Differential diagnosis of myasthenia gravis

INTRODUCTION — Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by fluctuating weakness involving ocular, bulbar, limb, and/or respiratory muscles. The weakness is due to an antibody-mediated immunologic attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (acetylcholine receptors or receptor-associated proteins). MG is the most common disorder of neuromuscular transmission.

This topic will discuss the differential diagnosis of MG. Other aspects of the disorder are discussed separately.

●(See "Pathogenesis of myasthenia gravis".)

●(See "Clinical manifestations of myasthenia gravis".)

●(See "Diagnosis of myasthenia gravis".)

●(See "Overview of the treatment of myasthenia gravis".)

DIFFERENTIAL BY CLINICAL PRESENTATION — Fluctuating muscle weakness is the core clinical feature of MG. Weakness may be focal or widespread, but specific patterns of weakness are characteristic of MG. Isolated ptosis and/or diplopia are most common, followed by bulbar presentations (eg, dysarthria or dysphagia). Other presentations such as limb or neuromuscular respiratory muscle weakness are uncommon. (See "Clinical manifestations of myasthenia gravis".)

The differential diagnosis of MG in adults and children varies by the body regions impacted (table 1).

Conditions that may mimic MG in newborns and infants are discussed separately. (See 'Differential for newborns and infants with weakness' below.)

Ocular weakness — Disorders that are likely to be confused with ocular MG involve weakness of both eyelid and oculomotor function, producing ptosis and/or diplopia. Ocular symptoms are the presenting features of more than half of patients with MG. Other conditions that feature prominent ocular weakness include:

●Thyroid ophthalmopathy

●Chronic progressive external ophthalmoplegia

●Oculopharyngeal muscular dystrophy

●Brainstem and motor cranial nerve pathologies

These conditions are discussed in greater detail separately. (See "Ocular myasthenia gravis", section on 'Differential diagnosis'.)

Bulbar weakness — Weakness due to dysfunction in cranial nerves other than those controlling ocular functions may present as dysphagia, dysarthria, and/or facial drooping. MG presents with bulbar weakness in approximately 15 percent of cases. Several other conditions may present with prominent or isolated bulbar dysfunction.

Progressive bulbar palsy and other forms of motor neuron disease — Progressive bulbar palsy (PBP) and amyotrophic lateral sclerosis (ALS) are forms of motor neuron disease that, like MG, can present with facial weakness, dysarthria, or dysphagia. PBP is characterized by bulbar symptoms of motor neuron disease (table 2), while such symptoms that subsequently spread to involve limbs or other body segments are referred to as bulbar-onset ALS. Ptosis or ocular dysmotility producing diplopia typically seen with MG are not features of ALS. Other manifestations that distinguish ALS from MG on clinical grounds are the presence of both upper motor neuron signs (hyperreflexia, jaw jerk, and Babinski signs) and lower motor neuron signs (muscle and tongue atrophy and fasciculations), together with the progressive nature of ALS. In addition, electrodiagnostic studies are useful in differentiating these disorders. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

Acute GQ1b immune-mediated polyneuropathies — Some acute immune-mediated polyneuropathies are characterized by acute onset of cranial nerve impairment, often associated with seropositivity to antibodies against GQ1b, a component of myelin. These variant forms of Guillain-Barré syndrome (GBS) include the Miller Fisher syndrome, which is characterized by ophthalmoplegia, ataxia, and areflexia, and the pharyngeal-cervical-brachial variant syndrome, which features dysphagia with weakness in oropharyngeal, neck, and shoulder muscles. These polyneuropathies may be clinically distinguished from MG by the progressive nature of acute symptoms and the presence of reduced deep-tendon reflexes. The GQ1b syndromes are typically diagnosed by characteristic findings on cerebrospinal fluid analysis and electrodiagnostic studies. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'GQ1b syndromes'.)

Botulism — Botulism can be confused with MG because it often presents with bulbar dysfunction due to symmetric (often multiple) cranial nerve palsies. Dysarthria, dysphagia, and diplopia are common. Patients may subsequently develop respiratory symptoms as well as limb weakness that typically progresses from upper to lower extremities and from proximal to distal muscles. Many patients require intubation for respiratory symptoms. Botulism may be distinguished from MG by its rapid progression and its usual association with ingestion of food contaminated by Clostridium botulinum. In addition, the botulinum toxin produces pupillary paralysis in approximately one-half of affected patients, whereas pupillary function is spared in MG. The presynaptic localization of the abnormality in botulism can be confirmed by an incremental response during high-frequency repetitive nerve stimulation or after brief exercise, similar to that seen in Lambert-Eaton myasthenic syndrome (LEMS). (See "Botulism" and "Overview of neuromuscular junction toxins", section on 'Botulism'.)

Brainstem stroke — Acute stroke involving small areas of the brainstem may present with isolated bulbar dysfunction such as dysarthria or oculomotor symptoms. Ataxia may also be present, and limb weakness or hyperreflexia may be found on examination in many cases. The onset of stroke is typically sudden, but initial symptoms may fluctuate, and transient symptoms may recur over hours or days. Brain and vascular imaging are used to diagnose stroke. (See "Posterior circulation cerebrovascular syndromes".)

Lyme disease — Disseminated Lyme disease may present with neurologic manifestations such as bilateral facial nerve palsies or dysfunction of other cranial nerves. Meningitis, radiculopathy, other neuropathies, and encephalomyelitis may also occur. Other systemic features may also be present and can help distinguish Lyme disease from MG. These include rash (erythema migrans), myalgias, arthralgias, or fever. Lyme disease is diagnosed with laboratory antibody testing. (See "Clinical manifestations of Lyme disease in adults", section on 'Neurologic manifestations'.)

Other conditions — Other less common conditions that may present with prominent bulbar weakness mimicking MG include oculopharyngeal muscular dystrophy and oropharyngeal tumors. They are typically distinguished by characteristic additional clinical features and by diagnostic testing. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Oculopharyngeal muscular dystrophy' and "Overview of the diagnosis and staging of head and neck cancer", section on 'Clinical presentation'.)

Limb weakness — Isolated limb weakness is an uncommon presenting feature of MG but may also accompany ocular or bulbar symptoms or develop during the course of the condition. Many cerebral or spinal conditions can be distinguished from MG by the presence of sensory impairment in addition to weakness. However, some conditions in the differential diagnosis of MG feature limb weakness without sensory involvement.

Lambert-Eaton myasthenic syndrome — LEMS presents with muscle weakness and involves pathophysiologic impairment of neuromuscular transmission, similar to MG. LEMS is often a paraneoplastic manifestation of small-cell lung or other cancers but also may occur in the setting of autoimmune conditions. LEMS frequently presents with proximal leg muscle weakness. Patients may report difficulty standing from a seated position or climbing stairs. Proximal arm weakness at presentation is more common in MG, but shoulder girdle weakness eventually develops in many patients with LEMS. Initial involvement of the bulbar muscles or diplopia is uncommon in LEMS, but ptosis may be seen. Symptoms in LEMS are more likely to be present in the morning and to improve with exercise, while MG symptoms are likelier to be worse at the end of the day or following exertion or exercise. LEMS may also feature autonomic dysfunction or dry mouth. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)

Characteristic findings of LEMS on electrodiagnostic testing that help discriminate from MG include a marked increase in the compound muscle action potential (CMAP) amplitude with repetitive nerve stimulation (RNS) at high rates (20 to 50 cycles per second) or after exercise (an incremental response). By contrast, RNS testing in patients with MG shows a decremental response of CMAP amplitude. In addition, a high titer of serum antibodies to the presynaptic voltage-dependent calcium channels are associated with LEMS. Less than 5 percent of patients with MG have such antibodies, typically at low titer. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)

Occasional patients with LEMS have acetylcholine receptor (AChR) antibodies [1]. Distinction from MG in this setting is made by the presence of small-cell lung cancer (in half), antibodies directed against the P/Q-type calcium channels, and the electrophysiologic features of a presynaptic disorder of neuromuscular transmission. Rarely, a patient will have the clinical, immunologic, and electrophysiologic features of both disorders [1-3].

Amyotrophic lateral sclerosis and limb-predominant forms of motor neuron disease — ALS and some other forms of motor neuron disease, such as the flail arm and flail leg syndromes, feature prominent limb involvement at presentation. Similarly, patients with primary lateral sclerosis may present with limb symptoms due to impaired gait. Unlike those with MG, patients with motor neuron disease have both upper as well as lower motor signs and symptoms (table 3). In addition, ptosis or ocular dysmotility producing diplopia typically seen with MG are not features of ALS. Motor neuron disease may be distinguished from MG by characteristic electrodiagnostic findings. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

A false-positive test for AChR autoantibodies may be found in approximately 3 to 5 percent of ALS patients, although usually in low titers [4].

Guillain-Barré syndrome and other immune neuropathies — The typical clinical features of GBS and chronic inflammatory demyelinating polyneuropathies (CIDP) include progressive symmetric muscle weakness and hyporeflexia. Ocular and bulbar symptoms may also be present in many patients. These immune-mediated polyneuropathies may be distinguished from MG by the progressive nature of symptoms, the presence of reduced deep-tendon reflexes, autonomic dysfunction, and by characteristic findings on cerebrospinal fluid analysis and electrodiagnostic studies. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)

Other conditions — Other conditions that are either uncommon or present infrequently with isolated limb weakness that mimics MG include:

●Stroke – Ischemic or hemorrhagic stroke involving corticospinal nerve pathways produce weakness. However, weakness due to stroke is frequently accompanied by additional speech, sensory, or brainstem symptoms. The onset of stroke symptoms is typically sudden. Diagnosis is by brain and vascular imaging. (See "Clinical diagnosis of stroke subtypes" and "Neuroimaging of acute stroke".)

●Botulism – Botulism can cause limb weakness that develops following the onset of multiple, symmetric cranial nerve palsies. Limb weakness in botulism often progresses from upper to lower extremities and from proximal to distal muscles. (See 'Botulism' above.)

●Penicillamine-induced myasthenia − Approximately 1 percent of patients treated with penicillamine, usually for rheumatoid arthritis or Wilson disease, develop an autoimmune MG that shares many of the characteristics of primary MG [5,6]. This occurs because penicillamine induces the production of AChR antibodies. This effect should not be confused with the exacerbation of MG that may occur due to drugs that pharmacologically interfere with neuromuscular transmission. (See "Overview of the treatment of myasthenia gravis".)

Myasthenia induced by penicillamine usually resolves within 3 to 12 months once the drug is withdrawn [5]. However, resolution of myasthenia may be quite slow, and treatment may be required if symptoms are severe. (See "Overview of the treatment of myasthenia gravis".)

●Other medication-related weakness – Statin treatment may be associated with a myasthenic syndrome or exacerbation of myasthenia symptoms. This issue is discussed separately. Checkpoint inhibitor immunotherapy may also be complicated by a myasthenic syndrome. (See "Overview of the treatment of myasthenia gravis", section on 'Avoidance of drugs that may exacerbate myasthenia' and "Toxicities associated with immune checkpoint inhibitors", section on 'Neurologic'.)

Respiratory weakness — Isolated respiratory symptoms due to neuromuscular weakness are an uncommon presentation in MG. Some other conditions may also present with isolated respiratory symptoms or respiratory symptoms that accompany bulbar and/or limb symptoms.

●Amyotrophic lateral sclerosis – ALS and other forms of motor neuron disease may uncommonly present with dyspnea due to impairment of respiratory muscles. The presence of upper and lower motor signs and symptoms and electrodiagnostic test findings are used to discriminate MG from ALS. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

●Acid maltase deficiency – Some patients with lysosomal acid alpha-glucosidase (acid maltase) deficiency may present with prominent or isolated respiratory symptoms, including sleep disordered breathing. Additional weakness, typically in a limb-girdle distribution, may also be present. (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)", section on 'Clinical features'.)

●Polymyositis – Polymyositis typically presents with insidious, progressive, symmetric proximal limb weakness, but some patients may also have early respiratory symptoms or coexisting interstitial lung disease. Polymyositis may be identified by the presence of elevated serum muscle enzymes and electrodiagnostic or biopsy evidence of myopathy. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

●Botulism – Dyspnea or respiratory distress due to diaphragmatic paralysis may be seen at presentation in patients with botulism, either in isolation or along with common cranial nerve and limb symptoms. Respiratory symptoms can develop quickly in patients with botulism and often require intubation and mechanical ventilation. (See 'Botulism' above.)

Generalized fatigue — Although fatigable weakness may be a major aspect of MG, it is important to differentiate this from complaints of generalized fatigue or tiredness. This lack of energy, often described as overwhelming fatigue, is not part of MG and is never the sole manifestation. This symptom is generally due to an underlying medical disorder (eg, anemia), progressive deconditioning, or psychologic etiology. The symptoms of MG usually include specific complaints of fatigable weakness. Examples include diplopia or ptosis that develop late in the day, difficulty with prolonged chewing, development of dysarthria or hypophonia with prolonged speech, or neck extensor weakness late in the day with the inability to keep the head upright.

DIFFERENTIAL FOR NEWBORNS AND INFANTS WITH WEAKNESS — Many conditions may cause neuromuscular weakness in infants, including uncommon neuromuscular junction disorders (table 4). Disorders of the neuromuscular junction in newborns and infants can present with isolated muscle weakness, poor feeding, generalized hypotonia, a weak cry, or apneas. These conditions include:

●Transient neonatal MG

●Congenital myasthenic syndromes

●Magnesium or aminoglycoside toxicity

●Infant botulism

Conditions that may cause weakness and hypotonia in infants are discussed in greater detail separately. (See "Neuromuscular junction disorders in newborns and infants".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myasthenia gravis" and "Society guideline links: Thymomas and thymic carcinomas".)

SUMMARY

●Symptom-based approach to differential diagnosis – Specific patterns of weakness are characteristic of MG. Isolated ptosis and/or diplopia are most common, followed by bulbar presentations (eg, dysarthria or dysphagia). Limb or neuromuscular respiratory muscle weakness are uncommon. The differential diagnosis of MG in adults and children varies by the body regions impacted (table 1). (See 'Differential by clinical presentation' above.)

•Ocular weakness – Disorders that are likely to be confused with ocular MG involve weakness of both eyelid and oculomotor function, producing diplopia and ptosis. Ocular symptoms are the presenting features of more than half of patients with MG. Such conditions include (see "Ocular myasthenia gravis", section on 'Differential diagnosis'):

-Thyroid ophthalmopathy

-Chronic progressive external ophthalmoplegia

-Oculopharyngeal muscular dystrophy

-Brainstem and motor cranial nerve pathologies

•Bulbar weakness – Weakness due to dysfunction in cranial nerves other than those controlling ocular functions may present as dysphagia, dysarthria, and/or facial drooping. MG presents with bulbar weakness in approximately 15 percent of cases. These conditions include (see 'Bulbar weakness' above):

-Amyotrophic lateral sclerosis (ALS) and other forms of motor neuron disease

-GQ1b immune-mediated polyneuropathies

-Botulism

-Brainstem stroke

-Lyme disease

•Limb weakness – Isolated limb weakness is an uncommon presenting feature of MG but may also accompany ocular or bulbar symptoms during the course of the condition in patients with generalized MG. Common conditions that may mimic MG include (see 'Limb weakness' above):

-Lambert-Eaton myasthenic syndrome (LEMS)

-ALS and other forms of motor neuron disease

-Guillain-Barré syndrome (GBS)

-Chronic inflammatory demyelinating polyneuropathy (CIDP)

Other conditions that may also present with limb weakness mimicking MG include stroke, botulism, penicillamine-induced myasthenia, checkpoint inhibitor-induced myasthenia, and statin-related weakness.

•Respiratory weakness – Isolated respiratory symptoms due to neuromuscular weakness are an uncommon presentation in MG. Some other conditions may also present with respiratory symptoms along with other neurologic symptoms. These include ALS, acid maltase deficiency, polymyositis, and botulism. (See 'Respiratory weakness' above.)

●Differential diagnosis for newborns and infants with weakness – Many conditions may cause neuromuscular weakness in infants, including uncommon neuromuscular junction disorders (table 4). Disorders of the neuromuscular junction in newborns and infants include transient neonatal MG, congenital myasthenic syndromes, magnesium or aminoglycoside toxicity, and infant botulism. (See "Neuromuscular junction disorders in newborns and infants".)