What are the signs, symptoms, evaluation, diagnosis, and management of neuromuscular diseases?

Neuromuscular Diseases: Clinical Approach

Signs and Symptoms

Neuromuscular diseases present with progressive muscle weakness as the cardinal feature, typically following a proximal-to-distal pattern, with associated functional impairments that vary by disease type. 1

Key Clinical Presentations by Disease Category

Muscular Dystrophies (e.g., Duchenne):

• Progressive proximal muscle weakness beginning in early childhood 1
• Calf pseudohypertrophy 1
• Gowers' maneuver (difficulty rising from floor) 1
• Scapular winging and progressive contractures 1
• Cardiac involvement with dilated cardiomyopathy (major cause of mortality) 1
• Respiratory muscle weakness leading to ventilatory failure 1

Limb-Girdle Muscular Dystrophies:

• Onset during childhood or adolescence affecting pelvic or shoulder girdle musculature 1
• Variable progression with loss of ambulation ranging from 10 years to young adulthood 1
• Cardiac arrhythmias and cardiomyopathy (very common in lamin A/C and sarcoglycan disease) 1
• Both dilated and hypertrophic cardiomyopathy phenotypes reported 1

Myotonic Dystrophy:

• Progressive facial, neck, and distal limb weakness with myotonia 1
• Cardiac manifestations in approximately 80% of DM1 patients, including progressive atrioventricular/intraventricular conduction defects 1
• Tachyarrhythmias (ventricular and supraventricular) as life-threatening complications 1
• Cataracts, neuropsychiatric deficits, and endocrine abnormalities 1

Congenital Myopathies:

• Hypotonia and weakness from birth with static or slowly progressive course 1
• Prominent facial weakness with or without ptosis 1
• Generalized hypotonic posture with hyporeflexia and poor muscle bulk 1
• Proximal muscle weakness with respiratory and bulbar muscle dysfunction 1
• Relatively normal cognitive development (distinguishing feature) 1

Metabolic Myopathies (e.g., Pompe Disease):

• Exercise intolerance and muscle fatigue 1
• Respiratory muscle weakness with positional dyspnea (especially supine) 1
• Progressive proximal weakness 1

Evaluation and Diagnosis

Begin genetic testing in blood samples for all suspected cases, as this provides definitive diagnosis and guides genetic counseling and mutation-specific therapies. 1

Diagnostic Algorithm

Step 1: Clinical Assessment

• Detailed medical and family history focusing on age of onset, tempo of progression, and pattern of weakness 1, 2
• Physical examination emphasizing musculoskeletal system and functional impairments 1
• Document proximal versus distal weakness distribution 2
• Assess for cardiac symptoms (palpitations, syncope, dyspnea) 1

Step 2: Laboratory Testing

• Serum creatine kinase (CK) levels (markedly elevated in dystrophies) 3
• Genetic testing via multiplex ligation-dependent probe amplification or PCR for deletions/duplications 1
• If deletion/duplication testing negative, proceed to dystrophin gene sequencing for point mutations 1
• Full mutation characterization required to correlate with reading frame and predict disease progression 1

Step 3: Muscle Biopsy (when genetic testing inconclusive)

• Histochemical staining on frozen sections 3
• Immunohistochemistry for dystrophin protein expression 1
• Electron microscopy for mitochondrial and structural abnormalities 3
• Morphometric analysis of fiber diameter 3

Step 4: Electrodiagnostic Studies

• Electromyography to distinguish neurogenic from myopathic patterns 4
• Nerve conduction studies to exclude peripheral neuropathy 4

Step 5: Cardiac Evaluation (Essential)

• Baseline ECG and echocardiography for all patients at diagnosis 1
• Cardiac evaluation mandatory before any anesthesia or sedation 1
• For high-risk conditions, cardiac monitoring within 3-6 months of surgical procedures 1

Functional Assessment Protocol

Ambulatory Patients (every 6 months): 1

• Manual muscle testing using MRC scale 1
• Goniometry for range of motion (hip, knee, ankle, iliotibial band, hamstrings, gastrocnemius) 1
• Timed function tests: 10-meter walk, Gowers' maneuver, 4-stair climb, chair rise, 6-minute walk 1
• Motor function scales (North Star Ambulatory Assessment, Vignos scale) 1

Non-Ambulatory Patients (every 6 months early, less certain value later): 1

• Upper and lower extremity strength testing 1
• Activities of daily living assessment (self-care, writing, wheelchair control) 1
• Range of motion for upper extremities (elbow, wrist, finger flexors) 1

Specialist physical and occupational therapy assessments every 4 months. 1

Differential Diagnosis

Key distinguishing features to narrow diagnosis:

• Neurogenic atrophy (27% of biopsies): Fiber atrophy with clustering of nuclei, group atrophy pattern, redundant basal laminae on electron microscopy 3
• Dystrophic muscle (26% of biopsies): Great variation in fiber size (10-110 microns), muscle necrosis, fatty changes 3
• Mitochondrial myopathy (7% of biopsies): Ragged red fibers, mitochondrial abnormalities on electron microscopy 3
• Inflammatory myopathies: Less frequent, require specific immunological workup 3

Critical pitfall: 33% of biopsies show only minor structural abnormalities or end-stage changes (fatty infiltration, fibrosis), preventing definitive diagnosis—emphasizing the primacy of genetic testing. 3

Management

Pharmacological interventions have begun to change the natural history of neuromuscular diseases, with glucocorticoids and enzyme replacement therapy as established treatments, while gene therapies represent emerging options. 1

Disease-Modifying Therapy

Duchenne Muscular Dystrophy:

• Glucocorticoid therapy (standard of care, prolongs survival) 1
• Mutation-specific therapies when available (exon skipping, stop codon readthrough) 1

Pompe Disease:

• Enzyme replacement therapy (ERT) with appropriate monitoring 1
• ERT differentially clears glycogen from cardiac and type I fibers more efficiently than type II fibers 1

Exercise and Physical Therapy

Exercise prescription must balance strengthening with muscle protection: 1

• Submaximal and aerobic exercise only (avoid excessive resistive and eccentric exercise) 1
• Functional activities for exercise with monitoring and rest periods 1
• Avoid overwork weakness, disuse atrophy, and excessive fatigue 1
• Gentle aerobic exercise stimulates glycogen degradation in metabolic myopathies 1

Common pitfall: Excessively strenuous exercise can worsen muscle damage in degenerative diseases—always use submaximal intensity. 1

Contracture Prevention

Daily interventions required: 1

• Daily stretching of at-risk muscle groups 1
• Ankle-foot orthoses (AFOs) to prevent plantar flexion contractures 1
• Thigh binders for iliotibial band contractures 1
• Knee splints for knee flexion contractures 1
• Resting wrist/hand/finger splints for flexor contractures 1
• Adapted seating systems with solid seat/back, hip guides, lateral trunk supports 1
• Supported standing (supine, prone, vertical, or hydraulic standers) to prevent osteoporosis 1

Cardiac Management

All neuromuscular disease patients require proactive cardiac screening and management, as cardiac disease represents a major cause of morbidity and mortality. 1

• Establish care with cardiologist experienced in neuromuscular diseases or collaborative electrophysiologist/heart failure specialist 1
• Pediatric heart failure specialist referral reasonable for childhood-onset conditions 1
• Standard heart failure therapies (ACE inhibitors, beta-blockers) for cardiomyopathy 1
• Implantable cardioverter-defibrillator consideration for high-risk arrhythmias 1
• Pacemaker placement for progressive conduction disease 1

Critical consideration: Respiratory complications and cardiac arrhythmias are the most frequent primary causes of death in myotonic dystrophy type 1. 1

Multidisciplinary Care Structure

Essential team members: 1

• Neuromuscular specialist experienced in disease natural history 1
• Cardiologist with neuromuscular disease expertise 1
• Physical and occupational therapists 1
• Respiratory therapist/pulmonologist 1
• Genetic counselor 1
• Nutritionist (for feeding disorders and malnutrition risk) 5

Routine clinic appointments every 6 months unless otherwise specified. 1