Can Amyotrophic Lateral Sclerosis (ALS) and Myasthenia Gravis (MG) coexist in a patient?

Can ALS and Myasthenia Gravis Coexist?

Yes, ALS and myasthenia gravis can coexist in the same patient, though this is a rare occurrence that requires strict diagnostic criteria and careful interpretation of clinical and electrophysiological findings. 1, 2

Evidence for Coexistence

The association between these two conditions is significantly higher than would be expected by chance alone:

• Population-based data from Italy demonstrated that the observed co-occurrence rate (1.87/10⁷) was substantially higher than the expected rate if these were independent events (7.5/10⁹), with statistical significance (p < 0.01). 3

• A French multicenter retrospective series identified 6 patients who strictly met diagnostic criteria for both ALS and MG over a 12-year period across 18 reference centers. 1

• A systematic review including cases from Peking Union Medical University Hospital identified 27 total cases in the literature, with 20 patients meeting strict criteria for both conditions. 2

Clinical Characteristics of the Overlap Syndrome

When ALS and MG coexist, specific patterns emerge:

Temporal Relationship

• The median delay between onset of the two conditions is approximately 19 months (range: 6-319 months). 1
• Most commonly, MG precedes ALS (12 patients), though ALS can precede MG (8 patients). 2

ALS Presentation

• Limb-onset ALS is predominant (83% of cases), rather than bulbar onset. 1
• Patients with both conditions tend to have more frequent bulbar onset and faster disease progression compared to typical ALS. 3

MG Presentation

• Myasthenia symptoms primarily affect ocular muscles (50% of cases) or present as generalized weakness (33%). 1
• Bulbar involvement occurs in approximately 17% of cases. 1
• Anti-acetylcholine receptor (AChR) antibodies are positive in all confirmed cases. 1

Critical Diagnostic Considerations

Avoiding False-Positive Diagnoses

The most important pitfall is false-positive anti-AChR antibody testing in ALS patients, which can lead to misdiagnosis of MG overlap. 1, 2

To establish true coexistence, you must:

• Demonstrate clear clinical fluctuation and fatigability characteristic of MG, not just progressive weakness from ALS. 1
• Perform repetitive nerve stimulation showing decremental response (>10% decrement) at low frequencies (2-3 Hz) typical of neuromuscular junction dysfunction. 4
• Obtain single-fiber EMG showing increased jitter when MG is suspected but antibodies are negative. 4
• Document clinical response to acetylcholinesterase inhibitors (pyridostigmine), which should improve MG symptoms but not ALS symptoms. 4
• Confirm positive anti-AChR antibodies with repeat testing, and consider MuSK and LRP4 antibodies if AChR is negative. 4

Electrophysiological Interpretation

The electrodiagnostic workup requires careful interpretation:

• Needle EMG must show both acute denervation (fibrillations, positive sharp waves) and chronic reinnervation (large motor unit potentials) consistent with motor neuron disease. 4
• Repetitive stimulation studies should demonstrate the characteristic decremental response of MG separate from denervation changes. 4
• Nerve conduction studies should exclude peripheral neuropathy as an alternative diagnosis. 4

Pathophysiological Implications

This association suggests that immunological mechanisms and alterations at the neuromuscular junction may be relevant to ALS pathogenesis, not just MG. 2, 5

• Recent evidence supports early neuromuscular junction involvement in ALS with subsequent motor neuron degeneration. 5
• The co-occurrence may reflect shared dysfunction of adaptive immunity. 1
• This raises potential therapeutic targets at the neuromuscular junction in ALS patients. 5

Management Approach

When both conditions are confirmed:

ALS Management

• Continue riluzole as standard ALS therapy. 1
• Implement multidisciplinary palliative care from diagnosis, including nutritional support for dysphagia and respiratory monitoring. 6, 7

MG Management

• Initiate pyridostigmine starting at 30 mg PO three times daily, gradually increasing to maximum 120 mg four times daily based on response. 4
• Add corticosteroids (prednisone 0.5 mg/kg daily) for moderate to severe MG symptoms. 4
• Consider IVIG (2 g/kg over 5 days) or plasmapheresis for severe or refractory symptoms. 4
• Avoid medications that worsen myasthenia: beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics. 4

Monitoring

• Perform frequent pulmonary function testing (negative inspiratory force and vital capacity) given dual risk of respiratory compromise from both conditions. 4
• Monitor for myasthenic crisis, which can deteriorate rapidly and requires ICU-level care. 4

Key Clinical Pearls

• The coexistence is rare but real—maintain high clinical suspicion when ALS patients develop fluctuating weakness or when MG patients develop progressive, non-fluctuating weakness. 1, 2, 3
• Always exclude false-positive antibody results through comprehensive clinical and electrophysiological correlation. 1, 2
• The presence of both conditions typically portends a more aggressive disease course with faster progression. 3