Myasthenia Gravis (MG) is an autoimmune disorder where the immune system attacks healthy proteins at the neuromuscular junction, the site where nerve cells communicate with muscles. This attack primarily targets the acetylcholine receptors (AChR), which are necessary for muscle contraction. MG is characterized by muscle weakness that fluctuates, often worsening with activity and improving after rest. Because this pattern of fatigable weakness is not unique, many other conditions present with similar symptoms, making diagnosis a complex challenge for physicians. Accurately distinguishing MG from these “mimic” conditions is important for ensuring appropriate and timely treatment.
Closest Neuromuscular Junction Mimics
Conditions affecting the neuromuscular junction (NMJ) present the most significant diagnostic overlap with MG. Lambert-Eaton Myasthenic Syndrome (LEMS) is a close mimic, but its antibodies target presynaptic voltage-gated calcium channels, which release acetylcholine. In contrast, MG antibodies attack the postsynaptic receptors. This difference leads to a distinct clinical finding: LEMS patients show paradoxical improvement in strength with repeated effort, while MG patients experience worsening weakness.
LEMS is frequently associated with small-cell lung cancer, classifying it as a paraneoplastic syndrome in about 50% of cases. Weakness in LEMS is often pronounced in the proximal muscles of the legs and can include autonomic symptoms like dry mouth or constipation, which are typically absent in MG.
Botulism, caused by a neurotoxin from Clostridium botulinum, impairs the NMJ by blocking acetylcholine release. Unlike the chronic onset of MG, botulism presents as an acute, rapidly progressive, descending flaccid paralysis, often starting with cranial nerve palsies. Systemic signs like gastrointestinal symptoms or fixed, dilated pupils provide clear differentiating features.
Certain medications can also cause or unmask myasthenia-like symptoms by interfering with neuromuscular transmission. Examples include aminoglycoside antibiotics and certain cardiac medications like beta-blockers, which can worsen weakness in a patient with subclinical MG or cause temporary symptoms.
Conditions Presenting with Ocular Symptoms
MG frequently begins with weakness in the eye muscles and eyelids, resulting in drooping eyelids (ptosis) and double vision (diplopia). Conditions primarily affecting the eye muscles are often considered in the differential diagnosis.
Thyroid Eye Disease (TED), or Graves’ ophthalmopathy, is an autoimmune disorder that shares this ocular presentation. TED involves inflammation and swelling of the extraocular muscles, leading to restricted eye movement and diplopia. A key distinction is that TED often causes eyelid retraction, exposing the sclera, whereas MG causes ptosis. Furthermore, TED weakness is generally restrictive and constant, lacking the pronounced fluctuation and fatigability that characterizes MG.
Chronic Progressive External Ophthalmoplegia (CPEO) is a mitochondrial disorder presenting with ptosis and restricted eye movement. CPEO involves the slow, symmetric, and progressive weakening of the external eye muscles over years. The resulting muscle weakness is fixed and permanent, contrasting with the variability seen in MG. CPEO diagnosis is often supported by the presence of proximal limb weakness or cardiac conduction abnormalities.
Broader Neurological Weakness Disorders
Disorders affecting the nerves or muscles can cause generalized weakness that overlaps with advanced MG. Amyotrophic Lateral Sclerosis (ALS), a motor neuron disease, can initially present with bulbar symptoms like difficulty speaking (dysarthria) and swallowing (dysphagia), which are also common in generalized MG. ALS involves the progressive degeneration of both upper and lower motor neurons.
The weakness is non-fluctuating and relentlessly progressive, lacking the temporary improvement after rest typical of MG. Differentiating signs include muscle twitching (fasciculations), brisk reflexes, and muscle wasting (atrophy), which are typically absent in MG.
Inflammatory myopathies, such as polymyositis (PM) and inclusion body myositis (IBM), are muscle diseases causing symmetric, proximal muscle weakness. The primary pathology lies within the muscle fibers themselves, not at the neuromuscular junction. While myositis causes muscle fatigue, it lacks the true fatigability pattern of MG, where strength temporarily returns after rest. Inclusion body myositis is further distinguished by its often asymmetrical presentation and the early involvement of specific muscles, such as the wrist and finger flexors and the quadriceps.
Distinguishing Features of Mimics
Physicians rely on specific clinical findings and laboratory tests to distinguish MG from its mimics. Blood testing for autoantibodies is a primary diagnostic tool. Detection of antibodies against the acetylcholine receptor (AChR) or the muscle-specific kinase (MuSK) protein provides strong evidence for an MG diagnosis. Most mimics, including LEMS and the myopathies, test negative for these MG-specific antibodies.
Electrodiagnostic studies, particularly Repetitive Nerve Stimulation (RNS) and Single-Fiber Electromyography (SFEMG), are important for assessing neuromuscular transmission. In MG, RNS typically shows a decremental response, where the muscle’s electrical response decreases with repeated stimulation. Conversely, LEMS is characterized by an incremental response, where the muscle response increases after brief maximal effort or high-frequency stimulation.
Clinical presentation offers important clues. Autonomic dysfunction, such as dry mouth or erectile issues, strongly suggests LEMS or Botulism, but not MG. The finding of fasciculations or hyperreflexia on a neurological exam points toward a motor neuron disease like ALS. A diagnostic trial with cholinesterase inhibitors, such as pyridostigmine, can also be used; a clear, positive response supports an MG diagnosis, while a lack of response suggests a mimic.