Differential Diagnosis of Myasthenia Gravis: Ruling Out Mimickers

Key Takeaways:

• MG's fluctuating weakness necessitates careful differentiation from other neuromuscular disorders (LEMS, MNDs) through clinical features (fatigability pattern, reflexes), serology (specific antibodies), and electrodiagnostic studies (RNS, SFEMG).
• Non-neurological conditions (thyroid disorders, mitochondrial myopathies) can mimic MG symptoms, requiring thyroid function tests, muscle biopsy, and/or genetic testing to avoid misdiagnosis.
• A comprehensive diagnostic approach combining clinical history, neurological examination, serological testing, electrodiagnostic studies, and other tests is crucial for accurately distinguishing MG from its mimickers.

While the hallmark symptoms of myasthenia gravis (MG) are fatigue and weakness, often affecting ocular, bulbar, facial, and limb muscles, a thorough differential diagnosis is crucial to ensure accurate diagnosis and appropriate treatment. Several neuromuscular and non-neurological conditions can mimic MG, necessitating careful clinical evaluation and targeted investigations.^1,2

Lambert-Eaton myasthenic syndrome (LEMS)

LEMS is another neuromuscular junction disorder, although it affects the presynaptic neuromuscular junction, as opposed to the postsynaptic in MG. LEMS often presents with proximal leg weakness and hyporeflexia that improves with exercise (post-exercise facilitation), contrasting with the worsening muscle weakness (e.g. fatigue) with exercise in MG.^1,3

Autonomic dysfunction, such as dry mouth and constipation, is also more common in LEMS. While both conditions can be associated with auto-antibodies, specific antibody testing is highly discriminatory. Autoantibodies to voltage-gated calcium channels (VGCC) are often seen in LEMS, while autoantibodies to acetylcholine receptors (AChR) or muscle-specific kinase (MuSK) are often found in MG.^1,3

Furthermore, repetitive nerve stimulation (RNS) studies typically show a decrement in MG, whereas LEMS often demonstrates a characteristic incremental response at higher stimulation frequencies after exercise.^1,3

Blood clot in the sinuses

This can be a serious condition. A blood clot in the sinuses is also called cavernous sinus thrombosis. These clots can cause similar symptoms in the eye muscles as ocular MG, notably double vision. But in the case of a blood clot, symptoms usually begin suddenly and can include other symptoms such as:^1,4

• Sensory loss on the face
• Vision loss
• Headache

Multiple sclerosis (MS)

Multiple sclerosis, like MG, is an autoimmune disorder. But MS is caused by the immune system targeting the protective cover on nerves in the brain and spinal cord. MS can cause weakness, but it can also cause other neurologic symptoms such as vision loss, sensory symptoms, and bowel and bladder dysfunction that are not seen in MG. MS is treated differently from MG.^1,3

Botulism

Botulism is an illness that causes weakness in the same facial muscles as MG, at least initially. It usually comes from eating contaminated foods. Symptoms develop very quickly. Botulism causes descending paralysis that starts in the face and then spreads to the arms and shoulders, torso, and possibly the legs. This is an emergency.^1,3

Lyme disease

Tick-borne diseases like Lyme can cause muscle weakness and difficulty breathing. But Lyme disease can also cause symptoms that are not linked to MG, like rash and fever.^1,3

Amyotrophic lateral sclerosis (ALS)

ALS is the most common motor-neuron disease (MND). In ALS, weakness typically starts in 1 limb and over time worsens and spreads, leading to severe muscle weakness all over the body. This can lead to difficulty breathing and ultimately death.³

Polymyositis and dermatomyositis

These 2 conditions are rare. Both cause muscle inflammation and weakness. The weakness gets worse over time and can cause trouble breathing.^1,5

Other conditions

Several non-neurological conditions can present with symptoms that may be mistaken for MG. For example, thyroid disorders, particularly hyperthyroidism and hypothyroidism, can cause muscle weakness and fatigue.⁶

Ocular manifestations, such as diplopia and lid retraction in thyroid eye disease, can mimic ocular MG. Thyroid function tests (TSH, free T4) are essential to rule out thyroid dysfunction.⁶

Mitochondrial myopathies are a diverse group of genetic disorders affecting mitochondrial function. They lead to muscle weakness, fatigue, and often other systemic manifestations like ophthalmoplegia, cardiac involvement, and lactic acidosis.⁷

While chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disorder, can present with ptosis and ophthalmoparesis resembling ocular MG, the weakness is typically more fixed and less fluctuating. Muscle biopsy with specialized stains and genetic testing is crucial for diagnosing mitochondrial myopathies.⁷

Take a comprehensive diagnostic approach

A comprehensive approach is crucial for accurate differential diagnosis. HCPs should consider the following when diagnosing MG:^1-3

• Detailed medical history – Careful assessment of the pattern and distribution of weakness, fatigability, diurnal variation, and associated symptoms
• Neurological exam – Thorough evaluation of muscle strength, reflexes, cranial nerves, and sensory function
• Serological testing – Measurement of AChR antibodies (binding, blocking, and modulating), MuSK antibodies, and LRP4 antibodies. Negative antibody tests do not exclude MG (seronegative MG).
• Electrodiagnostic tests – Repetitive nerve stimulation (RNS) and single-fiber EMG (SFEMG) can demonstrate impaired neuromuscular transmission. SFEMG is more sensitive than RNS.
• Pharmacological testing – The edrophonium (Tensilon) test, while less commonly used now due to safety concerns and availability of other tests, can provide temporary improvement in muscle strength in some MG patients.
• Imaging studies – Chest CT or MRI may be indicated to evaluate for thymoma, particularly in AChR antibody-positive MG.
• Genetic testing – Consider in suspected congenital myasthenic syndromes (CMS) or mitochondrial myopathies.
• Other lab tests – Thyroid function tests, creatine kinase (CK) levels (usually normal or mildly elevated in MG), and assessment for other autoimmune disorders