What are neurogenic myopathies, including their etiologies, clinical presentation, diagnostic approach, and management?

Neurogenic Myopathies: Overview and Clinical Approach

Clarification of Terminology

The term "neurogenic myopathy" is somewhat contradictory, as it conflates two distinct disease categories: neurogenic disorders (denervation) and primary myopathies (muscle disease). In clinical practice, these represent separate pathophysiologic entities that must be distinguished through careful diagnostic evaluation 1, 2.

Definition and Pathophysiology

Neurogenic muscular atrophy (NMA) results from denervation of muscle fibers due to dysfunction or injury at the level of motor neurons, peripheral nerves, or nerve roots, leading to characteristic patterns of muscle fiber atrophy and remodeling 1. This differs fundamentally from primary myopathies where the pathology originates within the muscle fiber itself 3.

Key Distinguishing Features:

• Neurogenic disorders affect the motor unit from anterior horn cells, through peripheral nerves, to the neuromuscular junction, causing secondary muscle changes 2
• Primary myopathies involve intrinsic muscle fiber pathology (muscular dystrophies, inflammatory myopathies, metabolic myopathies) 3
• Some conditions show overlap features, with both neurogenic and myopathic components, as seen in certain distal myopathies 4

Clinical Presentation

Neurogenic Patterns:

• Progressive muscle weakness with characteristic distribution depending on the site of nerve injury 2
• Muscle atrophy that follows nerve distribution patterns rather than muscle group patterns 1
• Fasciculations may be present, particularly in motor neuron diseases 2
• Preserved or brisk reflexes early in motor neuron disease, absent reflexes in peripheral neuropathies 2

Myopathic Patterns:

• Proximal muscle weakness is typical in most primary myopathies 3
• Symmetrical involvement without sensory changes 3
• Elevated muscle enzymes (CK, aldolase) are common in muscular dystrophies and inflammatory myopathies 3, 5

Diagnostic Approach

Electromyography (EMG):

EMG is essential for distinguishing neurogenic from myopathic processes 3, 6.

• Myopathic changes: Polyphasic motor unit action potentials of short duration and low amplitude with increased insertional activity, fibrillation potentials, and sharp waves 3, 6
• Neurogenic changes: Large amplitude, long duration motor unit potentials with reduced recruitment 1
• Neuromuscular junction testing with repetitive stimulation should be performed when junction disorders are suspected 5

Muscle Biopsy:

Muscle biopsy remains the gold standard for differentiating neurogenic from myopathic processes and establishing specific diagnoses 3, 7.

Neurogenic Histopathology:

• Grouped atrophy (clusters of atrophic fibers of both fiber types) indicating reinnervation 1
• Fiber type grouping from collateral sprouting and reinnervation 1
• Angulated atrophic fibers 1, 4
• Absence of inflammatory infiltrates or dystrophic features 3

Myopathic Histopathology:

• Muscular dystrophy: Reduction or absence of dystrophin, degenerating and regenerating fibers, replacement with fat/connective tissue 3
• Mitochondrial myopathy: Ragged red fibers on Gomori trichrome stain, subsarcolemmal mitochondrial accumulation 3, 7
• Inflammatory myopathy: Mononuclear cell invasion of muscle fibers 3

Critical technical point: Choose a weak muscle demonstrated by EMG abnormalities; biopsy the contralateral side of the same muscle to avoid sampling artifact from needle trauma 3

Laboratory Testing:

• Muscle enzymes (CPK, aldolase) to assess for myositis or muscular dystrophy 5
• Inflammatory markers (ESR, CRP) for inflammatory conditions 5
• Genetic testing for dystrophin gene in suspected muscular dystrophy 3
• Antibody testing (AChR, anti-striated muscle antibodies) when neuromuscular junction disorders are considered 5

Imaging:

MRI of proximal muscle groups using T1-weighted, T2-weighted, and STIR sequences provides non-invasive assessment of muscle inflammation, edema, atrophy, and chronic damage 3.

• T2-weighted images show increased signal in active muscle inflammation 3
• T1-weighted images demonstrate muscle atrophy and fatty replacement 3
• MRI can guide biopsy site selection 3

Differential Diagnosis Considerations

When Evaluating Proximal Weakness with Elevated CK:

Always consider muscular dystrophy (limb-girdle dystrophy, dysferlinopathies), mitochondrial myopathies, and late-onset genetic myopathies before attributing symptoms to inflammatory or neurogenic causes 3.

Additional considerations include:

• Drug-induced myopathy 3
• Endocrine myopathy (thyroid disorder, hyperparathyroidism) 3
• Metabolic myopathies (glycogen storage diseases, fatty acid oxidation disorders) 7
• Infectious myopathies 3

Cardiac Screening:

Cardiac involvement is critical to assess in multiple neuromuscular conditions, as it significantly impacts morbidity and mortality 3, 7, 6.

• Mandatory cardiac evaluation in limb-girdle muscular dystrophy (especially lamin A/C and sarcoglycan disease), myotonic dystrophy, mitochondrial disorders, and myofibrillar myopathy 3, 6
• Screen for cardiomyopathy and conduction defects with ECG and echocardiography 3, 7, 6
• Cardiac manifestations occur in approximately 80% of myotonic dystrophy type 1 patients and are a major cause of mortality 6

Management Principles

Neurogenic Conditions:

• Treatment targets the underlying cause (motor neuron disease, peripheral neuropathy, radiculopathy) 2
• Supportive care includes physical therapy, orthotics, and respiratory support as needed 2

Primary Myopathies:

• Inflammatory myopathies: Immunosuppression with corticosteroids, IVIG, or other agents 5
• Metabolic myopathies: Enzyme replacement therapy for Pompe disease, dietary modifications, avoidance of fasting 7
• Muscular dystrophies: Supportive care, cardiac monitoring, respiratory support 3

Critical Medication Avoidance:

In patients with neuromuscular junction disorders, avoid beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics, as these worsen myasthenic symptoms 5.

In metabolic myopathies, avoid succinylcholine due to rhabdomyolysis risk 7.

Common Pitfalls

• Misclassifying primary myopathies as neurogenic based solely on EMG findings showing fibrillation potentials, which can occur in both conditions 3
• Failing to perform genetic testing in young adults with proximal weakness, missing treatable or genetically important diagnoses 3
• Inadequate cardiac screening in conditions with high cardiac involvement, leading to preventable sudden death 3, 6
• Biopsying the same muscle used for EMG, which creates needle artifact and reduces diagnostic yield 3