MUSCLE AND NEUROMUSCULAR JUNCTION DISORDER
ARTICLE 1: A SYMPTOMS AND SIGNS APPROACH TO THE PATIENT WITH NEUROMUSCULAR WEAKNESS
Nicholas J. Silvestri, MD, FAAN. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1580–1595.
PURPOSE OF REVIEW
Muscle weakness is a common feature of many neuromuscular disorders. This article outlines a symptoms and signs approach to the patient presenting with neuromuscular weakness, highlighting key aspects of the clinical history and examination.
The past several years have seen a dramatic increase in the ability to test for many inherited and autoimmune neuromuscular disorders more reliably and accurately. Similarly, numerous targeted therapies have been recently approved to treat previously untreatable disorders. Therefore, timely and accurate diagnosis is essential so that patients can receive appropriate therapy, ultimately leading to better clinical outcomes.
Muscle weakness is a common symptom resulting from dysfunction that can occur at any level of the neuraxis and is a cardinal feature of many neuromuscular disorders. An accurate and meticulous history and a thorough neurologic examination are paramount in localizing the lesion in order to generate a differential diagnosis and guide appropriate ancillary testing. The patient’s age at symptom onset, any identified inciting factors, tempo of symptom progression, pattern of weakness, and associated symptoms and signs are all important diagnostic clues in the evaluation of a patient presenting with muscle weakness.
- It is important to differentiate true muscle weakness from other symptoms such as generalized fatigue or malaise, or physical limitations due to arthralgia, myalgia, or deconditioning.
- When evaluating a patient for muscle weakness, it is instructive to ask about the impact of the symptoms on routine activities to differentiate true weakness from other conditions.
- Muscle weakness can develop acutely over hours to days, subacutely over weeks, or chronically over months.
- Fatigability is often seen in neuromuscular junction disorders and must be differentiated from generalized fatigue or malaise.
- The age of the patient at the onset of muscle weakness is also important to accurately determine, as it directly affects the differential diagnosis.
- Vaccinations, gastrointestinal symptoms, or upper respiratory tract infections occur 2 to 3 weeks before the development of neurologic symptoms in roughly two-thirds of patients diagnosed with Guillain-Barré syndrome.
- With episodic weakness, the associations of symptoms with diet, exercise, rest after exercise, ambient temperature, and underlying illnesses such as infections are important clues to the diagnosis.
- Orthopnea is often an early symptom of neuromuscular respiratory failure, as the diaphragm is placed at a mechanical disadvantage in the supine position.
- A thorough past medical history is necessary to identify any concomitant diseases that may be associated with muscle weakness, such as organ system dysfunction, malignancy, connective tissue disorders, or autoimmune disorders.
- Examining a similarly affected family member with muscle weakness can prove invaluable when eliciting a family history.
- The pattern of muscle weakness must be determined using both the history and the neurologic examination.
- Most myopathies and disorders of the neuromuscular junction cause proximally predominant weakness.
- Distally predominant weakness is often seen initially in motor neuron disorders and neuropathies; it occurs rarely in myopathies and disorders of the neuromuscular junction.
- Oculobulbar-predominant weakness leading to ptosis, dysconjugate gaze and diplopia, dysarthria, dysphagia, or dysphonia is typical of myasthenia gravis.
- The symmetry or asymmetry of involvement is an important diagnostic clue in the evaluation of muscle weakness.
- It is necessary to directly inspect a patient’s muscles to evaluate for the presence of atrophy, hypertrophy, or abnormal movements.
- Sensory symptoms can co-occur with muscle weakness and indicate involvement of the spinal cord, nerve roots, or nerves.
- Ancillary tests should be ordered using a hypothesis-driven approach based on the differential diagnosis arrived at by the history and examination.
- Nerve conduction studies and EMG are invaluable tools to aid in the diagnosis of neuromuscular disorders and are best conceptualized as extensions of the history and neurologic examination.
ARTICLE 2: LAMBERT-EATON MYASTHENIC SYNDROME AND BOTULISM
Shruti M. Raja, MD. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1596–1614.
PURPOSE OF REVIEW
This article reviews the pathophysiology, epidemiology, clinical features, diagnosis, and treatment of Lambert-Eaton myasthenic syndrome (LEMS) and botulism, presynaptic disorders of neuromuscular transmission in which rapid diagnosis improves long-term outcomes.
Therapy for LEMS has seen significant advances in recent years due to the approval of amifampridine-based compounds. LEMS is likely still underdiagnosed, particularly when no underlying malignancy is identified. Clinicians must have a strong suspicion for LEMS in any patient presenting with proximal weakness and autonomic dysfunction. Botulism is another rare disorder of presynaptic neuromuscular transmission that is most commonly associated with improper storage or preservation of food products. Over the past 2 decades, wound botulism has been increasingly reported among users of black tar heroin. A high degree of clinical suspicion and electrodiagnostic studies can be beneficial in distinguishing botulism from other acute neurologic disorders, and early involvement of state and federal health authorities may assist in confirming the diagnosis and obtaining treatment. When botulism is suspected, electrodiagnostic studies can provide clinical evidence of disordered neuromuscular transmission in advance of serologic confirmation, and providers should not wait for confirmation of the diagnosis to initiate treatment.
A targeted clinical history and a thorough neurologic examination with support from serologic and electrodiagnostic studies are key to early diagnosis of LEMS and botulism. Early diagnosis of both conditions creates opportunities for therapy and improves outcomes.
- Lambert-Eaton myasthenic syndrome is associated with pathogenic P/Q-type voltage-gated calcium channel antibodies that impair the release of acetylcholine vesicles at the presynaptic neuromuscular junction.
- Presynaptic defects of neuromuscular transmission can cause weakness and autonomic dysfunction.
- Malignancy, particularly small cell lung cancer, is identified in over 50% of patients with Lambert-Eaton myasthenic syndrome.
- Lambert-Eaton myasthenic syndrome is a rare disease with worldwide prevalence of approximately 2.8 cases per million individuals.
- Misdiagnosis of Lambert-Eaton myasthenic syndrome is frequent because of the lack of awareness and confusion with other more common diseases.
- Lambert-Eaton myasthenic syndrome is a treatable condition, and most patients improve with appropriate therapy.
- Lambert-Eaton myasthenic syndrome is characterized by a clinical triad of proximal muscle weakness, autonomic dysfunction, and areflexia/hyporeflexia.
- Patients may not voluntarily disclose autonomic symptoms, particularly dry mouth, orthostatic hypotension, constipation, and erectile dysfunction.
- Symptoms of Lambert-Eaton myasthenic syndrome are often disproportionate to clinical examination abnormalities.
- Routine nerve conduction studies and EMG are necessary to narrow the differential diagnosis of Lambert-Eaton myasthenic syndrome.
- Electrodiagnostic features of Lambert-Eaton myasthenic syndrome include low-amplitude compound muscle action potentials with incremental increases with repeated stimulation and facilitation following 10 seconds of maximal exercise on 2-Hz to 3-Hz repetitive nerve stimulation.
- Malignancy screening should be performed for a minimum of 2 years after diagnosis of Lambert-Eaton myasthenic syndrome.
- Symptomatic therapies are first line for Lambert-Eaton myasthenic syndrome and include forms of amifampridine.
- Pyridostigmine augments the effects of amifampridine and may improve some autonomic symptoms.
- IV immunoglobulin and therapeutic plasma exchange can be used in severe cases of Lambert-Eaton myasthenic syndrome that are unresponsive to symptomatic therapy.
- Treatment of underlying malignancy reduces symptoms in cancer-associated Lambert-Eaton myasthenic syndrome.
- Immunosuppressive and immunomodulatory therapies such as corticosteroids, azathioprine, and mycophenolate can be used in patients with nontumor Lambert-Eaton myasthenic syndrome who have inadequate control with symptomatic therapies.
- Botulism is characterized by a toxidrome of acute, afebrile, descending weakness and autonomic dysfunction.
- Botulinum neurotoxin irreversibly binds to presynaptic neurons and cleaves soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) proteins to prevent formation of the synaptic fusion complex and release of acetylcholine vesicles.
- Intoxication with botulinum toxin is most commonly due to serotypes A, B, and E.
- Sources of botulinum toxin transmission include food, wounds, toxicoinfection, and others (including iatrogenic).
- Early botulism may present with limited symptoms, and it is important to look for signs of clinical weakness involving craniobulbar muscles and autonomic dysfunction.
- Infant botulism classically presents as “floppy baby.”
- An acute, descending paralysis without fever and sensory symptoms should raise suspicion for botulism.
- Confirmation of botulism requires identification of the neurotoxin and is performed in collaboration with the Centers for Disease Control and Prevention and state health departments.
- Providers should notify state health authorities and the Centers for Disease Control and Prevention immediately when botulism is suspected to assist with source identification, coordination of diagnostic testing, and acquisition of therapeutics.
- Moderate, long-lasting postactivation facilitation on 2-Hz to 3-Hz repetitive nerve stimulation and an absence of postactivation exhaustion are key electrodiagnostic features of botulism.
- A human immunoglobulin is available for infants and equine heptavalent botulinum antitoxin is available for adults through the Centers for Disease Control and Prevention.
ARTICLE 3: DIAGNOSIS AND MANAGEMENT OF MYASTHENIA GRAVIS
Michael K. II MD Li Yuebing Hehir, MD, PhD, FAAN. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1615–1642.
PURPOSE OF REVIEW
This article reviews updated diagnostic procedures and currently available treatment modalities for myasthenia gravis (MG).
Patients with MG can be classified based on antibody status and their clinical presentation; treatment responses may differ based on disease subtypes. Improved diagnostic methods and recognition of new antigenic targets such as lipoprotein-related protein 4 have led to improved diagnostic efficiencies. Corticosteroids remain the first-line immunotherapy, but there is a trend toward minimizing their use at high doses and for long durations. Oral immunosuppressants such as mycophenolate mofetil, azathioprine, and tacrolimus remain useful. An international, multicenter randomized trial comparing thymectomy plus prednisone with prednisone alone demonstrated that thymectomy improves clinical outcomes in selected patients with nonthymomatous MG. Eculizumab, efgartigimod, and ravulizumab have recently been approved by the US Food and Drug Administration (FDA) for adult patients with generalized MG who are acetylcholine receptor–antibody positive. These drugs take advantage of novel mechanisms of action and expand treatment options for patients with MG. Data on rituximab suggest that it can be a good option, especially for patients with MG who are positive for antibodies against muscle-specific tyrosine kinase (MuSK). The number of clinical trials and drugs in development for MG is steadily increasing.
The diagnosis of MG can generally be made from the patient’s history, a neurologic examination, and laboratory and electrodiagnostic testing. Carefully selected treatment improves outcomes in MG. Additional treatment options for MG will likely be available in the near future.
- Patients with myasthenia gravis (MG) develop characteristic muscle weakness that worsens with activity and fatigue. MG has a predilection to affect ocular, bulbar, neck, respiratory, and proximal limb muscles more than others.
- Two-thirds of patients with MG develop a combination of diplopia and eyelid ptosis. Up to 75% of these patients will progress to generalized MG within the first 2 to 3 years of developing symptoms.
- Classification of patients based on age, autoantibody status, and ocular versus generalized MG is essential to guide the diagnostic workup and treatment decisions.
- Evaluation of patients with suspected generalized MG relies on a combination of clinical history, clinical examination, bedside maneuvers, serum autoantibody testing, and electrodiagnostic testing.
- The MG Core Exam can be used to evaluate and follow patients in the clinic and through video telemedicine.
- In patients with ptosis, the ice pack test carries a sensitivity of 80% to 95% and a specificity of 79% to 97%.
- Anti-acetylcholine receptor–binding antibody can be elevated in about 75% to 90% of patients with generalized MG. At low titers, false positives can be observed in patients with other autoimmune disorders.
- Antibodies against muscle-specific tyrosine kinase, lipoprotein-related protein 4, and clustered acetylcholine receptors can be detected in a large portion of patients with generalized MG without anti-acetylcholine receptor–binding antibodies.
- Slow-rate repetitive nerve stimulation and single-fiber EMG can be used to confirm a diagnosis of MG in those who do not have measurable autoantibodies.
- Confirming the diagnosis of ocular MG relies on bedside testing and electrodiagnostics in many patients because of the low sensitivity of antibody testing when symptoms are restricted to ocular muscles.
- Slow-rate repetitive nerve stimulation has high specificity but low sensitivity in ocular MG.
- Single-fiber EMG has a high sensitivity in ocular MG. However, single-fiber EMG has the possibility of false-positive testing in ocular MG due to lower specificity (75% to 90%).
- The specificity of single-fiber EMG can be improved by combining it with an ice pack test for patients with ocular symptoms.
- Treatment of MG varies according to many patient characteristics and practical considerations and should be individualized.
- Patient education on typical MG symptoms, course, prognosis, and treatment is important for treatment success.
- Physical exercise is beneficial to patients with MG and can be modified based on tolerability.
- Fatigue in MG is multifactorial, and isolated perception of fatigue may not require medication escalation.
- Isolated perception of dyspnea at rest or with exertion does not indicate myasthenic crisis and rarely needs treatment escalation.
- Medications listed as “use with caution” in MG can be tolerated by patients with mild disease and may be given to patients with significant weakness under careful monitoring if no alternatives exist.
- Immune checkpoint inhibitors may cause a combination of MG, myositis, and myocarditis, and an aggressive treatment strategy for these complications is needed.
- Pyridostigmine is used alone in ocular and mild MG or in combination with immunosuppressants in severe cases and can be minimized or stopped after patients improve on immunotherapy.
- Prednisone remains the first-line immunotherapy for MG, and the starting dosage may vary depending on disease severity. A higher dosage may not be necessary for mild disease.
- Prednisone tapering should be slow, with a target goal of 5.0 to 7.5 mg/d at approximately 1 year.
- Selection of corticosteroid-sparing agents depends on many factors, including patient preference and providers’ familiarity.
- The tapering of corticosteroid-sparing agents in MG should be slow to avoid a relapse.
- For maintenance therapy of MG, patients can be kept on a stable low-dose corticosteroid, a low-dose corticosteroid-sparing agent, or a combination of both.
- Rituximab can be an option for refractory and new-onset MG, and the incidence of progressive multifocal leukoencephalopathy appears rare.
- Eculizumab and ravulizumab have a quick onset of action, and their efficacy is long lasting, but cost is a limiting factor.
- Efgartigimod has a quick onset of action and is well tolerated, but data on optimal long-term treatment are lacking.
- Plasma exchange and IV immunoglobulin can be used for acute exacerbation or as a maintenance therapy. Subcutaneous immunoglobulin has potential as maintenance immunotherapy in MG.
- Patients with impending myasthenic crisis should be monitored closely. The decision on extubation of intubated patients with MG should be made conservatively.
- Thymectomy should be considered for early-onset acetylcholine receptor antibody–positive MG, and endoscopic approaches can be used for most patients with MG.
- If ptosis or extraocular dysmotility in MG does not reverse with maximal treatment after 2 years, surgical options could be considered in selected cases.
- Fast-acting treatment of MG symptoms using plasma exchange or IV immunoglobulin may spare the use of high-dose corticosteroid therapy.
- Rituximab is particularly effective for anti–muscle-specific tyrosine kinase MG.
- Newer agents to treat MG are being developed and investigated at a rapid pace.
ARTICLE 4: INFLAMMATORY MYOPATHIES
Georgios Manousakis, MD, FAAN. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1643–1662.
PURPOSE OF REVIEW
This article outlines the salient clinical, serologic, electrophysiologic, imaging, and histopathologic findings and treatment options for the idiopathic inflammatory myopathies, including those related to immune checkpoint inhibitors and SARS-CoV-2.
The classification of idiopathic inflammatory myopathies has improved with the integration of myositis-specific antibodies and histopathologic findings. Characteristic features of immune checkpoint inhibitor–related myositis have been identified, allowing early recognition and treatment of the syndrome. The COVID-19 pandemic has had a profound impact on the care of patients with idiopathic inflammatory myopathies, and several mechanisms of virus-related muscle injury have been proposed.
A comprehensive evaluation including clinical examination, EMG, imaging, antibody testing, muscle biopsy, and cancer screening, when appropriate, can lead to an earlier accurate diagnosis and an individualized treatment approach for patients with idiopathic inflammatory myopathies.
- Symmetric proximal upper and lower extremity muscle weakness of subacute onset is common among all treatable idiopathic inflammatory myopathies.
- Anti–3-hydroxy-3-methylglutaryl coenzyme A (anti–HMG-CoA) reductase IgG myopathy may evolve slowly and mimic muscular dystrophy; antibody testing should be considered in suspected muscular dystrophy with negative genetic testing.
- Heliotrope sign and Gottron sign are the most common skin manifestations of dermatomyositis.
- Nail bed telangiectasias and cuticle overgrowth are more common with anti–Mi-2 dermatomyositis.
- Palmar papules and fingertip ulcerations are characteristic of anti–MDA-5 dermatomyositis.
- The most severe interstitial lung disease occurs with anti–MDA-5 dermatomyositis, antisynthetase syndrome, and overlap myositis with systemic sclerosis. Adding diffusion capacity of the lungs for carbon monoxide to routine spirometry is important to detect this complication.
- Symptomatic cardiac involvement is more likely with anti–signal recognition particle and antimitochrondrial antibody immune-mediated necrotizing myopathy and immune checkpoint inhibitor–related myositis.
- Creatine kinase level can be normal in dermatomyositis and antisynthetase syndrome and is usually very high in immune-mediated necrotizing myopathy. Intermediate-range creatine kinase elevations are not diagnostically helpful and can be seen in myositis mimics, including neurogenic disorders.
- Anti–TIF1-γ and anti–NXP-2 antibodies occur in both juvenile dermatomyositis without cancer and adult dermatomyositis, which has a strong association with cancer.
- Anti–Mi-2 antibody dermatomyositis is associated with typical skin rashes, nail changes, good response to treatment, and no interstitial lung disease or underlying cancer.
- Anti–MDA-5 and anti-SAE antibody dermatomyositis can present without weakness (“amyopathic”), although subclinical muscle involvement is frequently identified on imaging, EMG, or biopsy.
- Antisynthetase syndrome is the combination of myositis and interstitial lung disease, specific antibodies, mechanic’s hands, Raynaud syndrome, and arthralgias. Anti–Jo-1 is the most common antibody involved and is associated with the most severe muscle disease.
- Immune-mediated necrotizing myopathy is the most common subtype of immune myopathy. It is related to anti–signal recognition particle, anti–HMG-CoA reductase, or antimitochondrial antibodies. Seronegative cases are often paraneoplastic.
- Statins are unlikely to be causally related to anti–HMG-CoA reductase IgG immune-mediated necrotizing myopathy; at least one-third of cases have no history of statin exposure, and many are associated with cancer, regardless of statin use.
- Myositis associated with anti–PM-SCl and anti-Ku antibodies overlaps with systemic sclerosis and interstitial lung disease. Anti–PM-SCl antibody myositis presents with dropped head syndrome and upper more than lower extremity weakness.
- Spontaneous activity on EMG is predictive of inflammation, necrosis, or splitting on muscle biopsy. After treatment initiation, spontaneous activity can distinguish between active inflammatory myopathy and steroid-induced myopathy.
- MRI of skeletal muscle shows edema in recent-onset inflammatory myopathies and fatty atrophy in chronic cases. Neither edema nor fatty atrophy is pathognomonic.
- Dermatomyositis is pathologically characterized by capillary dropout and complement deposition, perivascular inflammation, perifascicular atrophy, and abnormal perifascicular expression of interferon-responsive elements and major histocompatibility complex class I.
- Antisynthetase syndrome is distinguished from dermatomyositis by the marked perimysial fragmentation and inflammation consisting of macrophages rather than lymphocytes, and lack of capillary pathology.
- Immune-mediated necrotizing myopathy is characterized by multifocal fiber necrosis and regeneration but scant or absent inflammation.
- Cancer screening should be performed in all adults over age 40 with dermatomyositis, especially those who are positive for anti–TIF1-γ or anti–NXP-2 antibodies, and all adults with seronegative or anti–HMG-CoA reductase IgG–positive immune-mediated necrotizing myopathy.
- First- and second-line treatments for inflammatory myopathies are corticosteroids and nonsteroidal immunosuppressant drugs such as azathioprine, mycophenolate mofetil, and methotrexate. They often have to be combined.
- Subtypes of idiopathic inflammatory myopathy with better response to IV immunoglobulin and rituximab have been identified.
- Immune checkpoint inhibitor–associated myositis is characterized by ocular myositis with ptosis or diplopia, myocarditis, lymphopenia, and pathologic evidence of immune-mediated necrotizing myopathy with creatine kinase levels lower than those seen in other forms of immune-mediated necrotizing myopathy. Corticosteroids and temporary discontinuation of immune checkpoint inhibitors are the mainstays of treatment.
- COVID-19 is associated with frequent myalgia and creatine kinase elevations. Rhabdomyolysis, dermatomyositis, and paraspinal myositis have been described. Immune-mediated muscle pathology is a frequent finding on autopsy.
- The most likely mechanism of muscle injury in COVID-19 infection is indirect due to adaptive and innate immunity dysfunction rather than direct muscle invasion by the virus.
- The care of patients with idiopathic inflammatory myopathies was significantly disrupted by the pandemic. The full impact of SARS-CoV-2 on the morbidity and mortality of patients with idiopathic inflammatory myopathy and the risk of future development of diopathic inflammatory myopathy remain to be determined.
ARTICLE 5: INCLUSION BODY MYOSITIS
Namita A. Goyal, MD, FAAN. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1663–1677.
PURPOSE OF REVIEW
This article highlights the clinical and diagnostic features of inclusion body myositis (IBM) and provides recent insights into the pathomechanisms and therapeutic strategies of the disease.
IBM is an often-misdiagnosed myopathy subtype. Due to the insidious onset and slow progression of muscle weakness, it can often be dismissed as a sign of aging as it commonly presents in older adults. While challenging to recognize upon initial clinical evaluation, the recent recognition of specialized stains highlighting features seen on muscle pathology, the use of diagnostic tools such as the anti-cytosolic 5’-nucleotidase 1A antibody biomarker, and the ability of muscle imaging to detect patterns of preferential muscle involvement seen in IBM has allowed for earlier diagnosis of the disease than was previously possible. While the pathogenesis of IBM has historically been poorly understood, several ongoing studies point toward mechanisms of autophagy and highly differentiated cytotoxic T cells that are postulated to be pathogenic in IBM.
Overall advancements in our understanding of IBM have resulted in improvements in the management of the disease and are the foundation of several strategies for current and upcoming novel therapeutic drug trials in IBM.
- Inclusion body myositis is the most common acquired muscle disease of the aging population, affecting individuals over age 45.
- Inclusion body myositis is often initially misdiagnosed as polymyositis or another condition in 40% to 50% of patients, leading to a diagnostic delay of up to 5 years with the average patient undergoing a diagnostic odyssey and unwarranted immunosuppressive therapies.
- Notable asymmetric atrophy of the quadriceps and medial forearm flexors, associated with knee extensor and wrist/finger flexor weakness, occurs in inclusion body myositis.
- The flexor digitorum profundus muscle is disproportionately weaker than other hand muscles in inclusion body myositis. This finding of flexor digitorum profundus weakness may alert the physician to a possible diagnosis of inclusion body myositis over other subtypes of myositis.
- Serum creatine kinase levels may be modestly elevated in inclusion body myositis; however, in some patients with inclusion body myositis, the creatine kinase levels may be normal.
- The needle EMG of a weak muscle in patients with inclusion body myositis may show a mixed population of both short-duration, low-amplitude and long-duration, high-amplitude motor unit potentials.
- The anti-cytosolic 5’-nucleotidase 1A antibody in the sera of patients with inclusion body myositis is a potential diagnostic biomarker.
- The anti-cytosolic 5’-nucleotidase 1A antibody is a useful noninvasive and complementary test that may aid in an earlier and more reliable diagnosis of inclusion body myositis when clinical suspicion is high.
- Fatty infiltration on MRI is more common than inflammation in patients with inclusion body myositis, with muscles most frequently involved including the flexor digitorum profundus in the forearm, anterior compartment muscles of the thigh with sparing of the rectus femoris, and severe involvement of the medial compartment of the gastrocnemius.
- Inflammatory mononuclear cell infiltration of the endomysium with lymphocytes specifically surrounding or invading a non-necrotic myofiber is an important pathologic feature seen in inclusion body myositis.
- A key finding that is sought in making the pathologic diagnosis of inclusion body myositis is the presence of rimmed vacuoles within myofibers; the challenge, however, has been that rimmed vacuoles are reported to be absent in 20% to 40% of muscle biopsies from patients with inclusion body myositis despite typical clinical features.
- Major histocompatibility complex (MHC)-I overexpression shows a high sensitivity in inflammatory myopathies but has a low specificity. Conversely, MHC-II staining has a much higher specificity to inflammatory myopathies, especially inclusion body myositis.
- Of the different diagnostic criteria for inclusion body myositis, the European Neuromuscular Centre 2011 criteria had one of the best performing categories, with 84% sensitivity for the probable inclusion body myositis category.
- The key question that remains is whether the inflammation in inclusion body myositis muscle is a primary autoimmune process or a secondary process that is a consequence of the degenerative pathway.
- A study evaluating killer cell lectin-like receptor G1 (KLRG1), a marker of highly differentiated effector memory and terminally differentiated effector cells, has demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity and identified that CD8+KLRG1+ cells appear pathogenic in inclusion body myositis.
- A large genetic study analyzing immune-related genes in inclusion body myositis identified strong associations with variants within the human leukocyte antigen (HLA) locus reaching genome-wide significance, with HLA-DRB1*03:01 showing the most significant association with inclusion body myositis.
- Several immunotherapeutic strategies have been trialed in inclusion body myositis; however, thus far none have shown robust sustained efficacy or effectively slowed the rate of disease progression.
- The mainstay of treatment for patients with inclusion body myositis is supportive care which involves a multidisciplinary team approach.
ARTICLE 6: THE DYSTROPHINOPATHIES
Bo Hoon Lee, MD. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1678–1697.
PURPOSE OF REVIEW
This article reviews the history, epidemiology, genetics, clinical presentation, multidisciplinary management, and established and emerging therapies for the dystrophinopathies.
The multidisciplinary care of individuals with dystrophinopathies continues to improve in many ways, including early surveillance and implementation of respiratory, cardiac, and orthopedic health management. The era of genetic therapeutics has altered the treatment landscape in neuromuscular disorders, including the dystrophinopathies.
The dystrophinopathies are a spectrum of X-linked genetic disorders characterized by childhood-onset progressive weakness and variable cardiac and cognitive involvement. Corticosteroids are the mainstay of therapy to slow disease progression. Additional strategies for disease amelioration and dystrophin restoration, including gene replacement therapy, are under investigation.
- Duchenne muscular dystrophy is the most common muscular dystrophy, affecting 1 in 3500 to 5000 males.
- DMD is the largest gene in the human genome and has a high rate of spontaneous variation.
- The dystrophinopathies are X-linked genetic disorders due to pathogenic variation in the DMD gene. Approximately one-third of DMD mutations occur de novo.
- Females with heterozygous DMD mutations are often asymptomatic but can manifest mild skeletal muscle symptoms and/or cardiac involvement. Identified carriers should be referred to a cardiologist for surveillance.
- The genotype-phenotype relationship in Duchenne and Becker muscular dystrophies often follows the reading-frame rule whereby in-frame mutations predict milder Becker muscular dystrophy phenotype and out-of-frame mutations predict Duchenne muscular dystrophy phenotype.
- Exceptions to the reading-frame rule occur in about 10% of patients and variability is seen even among individuals with the same DMD genotype. Environmental, socioeconomic, and additional genetic modifiers likely contribute to this variability.
- Dystrophin is part of a membrane-stabilizing complex and protects the muscle from injury during contraction. Absence of dystrophin therefore leads to destabilization and cellular damage.
- A dystrophinopathy should be suspected in any young boy presenting with gross motor delay. Cognitive, behavioral, and speech/language delays can be early presenting symptoms.
- The predictable progression in Duchenne muscular dystrophy is often categorized into the following phases: early ambulatory, late ambulatory, early nonambulatory, and late nonambulatory.
- Loss of ambulation with wheelchair dependency is a sentinel marker of progression and typically occurs by age 13 years in Duchenne muscular dystrophy and after age 16 years in Becker muscular dystrophy.
- Duchenne and Becker muscular dystrophies are the most common muscular dystrophies. As care across the spectrum improves, individuals with Duchenne muscular dystrophy and Becker muscular dystrophy are surviving longer into adulthood and requiring transitions of care from pediatric to adult specialists.
- Becker muscular dystrophy is milder than Duchenne muscular dystrophy and can have much more variability in symptom onset and progression, but symptom onset in childhood and early adulthood is typical.
- Several limb-girdle muscular dystrophies can resemble the dystrophinopathies but can be distinguished by clinical features, familial inheritance pattern, and additional testing.
- Serum creatine kinase is the best initial diagnostic test when suspecting a dystrophinopathy. Creatine kinase is 5 to 10 times the upper limits of normal in Duchenne and Becker muscular dystrophies.
- Genetic testing should be performed to confirm a suspected diagnosis of Duchenne or Becker muscular dystrophy. Rarely, when genetic testing is negative, muscle biopsy may be necessary.
- The histopathologic features of muscle in the dystrophinopathies include evidence of active and chronic myopathy, increased endomysial connective tissue fibrosis, and fat accumulation. Immunohistochemical staining for dystrophin will demonstrate reduced or absent staining.
- Muscle imaging via ultrasound and MRI are increasingly being used as additional measures of disease progression.
- The dystrophinopathies are multisystem disorders and best served by a multidisciplinary care approach that includes neurology, cardiology, developmental and behavioral pediatrics, endocrinology, gastroenterology, genetics, nutrition, orthopedics, physical therapy, pulmonology, and psychology.
- Cardiac surveillance in patients with dystrophinopathies should start at diagnosis or early childhood. Initiation of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers is recommended by age 10 for boys with Duchenne muscular dystrophy.
- Surveillance for respiratory involvement in patients with dystrophinopathies is recommended along with evaluation for sleep-disordered breathing and nocturnal hypoventilation. Patients benefit from timely implementation of lung volume recruitment techniques, cough assist, and ultimately noninvasive and invasive ventilatory support.
- There is a robust drug development pipeline for Duchene muscular dystrophy. Therapeutic approaches include restoration of dystrophin through genetic mechanisms (exon skipping, stop-codon readthrough, gene replacement) and disease amelioration through reduction of inflammation, fibrosis, and muscle protection.
- Corticosteroids slow the progression of disease in Duchenne muscular dystrophy and should be initiated before there is motoric decline, but the optimal age has not been delineated.
ARTICLE 7: THE LIMB-GIRDLE MUSCULAR DYSTROPHIES
Nicholas E. Johnson, MD, FAAN; Jeffrey M. Statland, MD. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1698–1714.
PURPOSE OF REVIEW
The limb-girdle muscular dystrophies (LGMDs) are a group of inherited muscle disorders with a common feature of limb-girdle pattern of weakness, caused by over 29 individual genes. This article describes the classification scheme, common subtypes, and the management of individuals with LGMD.
Advances in genetic testing and next-generation sequencing panels containing all of the LGMD genes have led to earlier genetic confirmation, but also to more individuals with variants of uncertain significance. The LGMDs include disorders with autosomal recessive inheritance, which are often due to loss-of-function mutations in muscle structural or repair proteins and typically have younger ages of onset and more rapidly progressive presentations, and those with autosomal dominant inheritance, which can have older ages of presentation and chronic progressive disease courses. All cause progressive disability and potential loss of ability to walk or maintain a job due to progressive muscle wasting. Certain mutations are associated with cardiac or respiratory involvement. No disease-altering therapies have been approved by the US Food and Drug Administration (FDA) for LGMDs and standard treatment uses a multidisciplinary clinic model, but recessive LGMDs are potentially amenable to systemic gene replacement therapies, which are already being tested in clinical trials for sarcoglycan and FKRP mutations. The dominant LGMDs may be amenable to RNA-based therapeutic approaches.
International efforts are underway to better characterize LGMDs, help resolve variants of uncertain significance, provide consistent and improved standards of care, and prepare for future clinical trials.
- Limb-girdle muscular dystrophies can be inherited in autosomal dominant or recessive patterns.
- Limb-girdle muscular dystrophies affect children and adults, and both men and women.
- Autosomal recessive limb-girdle muscular dystrophies affect muscle structural, maintenance, or repair proteins.
- Autosomal dominant limb-girdle muscular dystrophies are less prevalent than autosomal recessive LGMDs, tend to affect individuals at older ages, and are chronically progressive.
- Autosomal recessive limb-girdle muscular dystrophies often have younger age of onset, more rapid loss of strength, and higher creatine kinase than autosomal dominant LGMDs.
- Cardiac involvement, while rare, is suggestive of particular limb-girdle muscular dystrophies.
- New next-generation sequencing panels can include all limb-girdle muscular dystrophy genes, and have upended traditional flowcharts of diagnostics, with gene testing coming earlier.
- Standard care addresses weakness and any other limb-girdle muscular dystrophy–related area of disability and is most commonly performed in multidisciplinary clinics.
- Systemic gene replacement therapies are being developed for many autosomal recessive limb-girdle muscular dystrophies, including clinical trials underway for sarcoglycan and FKRP mutations.
- Autosomal dominant limb-girdle muscular dystrophies may be amenable to RNA-based modulating therapies.
ARTICLE 8: MYOTONIC DYSTROPHY
Johanna I. Hamel, MD. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1715–1734.
PURPOSE OF REVIEW
Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are genetic disorders affecting skeletal and smooth muscle, heart, brain, eyes, and other organs. The multisystem involvement and disease variability of myotonic dystrophy have presented challenges for clinical care and research. This article focuses on the diagnosis and management of the disease. In addition, recent advances in characterizing the diverse clinical manifestations and variability of the disease are discussed.
Studies of the multisystem involvement of myotonic dystrophy, including the most lethal cardiac and respiratory manifestations and their molecular underpinnings, expand our understanding of the myotonic dystrophy phenotype. Advances have been made in understanding the molecular mechanisms of both types of myotonic dystrophy, providing opportunities for developing targeted therapeutics, some of which have entered clinical trials in DM1.
Continued efforts focus on advancing our molecular and clinical understanding of DM1 and DM2. Accurately measuring and monitoring the diverse and variable clinical manifestations of myotonic dystrophy in clinic and in research is important to provide adequate care, prevent complications, and find treatments that improve symptoms and life quality.
- Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are autosomal dominant diseases due to expanded CTG repeats in DMPK (DM1) and CCTG repeats in CNBP (DM2). While genetically distinct, both diseases share many mechanistic and clinical features, such as myopathy, myotonia, and multisystem disease.
- Both types of myotonic dystrophy are caused by toxic foci of expanded (C)CUG repeats that sequester RNA-binding proteins. Depletion of these RNA-binding proteins results in the missplicing of transcripts from several genes.
- A recent screen of 50,382 consecutive births showed that 1 in 2100 individuals carries the DM1 mutation in the US. DM2 is considered less common, but likely overlooked and underdiagnosed.
- Disease variability is a hallmark of DM1 and is present but less pronounced in DM2. In DM1, the age of symptom onset ranges from in utero to after the sixth decade. Earlier onset is typically associated with more severe disease. No congenital form of DM2 exists.
- The genetic determinants of disease variability are not well understood in DM1. Clinicians and genetic counselors should remain cautious or refrain from prognostic counseling based on CTG repeat size.
- The expanded CTG repeat in DM1 grows over time in different tissues at different rates (somatic instability). For example, while the repeat remains relatively stable in leucocytes, the repeat expands remarkably over time in clinically preferentially affected tissues, such as muscle.
- The most severe form of DM1, congenital myotonic dystrophy, mostly occurs via maternal transmission.
- Characteristic muscle features of DM1 are weakness of distal limb muscles prominently affecting finger flexors, neck flexion, orofacial, pharyngeal, and respiratory muscles, as well as grip and percussion myotonia.
- Management of muscle symptoms includes physical therapy and the use of assistive devices. Establishing an individual and safe plan for exercise and avoiding a sedentary lifestyle are beneficial in both DM1 and DM2. Cognitive behavioral therapy can help increase activity levels and decrease fatigue in patients with DM1.
- If grip or oropharyngeal myotonia is impacting a patient’s function (DM1 and DM2), mexiletine can be used if no cardiac contraindications are present.
- DM2 is characterized by symptom onset typically between ages 34 to 48. Patients live with symptoms for on average 12 years before the correct diagnosis is made.
- Initial symptoms of DM2 include leg weakness, myalgia, and myotonia. Muscle pain is common. On examination, patients reveal weakness of neck flexion and proximal muscles.
- Respiratory failure related to progressive muscle weakness is the most common mechanism of death in patients with DM1.
- Noninvasive ventilation for respiratory weakness and sleep apnea improves nocturnal hypoventilation and sleep apnea but is often not tolerated by patients.
- Cardiac involvement is the second leading cause of death in DM1. Cardiac involvement includes progressive conduction abnormalities resulting in heart block, arrhythmia, and risk of sudden death. Heart failure is less common.
- In addition to skeletal muscle, smooth muscle is affected by myotonic dystrophy. Gastrointestinal symptoms are common and include dysphagia, acid reflux, constipation, diarrhea, and sphincter dysfunction.
- Ocular manifestations of DM1 and DM2 include cataracts, often before age 55. Patients with DM1 can develop corneal dystrophy.
- The risk of developing cancer is increased in both forms of myotonic dystrophy, including melanoma and cancer of the thyroid, colon, and uterus. Age-appropriate cancer screening is recommended.
- Important metabolic and endocrinological manifestations of DM1 and DM2 include diabetes (insulin resistance), increased cholesterol, primary hypogonadism in men, and issues with fertility.
- Our understanding of the underlying mechanism in DM1 and particularly DM2 is expanding, which is a prerequisite for targeted drug development.
- To date, no therapies are available that change the trajectory of the disease, but clinical trials targeting the root cause of DM1 are currently being conducted.
ARTICLE 9: FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY
Karlien Mul, MD, PhD. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1735–1751.
PURPOSE OF REVIEW
This article reviews the current knowledge on the clinical characteristics and disease mechanism of facioscapulohumeral muscular dystrophy (FSHD), as well as advances in targeted therapy development.
FSHD has a wide range of severity, yet a distinct phenotype characterized by weakness of the facial, shoulder, and upper arm muscles, followed by weakness of the trunk and leg muscles. It can be caused by two genetic mechanisms that share a common downstream pathway, namely, the epigenetic derepression and subsequent misexpression of the myotoxic DUX4 transcription factor. Treatment is currently supportive and outlined in evidence-based guidelines. Advances in the understanding of the pathogenic mechanism of FSHD are paving the way for targeted therapy development. Approaches for targeted therapies to reduce DUX4 expression that are currently being explored include small molecules, antisense oligonucleotides, vector-based RNA interference, and gene therapy. In anticipation of more clinical trials, “clinical trial preparedness,” including the development of sensitive biomarkers and clinical outcome measures, are needed.
The cornerstones of the diagnosis of FSHD are clinical observation and genetic testing. Management is currently supportive, but progress in the understanding of the disease mechanism has shifted the field of FSHD toward targeted therapy development.
- Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a prevalence of 5 to 12 per 100,000 individuals.
- FSHD has a highly characteristic phenotype that starts with asymmetric weakness of the facial, shoulder, and upper arm muscles, and later of the trunk and leg muscles. Severity, age at onset, and rate of progression of muscle weakness vary greatly.
- In most cases of FSHD, a positive family history is present. However, family history can be negative due to de novo mutations, incomplete penetrance, or a genetic form of FSHD with a digenic inheritance pattern (FSHD2).
- The infantile form of FSHD is characterized by an early disease onset (before age 10 years) with generalized and rapidly progressive muscle weakness and a higher chance of extramuscular complications.
- Extramuscular disease manifestations in FSHD are mostly subclinical and can include retinal vasculopathy, sensorineural hearing loss, restrictive lung disease, and (incomplete) right bundle branch block. Cardiomyopathy is not associated with FSHD.
- Two genetic forms of FSHD, FSHD1 and FSHD2, occur and share a common downstream “gain of function” mechanism, namely, the misexpression of the myotoxic DUX4 gene. Clinically, the two forms are indistinguishable.
- FSHD1 is caused by a contraction of the D4Z4 repeat array on chromosome 4q35 to 1 to 10 D4Z4 units, resulting in a more open chromatin structure allowing expression of the DUX4 gene. A permissive polymorphism provides a polyadenylation sequence to stabilize the DUX4 transcript.
- In patients with FSHD2, D4Z4 chromatin relaxation is caused by mutations in chromatin modifier genes (most often SMCHD1) in the absence of a repeat contraction. Due to the required polyadenylation sequence on chromosome 4, FSHD2 has a digenic pattern of inheritance.
- In FSHD1, patients with very short D4Z4 repeat array sizes of 1 to 3 units have a higher risk of a severe phenotype, while patients with 7 to 10 repeat units tend to have a milder disease course and decreased penetrance.
- A diagnosis of FSHD is based on clinical observation and genetic testing. Ancillary investigations such as blood creatine kinase, electrodiagnostic testing, and muscle histology show nonspecific findings and are only useful to exclude other diagnoses.
- As FSHD1 is caused by a repeat contraction, it is not detected by high-yield sequencing techniques like gene-sequencing panels or whole-exome sequencing.
- Disease management of FSHD is currently supportive and outlined in evidence-based guidelines published by The American Academy of Neurology (AAN).
- Approaches for targeted therapies to reduce DUX4 expression that are currently being explored include small molecules, antisense oligonucleotides, vector-based RNA interference, and gene therapy.
- Due to the generally slow yet highly variable rate of disease progression in FSHD, the development of sensitive biomarkers and clinical outcome measures is of great importance to prepare for upcoming clinical trials.
ARTICLE 10: METABOLIC MYOPATHIES
Mark A. Tarnopolsky, MD, PhD, FRCP. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1752–1777.
PURPOSE OF REVIEW
Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this review will focus on the genetic metabolic myopathies.
Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies; however, they often overlap clinically with structural genetic myopathies, referred to as pseudometabolic myopathies. Although metabolic myopathies can present in the neonatal period with hypotonia, hypoglycemia, and encephalopathy, most cases present clinically in children or young adults with exercise intolerance, rhabdomyolysis, and weakness. In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever). The neurologic examination is often normal between events (except in the pseudometabolic myopathies) and evaluation requires one or more of the following tests: exercise stress testing, blood (eg, creatine kinase, acylcarnitine profile, lactate, amino acids), urine (eg, organic acids, myoglobin), muscle biopsy (eg, histology, ultrastructure, enzyme testing), and targeted (specific gene) or untargeted (myopathy panels) genetic tests.
Definitive identification of a specific metabolic myopathy often leads to specific interventions, including lifestyle, exercise, and nutritional modifications; cofactor treatments; accurate genetic counseling; avoidance of specific triggers; and rapid treatment of rhabdomyolysis.
- Metabolic and pseudometabolic disorders present during or following some form of exercise/physical activity and with generalized “tiredness” or daily fatigue.
- Metabolic myopathies present with muscle pains and/or cramps during exercise with some patients progressing to rhabdomyolysis (the breakdown of skeletal muscle leading to a creatine kinase rise of greater than 10 times the upper limit of normal).
- Severe vitamin D deficiency can lead to hyperCKemia and/or rhabdomyolysis.
- Common drugs such as statins and common disorders such as vitamin D deficiency and hypothyroidism can lower the threshold for rhabdomyolysis in patients with inborn errors of metabolism and can even rarely lead to rhabdomyolysis in otherwise healthy individuals.
- Most of the metabolic myopathies will have some symptoms present in childhood but often the compensatory strategies can mask the earlier presentation.
- The history is a critical part of the workup in a patient presenting with rhabdomyolysis, with a lifelong history of exercise intolerance and recurrent rhabdomyolysis (even if induced by fever or other metabolic insult) being the two most common predictors of an underlying genetic metabolic myopathy/inborn error of metabolism.
- All patients with rhabdomyolysis require a complete neurologic examination.
- The creatine kinase will normalize in most of the glycogen storage diseases, except in McArdle disease where it is persistently elevated.
- Patients with myopathic glycogen storage diseases typically have recurrent bouts of cramps with or without rhabdomyolysis with shorter-duration/repetitive and/or higher-intensity physical activities.
- There is no added diagnostic value from an ischemic versus nonischemic forearm exercise test, yet it adds to the risk of local rhabdomyolysis and compartment syndrome; consequently, the nonischemic version is recommended.
- Next-generation sequencing panels are replacing many of the previously used diagnostic tests but must be interpreted in the clinical context and may need additional metabolomic, histological, or biochemical support.
- Although acute exercise can be a trigger for rhabdomyolysis in patients with inborn errors of metabolism, all patients can adapt to carefully designed exercise training programs and raise the exercise threshold for induction of rhabdomyolysis and confer long-term protection.
- Given that sucrose is a disaccharide made from glucose and fructose, one can get approximately 25 g of preexercise sucrose equivalent carbohydrate from 250 mL of fruit juice (fructose and glucose) or soda, or 400 mL of sport drink. (Although the latter two examples have no other nutritional value, they do contain high-fructose corn syrup [fructose and glucose].)
- Creatine monohydrate (approximately 100 mg/kg/d) and a high-protein diet may confer some benefit in patients with glycogen storage diseases, but it is important to not use higher creatine doses.
- Carnitine palmitoyltransferase 2 deficiency is the most common fatty acid oxidation defect, but trifunctional protein and very-long-chain acyl-CoA dehydrogenase deficiencies can present in an identical manner.
- A serum acylcarnitine profile, especially when fasted or during a bout of rhabdomyolysis, is the most sensitive and specific test for fatty acid oxidation defects.
- A high-carbohydrate diet is the main recommendation to reduce symptoms in patients with fatty acid oxidation defects.
- The mitochondria are the final common pathway for the oxidation of fat, carbohydrates, and proteins.
- Many of the mitochondrial myopathies are labeled as acronyms that describe the canonical clinical features.
- A normal mtDNA sequence from blood-derived DNA does not rule out a primary mitochondrial myopathy due to a pathologic mtDNA mutation.
- Most patients with primary mitochondrial myopathies will have exercise intolerance, and chronic daily fatigue is not a distinguishing clinical feature of primary mitochondrial myopathies and can be seen in many other nonmitochondrial disorders.
- Abnormal neurologic examination findings should prompt a further consideration of a primary mitochondrial myopathy in a patient with rhabdomyolysis.
- A normal lactate does not rule out a primary mitochondrial myopathy.
- For nuclear DNA–encoded mitochondrial testing (and for all other myopathies) a blood sample is sufficient for diagnosis with the usual caveats (eg, deep intronic mutations, trinucleotide repeat disorders) that are not identified by standard next-generation sequencing testing.
- A mitochondrial cocktail (multi-ingredient supplement) approach is superior to single agents to target the multiple final common pathways of cellular dysfunction.
ARTICLE 11: MUSCLE CHANNELOPATHIES
Jaya R. Trivedi, MD, FAAN. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1778–1799.
PURPOSE OF REVIEW
This article describes the clinical features, diagnosis, pathophysiology, and management of nondystrophic myotonia and periodic paralysis.
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.
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.
- Nondystrophic myotonias are classified based on genotype as either skeletal muscle chloride or sodium channelopathies. Phenotypically, nondystrophic myotonias are classified as myotonia congenita, paramyotonia congenita, and sodium-channel myotonias.
- Common symptoms in nondystrophic myotonia include muscle stiffness, weakness, fatigue, and pain.
- In nondystrophic myotonia, muscle stiffness occurs in the absence of severe fixed weakness or atrophy. This is in contrast to myotonic dystrophy types 1 and 2, which present with progressive muscle weakness and multisystem involvement.
- The most common site of stiffness in myotonia congenita is the legs, while the face is less commonly affected. The stiffness in myotonia congenita improves with exercise, referred to as the “warm-up phenomenon.”
- In contrast to myotonia congenita, muscle stiffness worsens with sustained exercise in paramyotonia congenita in a phenomenon referred to as “paradoxical myotonia” (hence the name “paramyotonia”).
- Paradoxical eye closure myotonia is unique to paramyotonia congenita and is a useful distinguishing feature from other forms of nondystrophic myotonia.
- Genetic testing is the gold standard in making a definitive diagnosis of nondystrophic myotonia.
- In the long-exercise test, a compound muscle action potential (CMAP) amplitude reduction of greater than 40% from the maximum CMAP during or postexercise is considered abnormal.
- The quality of life of patients with nondystrophic myotonia is comparable to that of some muscular dystrophies, where about one-quarter of patients are disabled or unemployed. About 40% are not on any antimyotonic treatment.
- Clinical trials of mexiletine in nondystrophic myotonia, at a dosage of 200 mg 3 times a day, demonstrated reduction in muscle stiffness, electrical myotonia, and quality-of-life measures.
- Succinylcholine should be avoided in nondystrophic myotonia as it can cause myotonic crisis and severe generalized muscle stiffness. Volatile anesthetics and propofol are okay to use.
- In hypokalemic periodic paralysis, patients experience attacks of flaccid paralysis that typically occur upon awakening in the night or early morning. The attacks range from mild weakness to profound paralysis and last hours to days.
- Andersen-Tawil syndrome is characterized by a triad of episodic weakness, cardiac abnormalities, and distinctive skeletal features.
- Ictal potassium is low in primary hypokalemic periodic paralysis, often less than 3.0 mmol/L; in hyperkalemic periodic paralysis, elevations in potassium greater than 5 mmol/l or increases greater than 1.5 mmol/L are often seen.
- Genetic testing is required for confirmation of periodic paralysis and will identify a mutation in approximately 60% to 70% of patients who meet clinical criteria of periodic paralysis.
- Patients with hypokalemic periodic paralysis should avoid large amounts of carbohydrates as these stimulate insulin secretion, which in turn drives potassium intracellularly and triggers the episodes of weakness.
- In a randomized placebo-controlled trial, dichlorphenamide reduced the median attack rate in hypokalemic periodic paralysis compared to placebo.
- Patients with hypokalemic periodic paralysis with SCN4A mutations may respond less favorably to carbonic anhydrase inhibitors or may have worsening of symptoms.
- Succinylcholine can trigger myotonia and cause hyperkalemia and so it should be avoided in hyperkalemic periodic paralysis. It is preferable to use short-acting nondepolarizing neuromuscular blockers for all forms of periodic paralysis.
ARTICLE 12: GENETIC-BASED TREATMENT STRATEGIES FOR MUSCULAR DYSTROPHY AND CONGENITAL MYOPATHIES
Andrew R. Findlay, MD; Conrad C. Weihl, MD, PhD. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1800–1816.
PURPOSE OF REVIEW
This article discusses the foundational concepts of genetic treatment strategies employed in neuromuscular medicine, as well as the importance of genetic testing as a requirement for applying gene-based therapy.
Gene therapies have become a reality for several neuromuscular disorders. Exon-skipping and (in Europe) ribosomal read-through approaches are currently available to a subset of patients with Duchenne muscular dystrophy. Microdystrophin gene replacement has shown promise and is nearing the final stages of clinical trials. Numerous gene-based therapies for other muscular dystrophies and congenital myopathies are progressing toward approval as well.
Muscular dystrophies and congenital myopathies are a heterogenous group of hereditary muscle disorders. Confirming a diagnosis with genetic testing is not only critical for guiding management, but also an actual prerequisite for current and future gene therapies. Recessive loss-of-function or dominant haploinsufficiency disorders may be treated with gene replacement strategies, whereas dominant negative and toxic gain-of-function disorders are best addressed with a variety of knockdown approaches. It is important to recognize that many therapeutics are mutation specific and will only benefit a subset of individuals with a specific disease.
- Genetic diseases are inherited in a recessive, dominant, or mitochondrial pattern.
- Recessive disorders result from mutations causing reduced expression or loss of function despite preserved expression.
- Dominant disorders result from several mechanisms including haploinsufficiency, dominant negative, or toxic gain of function.
- Recessive disorders may be treated via gene therapies aimed at replacing or restoring lost function.
- Dominant disorders are primarily treated via knockdown gene therapy approaches.
- Dominant disorders due to haploinsufficiency, where 50% of functional protein is deleterious, may be addressed via gene replacement therapies.
- Dominant toxic gain-of-function disorders result from mutations increasing a protein’s activity or stability, or by imparting an additional toxic function.
- Dominant negative mechanisms commonly occur in proteins that multimerize and result from the mutant allele negating the function or activity of the normal allele.
- Allele-specific knockdown is an ideal treatment approach for dominantly inherited disorders if haploinsufficiency is not deleterious.
- Gene therapies may target the disease gene or nondisease genes.
- Gene therapies may be categorized as gene replacement, modulation, correction, or knockdown.
- Nondisease genes may be targeted for therapeutic benefit when they are involved in downstream portions of the pathomechanism (eg, fibrosis, atrophy), or are homologs of the disease gene (ie, utrophin).
- Gene replacement strategies such as microdystrophin for Duchenne muscular dystrophy are capable of addressing any DMD mutation.
- Adeno-associated viruses are the primary vector used for gene therapy. Their immunogenicity is tolerable, their genomes are largely nonintegrative, and they have modifiable capsids that determine tissue tropism.
- The immune system is a major barrier to gene therapy due to preexisting antibodies to adeno-associated viruses (AAVs) and clearance of transduced cells by cytotoxic CD8+ T cells after AAV capsid proteins are presented on major histocompatibility complex class I surface molecules.
- Hepatotoxicity is a major concern with adeno-associated virus–mediated gene therapies.
- Exon skipping for Duchenne muscular dystrophy is a key example of a gene-modulation therapy where the disease gene is not replaced or knocked down, but instead is altered for therapeutic benefit.
- Antisense oligonucleotides are capable of gene knockdown via ribonuclease H–mediated destruction of RNA or by sterically blocking protein translation initiation. In exon skipping, antisense oligonucleotides modify pre-mRNA splicing by sterically blocking exon/intron definition elements.
- Exon-skipping therapies are available for a subset of boys with Duchenne muscular dystrophy. Their mutations must be put back into frame by skipping exon 51, 53, or 45.
- Cytoplasmic RNA interference pathways in cells are utilized for knockdown approaches with microRNA or small inhibitory RNA. Antisense-oligonucleotide gapmers use the nuclear and cytoplasmic RNase H pathway and are therefore capable of targeting both mRNA and pre-mRNA.
- Knockdown strategies for dominantly inherited disorders may require allele specificity if haploinsufficiency is deleterious.
- An additional strategy for dominantly inherited disorders with toxic gain-of-function or dominant negative mechanisms involves a combination of knockdown with gene replacement, where the transgene has been codon optimized to avoid knockdown.
ARTICLE 13: THE PRACTICE OF EXPERIMENTAL NEUROTHERAPEUTICS IN NEUROMUSCULAR DISEASE
Lauren B. Reoma, MD, FAAN; Avindra Nath, MD, MBBS, FAAN; Robert C. Griggs, MD, FAAN. Continuum (Minneap Minn). December 2022; 28 (6 Muscle and Neuromuscular Junction Disorder):1817–1834.
PURPOSE OF REVIEW
The discipline of experimental neurotherapeutics targets the process and operation of translating scientific discoveries into new treatments for neurologic diseases and has been instrumental in the progression of many areas of neurology.
From the US Food and Drug Administration (FDA) market approval of the first systemic in vivo gene therapy in neurology to multiple current gene-targeting therapeutics, monoclonal antibodies, and new drugs under development or approved in the last several years, the field of experimental neurotherapeutics has a presence in every neuromuscular clinic in the United States.
This article provides an overview of experimental neurotherapeutics with guidance on the clinical trials landscape, using examples in the field of neuromuscular disease. It covers the regulatory framework, clinical trial methodology, and offers advice on common pitfalls encountered when embarking on a clinical trials program in the clinic.
- The discipline of experimental neurotherapeutics targets the process and operations of translating scientific discoveries into new treatments for neurologic diseases.
- The United States has not regulated the costs of drugs or biologics, instead relying on traditional market forces and competition to regulate prices.
- The US Food and Drug Administration (FDA) has no legal authority to control the prices set by manufacturers, distributors, or retailers of drugs and biologics.
- It is important for the clinician to understand the price structuring process of drugs and therapeutics and to engage with the advocacy community to achieve equitable access for their patients.
- Neurologic products, on average, take 9.8 years to proceed through a clinical program to market approval.
- The FDA conducts surveillance of drug manufacturers and facilities, reviews drug advertising, coordinates a network for device surveillance safety, publishes a monthly newsletter, and receives reports on postapproval adverse reactions through the MedWatch system.
- The Centers for Disease Control and Prevention (CDC) also monitor the adverse reactions to vaccines via the Vaccine Adverse Event Reporting System (VAERS).
- Commercial investigational new drugs (INDs) are the traditional pathway to regulatory approval in the United States.
- A research investigational new drug (IND) offers a route to investigators studying a pharmaceutical that is not approved for use on the US market for the treatment of the condition being studied.
- Site investigators are chosen by the sponsor for their scientific expertise, projections of target patient availability, geographic distribution in the larger trial schema, historical productivity, and anticipated site capacity.
- It is the responsibility of the site principal investigator (PI) to interact with the local or contracted institutional review board (IRB).
- A good site principal investigator (PI) is actively engaged in the research and trial process, has a thorough understanding of trial procedures and regulations, provides consistent and frequent oversight of the trial data collection and reporting process, assembles an experienced and knowledgeable team of clinical trial staff, and is available and accessible to study staff.
- Many academic clinical trials do not require an investigational new drug (IND).
- The FDA does not regulate the practice of medicine.
- For any drug legally on the US market, regardless of the indications stated on the label, a physician can, in good conscience, use that drug off-label in the practice of medicine.
- The Right to Try Act allows patients and their physicians to bypass the typical route of expanded access available through the FDA review process, namely the single-patient investigational new drug (IND) and emergency IND applications, to access pharmaceuticals under clinical drug development.
- Under the Right to Try Act provisions, no interaction with the FDA is necessary.
- Emergency use individual patient investigational new drugs (INDs) are unique in that, once authorization is given by the FDA, often after a phone call to the reviewing division, treatment may proceed immediately.
- An internal review board (IRB) is a committee charged with protecting the rights and welfare of human subjects in research, following federal regulations in 45 CFR 46 and 21 CFR 56.
- Under the “revised Common Rule” all human subjects research is subject to the protections outlined in the code of federal regulations if the research is in any way supported, conducted, or subject to regulation by any federal department or agency of the US government.
- A study activation checklist keeps the study team focused and ensures that essential trial initiation events have been completed.