creation date: 2026-04-22 17:54
tags: Pathologies

Myasthenia Gravis

Background

Definitions

Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction of skeletal muscles causing weakness.

MG has a bimodal age of onset with sex predominance.

Female predominance in 2nd-3rd decades
Male dominance in 6th-8th decades

Etiology and Pathogenesis

Occurs in genetically susceptible individuals affected by some precipitating factor:

Infections
Immunization
Surgeries
Drugs

Proteins within the neuromuscular junction (NMJ) have autoantibodies produced against which results in destruction of said proteins. In approximately 10% of cases, a thymoma is implicated in autoantibody production.

The exact pathophysiological mechanism varies depending on the type of antibody present:

IgG1 and IgG3: binds to postsynaptic ACh receptor, activating complement system and forming membrane attack complex
IgG4: binds to protein complex responsible for maintenance of NMJ (including ACh receptor distribution and clustering)

The common result is impaired ACh receptor function and thus an inability to generate a post-synaptic action potential. With repeated use, ACh stores in the NMJ also deplete and muscle weakness becomes more pronouced.

Clinical Presentation

Signs & Symptoms

Clinical manifestations vary in severity and features based on classification. The subcategories are discussed below.

The cardinal feature is skeletal muscle weakness:

Worsening contractile force (not sensation of fatigue, but may be concomitant)
Fluctuates throughout the day, but commonly worse later in day or after exercise

Muscle weakness may occur in any muscle but most frequently affects eye or bulbar muscle function.

Ocular symptoms due to weakness of levator palpebral and extraocular muscles:

Ptosis
Diplopia
These are common (2/3 of patients present with ocular symptoms) and are frequently asymmetric.

Bulbar symptoms due to weakness of oropharyngeal or facial expression muscles:

Dysarthria
Dysphagia
Expressionless (“lost their smile”)

Neck and limb weakness is common although not as a presenting symptom:

Dropped head syndrome (unable to maintain head posture later in day)
Proximal limb weakness, typically in arms moreso than legs

Respiratory muscle weakness may compromise respiration:

Dyspnea with exertion
Orthopnea

A typical clinical course may be seen:

Episodic symptoms with asymptomatic intervals lasting hours to even weeks
New symptoms develop in the weeks or months following initial presentation
Muscle weakness worsens and become more persistent, peaking within a few years

History & Physical Exam

MG should be suspected in patients with fatiguable muscle weakness. However, other causes of muscle weakness should be considered in evaluation.

History should elucidate character of weakness in addition to confirming muscle weakness over fatigue/tiredness.

Physical exam should include:

Neurological examination, including testing muscle strength against gravity and resistance

Diagnosis

Criteria

Diagnosis is made by presence of autoantibodies against the acetylcholine receptor (AChR) or other muscle receptor-associated proteins.

Seronegative or atypical cases can be diagnosed by electrodiagnostic confirmation.

Nerve conduction testing with repetitive nerve stimulation
Electromyography

Classification

Patients can be classified by several features to aid management and prognostication.

Clinical form:

Ocular (weakness limited to eyelids and extraocular muscles)
Generalized (combination of ocular, bulbar, limb, and respiratory muscles)
Antibody status:
Antibody positive (against AChR, MuSK, LRP4 etc.)
Seronegative
Age of onset:
Early onset (before 50)
Late onset (after 50)
Presence of thymoma:
Thymomatous
Nonthymomatous
Symptom severity:
Class I - isolated ocular weakness
Class II - mild weakness involving nonocular muscles
Class III - moderate weakness involving nonocular muscles
Class IV - severe weakness involving nonocular muscles
Class V - intubation due to respiratory muscle weakness

Work-up

In cases of atypical clinical features, additional testing may be used:

MRI brain
CT/ultrasound of orbits
Lumbar puncture for CSF analysis

Evaluation of associated conditions
Thymomas and other thymic masses:

CT chest or MRI chest

Thyroid conditions (autoimmune):

Differential

Red Flags / Complications

Patients generally will improve with treatment and may be free of symptoms with immunotherapy or even without medications. Prognosis and complication depends on a few factors.

Factors associated with worse prognosis are:

Frequent exacerbations (“brittle” MG)
Severe bulbar symptoms
Myasthenic crisis (worsening weakness resulting in respiratory failure)
Presence of thymoma
Onset at age >50 years

Management

The goal of management is to minimize clinical manifestations and adverse effects from manifestations. In many patients, full and sustained remission is possible.

Initial Symptomatic Therapy

Initial therapy for mild to moderate MG is an oral acetylcholinesterase inhibitor (anticholinesterase):

Pyridostigmine 30 mg PO TID with meals

If cholinergic side effects are excessive:

Glycopyrrolate 1 mg PO with each dose of pyridostigmine

Pyridostigmine is titrated up by 30 mg every 2-3 days until therapeutic effect is adequate or side effects intolerable.

Additional Treatment

If initial therapy is insufficient, immunotherapy may be added:

Glucocorticoids
Nonsteroidal immunotherapeutic agent (azathioprine or mycophenolate)

In patients with thymoma and in some select cases without, a thymectomy may be indicated.

Acute Exacerbations

Some medications may be used as a short-term adjunctive when rapid treatment is necessary:

Severe acute exacerbations including myasthenic crisis
Preoperatively before surgery (incl. thymectomy)
As a bridge to slower-acting immunotherapies

Options include:

IV immune globulin (IVIG)
Plasma exchange
Antibody-based biologic therapies

MD Notes

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