis and management in women during pregnancy and in children will also be reviewed. This article also includes an overview of congenital myasthenic syndromes.

RECENT FINDINGS

Recent significant efforts in standardizing and improving the care of patients with MG have occurred, as well as new momentum in developing new drugs for patients with MG who do not adequately respond to currently available treatments. The number of clinical trials and drugs in development for MG is steadily increasing. Eculizumab has been recently approved by the US Food and Drug Administration (FDA) for adult patients with generalized MG who are acetylcholine receptor–antibody positive, based on the REGAIN (Safety and Efficacy of Eculizumab in Refractory Generalized Myasthenia Gravis) study, a phase 3, randomized, double-blind, placebo-controlled, multicenter trial. An international, multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone has demonstrated that thymectomy improves clinical outcome in patients with nonthymomatous MG. Clinical care guidelines have been published, and the recommendations for clinical research standards and the Myasthenia Gravis Foundation of America MGFA clinical classification published in 2000 have become widely accepted by the clinical and research community of MG experts.

SUMMARY

MG is a highly treatable disease with many effective treatment modalities available and with a natural history that continues to improve thanks to better diagnostic tests and effective drugs. The diagnosis and management of patients affected by MG can be highly rewarding for any neurologist as most patients are able to live normal lives if treated appropriately. Nevertheless, future research is needed to address unresolved clinical issues, such as when and how to discontinue immunosuppressive medications in patients in remission, the role and timing of thymectomy in children, and better treatment options for refractory patients.

KEY POINTS

  • Autoimmune myasthenia gravis can occur at any age.
  • Thymoma is found in about 15% of patients with myasthenia gravis and should always be surgically removed. Thymoma is more frequently found in males and patients older than 40, and about 50% of patients with thymoma develop myasthenia gravis.
  • Antibody testing should be used for diagnostic purpose only and not as a repeat test to assess response to therapy. False-positive results are extremely rare.
  • Patients with anti–muscle specific tyrosine kinase–positive myasthenia gravis are more often women and may present with predominant facial, pharyngeal, tongue, and respiratory weakness with or without ocular weakness. Patients respond more frequently to plasma exchange than IV immunoglobulin and may have less improvement and more side effects (prominent fasciculations) from cholinesterase inhibitors.
  • In predominantly bulbar myasthenia gravis with minimal or no ocular weakness, the differential diagnosis with bulbar amyotrophic lateral sclerosis can be challenging: the absence of tongue atrophy and fasciculations, jaw jerk, and spastic speech is helpful for diagnosis. Electrodiagnostic tests, including EMG and single-fiber EMG of weak muscles, are most helpful in confirming the correct diagnosis.
  • The most limiting side effect of pyridostigmine is abdominal cramping and diarrhea because of its muscarinic effect. One of the advantages of using pyridostigmine is its lack of long-term side effects.
  • A common mistake in practice, especially in the inpatient setting, is prescribing pyridostigmine 3 or 4 times a day rather than as needed 30 minutes prior to meals when dysphagia is the targeted symptom.
  • Thymectomy improves clinical outcome in patients with nonthymomatous myasthenia gravis who are between 18 and 65 years old. Thymectomy is generally not indicated in patients older than 65. The timing and role of thymectomy in children are not yet standardized.
  • Pregnancy outcome in women with myasthenia gravis is generally good. Exacerbation of myasthenia gravis occurs in 20% to 30% of women during pregnancy and more commonly in the first trimester or postpartum period. Myasthenia gravis, per se, is not an indication for Cesarean delivery.
  • IV immunoglobulin, plasma exchange, prednisone, and pyridostigmine are generally safe in pregnancy and lactation. Mycophenolate mofetil should be avoided during conception and pregnancy.
  • Seronegative autoimmune myasthenia gravis in children can be difficult to differentiate from congenital myasthenic syndrome, and DNA testing, repetitive nerve stimulation, and the response to a trial of IV immunoglobulin or plasma exchange can help establish a definite diagnosis of seronegative autoimmune myasthenia gravis.
  • Of newborns of mothers with myasthenia gravis, 10% to 15% develop transient neonatal myasthenia gravis, and it can resolve spontaneously after the maternal antibodies transmitted through the placenta are cleared. Arthrogryposis multiform congenita can occur, although rarely, in newborns of mothers affected by myasthenia gravis, even of mothers who are asymptomatic.
  • The diagnosis of congenital myasthenic syndrome should be considered in children with proximal muscle weakness and facial features consistent with a myopathy but in whom the creatine kinase level and muscle biopsy are normal.

Article 13: Lambert-Eaton Myasthenic Syndrome, Botulism, and Immune Checkpoint Inhibitor–Related Myasthenia Gravis

Amanda C. Guidon, MD. Continuum (Minneap Minn). December 2019; 25 (6 Muscle and Neuromuscular Junction Disorders):1785–1806.

ABSTRACT

PURPOSE OF REVIEW

This article reviews the pathophysiology, epidemiology, clinical presentation, diagnosis, and treatment of Lambert-Eaton myasthenic syndrome (LEMS) and of botulism, and immune-related myasthenia gravis (MG) occurring in the context of immune checkpoint inhibitor therapy for cancer.

RECENT FINDINGS

The suspicion that LEMS is rare but also likely underdiagnosed is supported by recent epidemiologic data. A validated, LEMS-specific scale now exists to assess and monitor disease, and symptomatic and immunomodulatory treatments are available. As presynaptic disorders of neuromuscular transmission, LEMS and botulism share electrodiagnostic abnormalities but have important distinguishing features. Knowledge of the clinical features of botulism is needed, particularly with continued cases of infant botulism, the opioid epidemic increasing the incidence of wound botulism, and medical use of botulinum toxin, which may cause iatrogenic botulism. Foodborne botulism remains rare. Prompt recognition of botulism and administration of antitoxin can improve outcomes. MG may be exacerbated or may present de novo in the context of immune activation from immune checkpoint inhibitor therapies for cancer. Immune-related MG commonly overlaps with myositis and myocarditis. Corticosteroids typically result in improvement. However, immune-related MG can be more fulminant than its idiopathic counterpart and may cause permanent disability or death.

SUMMARY

The diagnosis of LEMS, botulism, or immune-related MG can generally be made from the patient’s history, supplemented with directed questions, a physical examination designed to demonstrate abnormalities, and laboratory and electrodiagnostic testing. Early diagnosis and carefully selected treatment not only improve outcomes of the neuromuscular disease but can affect the prognosis of underlying malignancy, when present.

KEY POINTS

  • In Lambert-Eaton myasthenic syndrome (LEMS), pathogenic P/Q-type voltage-gated calcium channel antibodies cause fewer quanta of acetylcholine to be released from presynaptic nerve terminals.
  • Failure of neuromuscular transmission in LEMS results in symptoms of skeletal muscle weakness and autonomic dysfunction.
  • LEMS is a rare disease that affects mostly adults and is likely underdiagnosed.
  • More than half of patients with LEMS have an underlying cancer, most commonly small cell lung cancer, diagnosed within 2 years of disease onset.
  • LEMS is generally a treatable disorder that may even improve the prognosis related to small cell lung cancer, when present.
  • Symptoms of LEMS include a triad of gait dysfunction/lower extremity weakness, areflexia or hyporeflexia, and autonomic dysfunction.
  • Patients should be specifically asked about autonomic symptoms of LEMS, including constipation, dry mouth, and orthostasis.
  • Symptoms of LEMS typically exceed abnormal findings on examination; therefore, a high clinical suspicion is needed for diagnosis.
  • Most patients with LEMS have diagnostic P/Q-type voltage-gated calcium channel antibodies.
  • Electrodiagnostic studies are warranted in patients with LEMS, even in patients with positive antibody testing, to confirm a presynaptic disorder of neuromuscular transmission.
  • In LEMS, low-amplitude compound muscle action potentials that facilitate after 10 seconds of exercise and show a decrement in distal nerve-muscle combinations with 3-Hz repetitive nerve stimulation are seen.
  • Once the diagnosis of LEMS is suspected, patients should be screened for malignancy. If initial testing is negative, screening continues for up to 2 years.
  • The Triple Timed Up and Go test is a reliable and validated outcome measure that can be easily performed in clinic and is used to monitor disease severity in clinical trials of patients with LEMS.
  • Amifampridine phosphate and 3,4-diaminopyridine are the primary symptomatic therapies for LEMS. Immunosuppressive therapies are second- or third-line therapies.
  • Botulinum neurotoxin is produced by an anaerobic gram-positive spore-forming bacillus. The toxin inhibits presynaptic acetylcholine release in motor and autonomic nerves.
  • Cases of botulism are categorized into one of four major transmission categories: foodborne, wound, infant, and other (which includes iatrogenic).
  • Botulism presents as acute descending flaccid weakness and respiratory and autonomic dysfunction. Botulism is considered in the differential diagnosis for the acutely “floppy baby” under 1 year of age.
  • Physicians should notify the state or other relevant health department to obtain treatment and work to isolate a source as soon as botulism is suspected.
  • Electrodiagnostic studies are critical in helping narrow the differential diagnosis and may demonstrate the presynaptic abnormalities of botulism. However, normal studies do not exclude the diagnosis of botulism, especially early in disease.
  • Early public health notification of the suspected botulism diagnosis allows for early treatment with human botulism immunoglobulin intravenous (BIG-IV) or antitoxin, which improves outcomes.
  • Mortality from botulism is low; however, recovery can be protracted.
  • A myasthenic syndrome is now associated with immune checkpoint inhibitor therapy for cancer. It frequently overlaps with other neurologic and non-neurologic immune-related adverse events.
  • Currently, treatment of immune-related myasthenia gravis from immune checkpoint inhibitor therapy first involves treatment interruption and often corticosteroids.
© 2019 American Academy of Neurology.