How do I distinguish multifocal motor neuropathy from motor neuron disease (amyotrophic lateral sclerosis) in a patient with progressive asymmetric limb weakness?

Distinguishing Multifocal Motor Neuropathy from Motor Neuron Disease

The critical distinction between multifocal motor neuropathy (MMN) and motor neuron disease (MND/ALS) rests on the presence of motor conduction block on nerve conduction studies, the absence of upper motor neuron signs, and the asymmetric distal upper limb predominance in MMN—this differentiation is essential because MMN is treatable with intravenous immunoglobulin while ALS is progressive and fatal. 1, 2

Key Clinical Features That Distinguish MMN from ALS

Multifocal Motor Neuropathy Characteristics

• Asymmetric distal limb weakness with marked predilection for upper limb involvement, particularly hand muscles, progressing slowly over years 1, 3, 2
• Absence of upper motor neuron signs—no hyperreflexia, no spasticity, no Babinski sign 1, 4
• No sensory loss on clinical examination, though mild sensory nerve abnormalities may appear on pathology 1, 4
• Muscle atrophy, cramps, and fasciculations may occur but are confined to affected nerve distributions 4, 5
• Reflexes are typically reduced or absent in affected limbs 2

Motor Neuron Disease (ALS) Characteristics

• Combined upper and lower motor neuron signs: hyperreflexia, spasticity, and Babinski sign coexist with weakness, atrophy, and fasciculations 6, 7, 8
• Symmetric or bilateral progression is more typical, though asymmetric onset can occur 8
• Bulbar involvement (dysarthria, dysphagia) develops in most patients, particularly in bulbar-onset ALS 9, 6
• Rapid progression over weeks to months rather than years 8
• Median survival of 3-4 years from symptom onset 6, 8

Electrodiagnostic Studies: The Definitive Differentiator

MMN Electrodiagnostic Findings

• Motor conduction block at non-compressible sites is the hallmark: >50% reduction in compound muscle action potential (CMAP) amplitude on proximal versus distal stimulation without change in duration 1, 4, 2
• Conduction block remains stable at the same site for years and is confined to motor axons 4
• Normal sensory nerve conduction studies are essential for diagnosis 1, 5
• EMG may show chronic denervation in affected muscles but is confined to specific nerve distributions 3

ALS Electrodiagnostic Findings

• Widespread denervation (fibrillation potentials, positive sharp waves) with chronic reinnervation (large polyphasic motor units) across multiple body regions 7, 8
• No conduction block—motor amplitudes may be reduced but without focal block 8
• Normal sensory responses throughout 7, 8

Critical Pitfall: Conduction block can be difficult to detect and requires meticulous technique; absence of demonstrable block does not exclude MMN if clinical features are suggestive 1, 3

Serological Testing

• Anti-GM1 IgM antibodies are present in approximately 50% of MMN patients and support the diagnosis when present 1, 3, 5
• Absence of anti-GM1 antibodies does not exclude MMN—many patients without these antibodies respond equally well to treatment 3
• In suspected ALS, exclude mimics by testing vitamin B12, thyroid function, serum protein electrophoresis, anti-GM1 antibodies, HIV, and Lyme serology 8

Neuroimaging

For Suspected ALS

• MRI brain without contrast is the initial study to exclude structural mimics 6, 7, 8
• T2/FLAIR hyperintensity in corticospinal tracts (posterior limb of internal capsule, cerebral peduncles) supports ALS 6, 8
• T2* hypointensity in the precentral gyrus provides high sensitivity and specificity 8
• Spine MRI may show "snake eyes" appearance (anterior horn T2 hyperintensity) but is often normal early 6, 7, 8

For Suspected MMN

• Neuroimaging is primarily used to exclude structural lesions (cervical myelopathy, nerve root compression) that could mimic MMN 2
• Brain and spine imaging are typically normal in MMN 1

Treatment Implications: Why This Distinction Matters

MMN Treatment

• Intravenous immunoglobulin (IVIg) is efficacious in most patients and is the sole established treatment 1, 5
• Cyclophosphamide is effective but has substantial adverse effects 1, 4
• Corticosteroids are ineffective and may worsen MMN—this contrasts sharply with chronic inflammatory demyelinating polyneuropathy 4, 5
• Long-term maintenance therapy is required but does not prevent slowly progressive axonal degeneration 1

ALS Treatment

• Multidisciplinary care involving neurology, pulmonology, nutrition, physical/occupational therapy, and palliative services is essential 6, 7, 8
• Riluzole 50 mg twice daily modestly prolongs survival by 2-3 months 8
• Non-invasive ventilation when forced vital capacity falls below 50% 9, 8
• Percutaneous endoscopic gastrostomy for nutritional support when swallowing is compromised 8

Diagnostic Algorithm

1. Clinical examination: Look for upper motor neuron signs (hyperreflexia, spasticity, Babinski)

   • Present → strongly favors ALS 6, 7
   • Absent with asymmetric distal upper limb weakness → suspect MMN 1, 2

2. Nerve conduction studies with proximal stimulation:

   • Motor conduction block at non-compressible sites + normal sensory studies → MMN 1, 4, 2
   • No conduction block + widespread denervation on EMG → ALS 7, 8

3. Anti-GM1 antibody testing:

   • Positive → supports MMN diagnosis 1, 3
   • Negative → does not exclude MMN; proceed based on electrodiagnostic findings 3

4. MRI brain and spine:

   • Corticospinal tract T2 hyperintensity + precentral gyrus hypointensity → supports ALS 6, 8
   • Normal imaging with conduction block → consistent with MMN 1, 2

Critical Pitfall: Do not delay referral to a neuromuscular specialist if MMN is suspected—early treatment with IVIg can prevent irreversible axonal loss, whereas misdiagnosis as ALS denies patients effective therapy 3, 2