Author(s): Kristen Courtney, DO, Melissa Trovato, MD
Originally published: September 14, 2015 Last updated: April 24, 2025
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Disease/Disorder

Definition

A group of disorders involving the neuromuscular junction (NMJ), resulting from either antibodies against elements of the postsynaptic membrane, such as nicotinic acetylcholine receptors (AChR) or mutational defects in the proteins required for neuromuscular transmission and its integrity. Both etiologies result in abnormal neuromuscular transmission, which characteristically manifests as muscle weakness and fatigability.1

Etiology

  • Neonatal myasthenia gravis (NMG) is a distinct, temporary form of myasthenia gravis that results from transplacental passage of antibodies to neonates from mothers with autoimmune myasthenia gravis.2  
  • Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders with mutations in the genes that encode proteins essential for neuromuscular transmission.3
  • Acquired myasthenia gravis (MG), also known as Juvenile Myasthenia Gravis (JMG) in children, is an acquired, autoimmune disorder similar to the disorder seen in adults.1

Epidemiology including risk factors and primary prevention

  • NMG is a rare, transient disorder, occurring in 10-15% of newborns born to mothers with autoimmune MG. Epidemiological data for NMG is scarce; likely due to underreporting with difficulty detecting in mildly affected infants. The risk of NMG in subsequent pregnancies for siblings in significantly higher.2 Mothers with autoimmune MG should plan to deliver at hospitals with intensive care for neonates. And women who have given birth to an NMG baby should be treated with regular cycles of IVIG or plasma exchange in future pregnancies to minimize antibody exposure.1
  • CMS has an estimated total prevalence of 10 per million person cases.1 Approximately 35 causative genes and pathogenic mutations have been found with genetic testing and development of next generation sequencing. There is moderate phenotypic variability between the mutations with variability in onset age, pattern of weakness, severity, progression of disease over time, and treatment response.4 Most of the mutations are autosomal recessive, with few defined as autosomal dominant. There is an expected increase in risk if positive family history of CMS in another sibling.1 
  • MG has a prevalence of 150-250 individuals per million total population. The annual incidence is estimated to 8-10 individuals per million population. For disease prevalence, it is notable that today patients with MG have a near normal expected life length, in contrast to previous years. The onset age for generalized MG with AChR has a bimodal pattern. There is a lower peak around age 30 years and an increasing incidence with higher age from 50 years and til 70-80 years. Of note, in China, there is an additional peak around age 5 years. Among the group with onset <30 years, the male:female ratio is 3:1.1
  • JMG is defined as myasthenia gravis in children younger than 18 years of age. Generally, pre-pubertal onset is more common.5

Patho-anatomy/physiology

  • NMG results from transplacental transfer of AChR antibodies from a mother with autoimmune myasthenia gravis to her fetus causing nicotinic ACh receptor loss, leading to increased degradation, blockage of ACh binding, and lysis of post-synaptic membrane The most common antigens are nicotinic AChR and receptor tyrosine kinases (MuSKR). This is a temporary disease process that disappears weeks to months after birth as the antibodies are replaced.2
  • CMS results from defective or absent presynaptic, synaptic or post-synaptic proteins required for neuromuscular transmission or maintenance of neuromuscular junction structure. Approximately 75% of cases are due to post-synaptic (acetylcholine receptor) defects; these are classified further into AChR deficiency, kinetic defects of AChR (fast and slow channel syndromes), defective AChR clustering, and glycosylation defects. Pre-synaptic deficiency (impaired ACh synthesis, storage, release, or recycling) and synaptic basal lamina associated dysfunction also occur.3 The myasthenia autoantibody testing with be negative.
  • MG is characterized by the antibody-mediated inference at the neuromuscular junction, where disease-inducing antibodies bind to the postsynaptic membrane, disrupting acetylcholine receptor function, and causing muscle weakness. In binding to the AChR, antibodies accelerate receptor degradation while also preventing acetylcholine (ACh) from binding to the receptors, thus disrupting normal neuromuscular transmission.1

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

  • NMG symptoms appear within 3-72 hours of birth and include poor sucking, respiratory distress, generalized hypotonia (rest in frog-leg positioning of lower limbs), weak cry, facial diplegia. Of note, ptosis and ophthalmoplegia are uncommon at presentation. Most will completely recover before 4 months of age and >90% will resolve before 2 months of age.2
  • CMS has a variable presentation given numerous mutations and phenotypes, but typically presents with fatigable weakness. More commonly, there will be a presentation of ocular and cranial muscle weakness; specifically, partial ophthalmoparesis with downgaze sparing, facial weakness, bulbar symptoms, and masticatory weakness. Other nonspecific symptoms may include feeding difficulties, weak cry, hypotonia, and arthrogryposis.4The first myasthenic symptoms (fatigable weakness in ocular and cranial skeletal muscles) typically occur between birth and early childhood.6
  • JMG typically presents with ocular symptoms and can progress to more generalized symptoms. Onset time of symptoms is variable, and fluctuation in the disease course is typical.1 Compared to adult MG, JMG has a more benign course with better prognosis.5

Specific secondary or associated conditions and complications

  • Thymus pathology is common in MG with AChR antibodies. Ten percent of all patients with MG have a thymoma and 30% of patients with a thymoma develop MG. The thymoma may appear before any symptoms of muscle weakness.1 In JMG, the thymus is generally hyperplastic, producing AChR antibodies. Thymomas are not typical of JMG, contributing to lower mortality.5
  • Myasthenic Crisis is a life-threatening condition, triggered by stress or infection, during which weakness becomes severe enough to require intubation.1

Essentials of Assessment

History

  • With MG, patients will demonstrate generalized skeletal muscle weakness that typically increases with repetitive use and improves with rest. Muscle weakness is usually absent or mild in the morning and progresses throughout the day, or with exercises. Some patients may experience improvement in muscle strength in cold surroundings, particular ocular and facial muscles. The presence of weakness in extraocular muscles (commonly asymmetrical) with subsequent diplopia and ptosis is seen in nearly all patients. Additionally, common clinical features may include facial weakness, dysphagia, proximal muscle weakness, fatigue, and respiratory involvement.1 Daytime somnolence may be reported, which can be indicative of sleep apnea.
  • NMG is primarily a clinical diagnosis; however, there is a history of autoimmune MG in the mother. Of note, if mother is asymptomatic, diagnosis will require positive results on 1+ standardized diagnostic tests.2
  • In CMS, there may be a positive family history of a similar disorder and early infancy clinical features (neonatal hypotonia, breast feeding difficulties, delayed motor milestones).4 Family history may be negative, thus, in children and young adults diagnosed with atypical myasthenia gravis but without antibodies, one should suspect a myasthenic syndrome.1
  • In JMG, there is a higher rate of autoimmune disorders in these individuals and their relatives. The most common autoimmune comorbidity is thyroid disease, specifically hyperthyroidism.5
  • The differential diagnosis includes mitochondrial neuromuscular disorders and myopathies, Lambert Eaton Syndrome, motor neuron disease, spinal muscular atrophy, congenital myopathies, congenital muscular dystrophy, infantile muscular dystrophy, and infantile botulism.1,2

Physical examination

Patients may present with variable degrees of ptosis, open mouth, facial weakness, bulbar symptoms, hypotonia, difficulty in eliciting primitive reflexes, and proximal muscle weakness. Dropped head, inability to whistle, and difficulty raising arms above the head may be noted. Predominant distal weakness is rare.2,3,4 Weakness intensifies with repetitive activity and improves with rest. There is no autonomic or sensory involvement in any forms of MG.

Clinical functional assessment: mobility, self-care, cognition/behavior/affective state

Children may demonstrate an inability to run, climb stairs, and keep up with peers. They may also require frequent rest breaks or naps due to fatigability throughout the day. Difficulty getting through the school day without a rest period is a common occurrence. There should be no abnormalities in mental state, cognition, or behavior as a direct result of MG. In fact, the presence of intellectual disability is more supportive against a myasthenic syndrome.4

Laboratory studies

  • In NMG and MG, 85-90% of individuals have detectable AChR antibodies; however, there is a high frequency of seronegative MG in very young children.7 Muscle-specific kinase (MuSK) antibodies are present in 40% of seronegative individuals.8
  • In CMS, AChR antibodies are absent, and the specific diagnosis instead depends on genetic testing (single gene testing, multiple gene panel testing, and comprehensive genetic testing such as whole genome sequencing and next generation sequencing).6

Imaging

Although thymomas are relatively rare compared to the adult population, chest imaging with MRI or CT should be considered, particularly in generalized JMG.5

Supplemental assessment tools

  • In the Tensilon Test, improvement in fatigued muscle is seen with administration of edrophonium, a short-acting acetylcholinesterase inhibitor (anti-AChE), which prolongs the presence of ACh in the synaptic cleft by inhibiting acetylcholinesterase enzymes. Apparent, transient resolution of muscle weakness following administration, signifying improved neuromuscular transmission, is considered a positive test.
  • In the Ice Pack Test, placing ice over an eyelid for minutes can improve ptosis since lower temperatures facilitate neuromuscular transmission.
  • Electrodiagnostic studies aimed at the affected muscles may demonstrate a decrement with repetitive stimulation. A decreased response of at least 10% by the 4th or 5th stimulation of 2-3Hz is indicative of a neuromuscular transmission disorder. As this test is painful and provider-dependent, it has less utility in children than in adults with MG.
  • Single-fiber EMG has the highest sensitivity and is useful in diagnosing seronegative MG.
  • Since these tests may be technically difficult to perform in infants and young children, response to treatment can be confirmatory. However, a positive response may also be deceptive due to placebo effects and subtle increases or boosts in endurance for individuals without any actual NMJ deficits.

Early prediction of outcomes

  • In NMG, complete resolution of symptoms is seen within weeks to months.2
  • CMS has a variable prognosis depending on the subtype. Genes related to receptor deficiency tend to have better outcomes compared to abnormalities in the synapse or presynapse.9
  •  A retrospective study of 133 JMG patients between 1987-2015 treated at a tertiary care pediatric hospital demonstrated that 10% of the cases obtained complete spontaneous remission.10

Environmental

Certain medications including aminoglycosides, macrolides, B-blockers, ACE inhibitors, quinidine, lidocaine, procainamide, phenytoin, prednisone, interferon, and D-penicillamine, can cause exacerbation of MG symptoms.

Social role and social support system

  • The Myasthenia Gravis Foundation of America is a good resource for individuals with MG. The foundation serves patients, families, and caregivers through a network of chapters, support groups, and programs.
  • The Muscular Dystrophy Association (MDA) considers MG a covered condition even though the disease does not affect muscles directly. Services for patients with MG may be provided through MDA clinics.
  • Other support groups include Rare Disease Foundations such as the National Organization for Rare Disorders (NORD).

Professional issues

MG is a heterogeneous disease and requires a high index of suspicion for diagnosis. If a patient is evaluated early in the day or in the early stage of the disease, it may be easy to attribute symptoms of fatigue to psychosomatic or psychogenic causes. The relative rarity of the condition and the difficulties around diagnosis are challenges best dealt with by pediatric neuromuscular and genetic medicine specialists.11

Rehabilitation Management and Treatments

Available or current treatment guidelines

  • For NMG treatment is supportive and symptoms are self-limiting. If treatment is employed, it typically only lasts for a few days up to a few months. Pharmacotherapy may consist of immunomodulators or immunosuppressants to increase available of ACh neurotransmission. Aminoglycosides should be cautioned in neonates as they may cause potentiation of symptoms. For severe cases, oral or IM neostigmine may be used for symptomatic treatment. If gavage feeding is required for nutrition, may consider administration of neostigmine 30 minutes prior to feed sessions to reduce dysphagia. Plasmapheresis, IVIG, corticosteroids are reserved for severely affected neonates requiring rapid removal of antibodies. Thymectomy is not necessary.2
  • For CMS, treatment depends on the subtype. Pyridostigmine and other cholinergic agonists often work well for the fast-channel post-synaptic conditions or ACh deficiency. They will typically worsen the slow channel post-synaptic conditions, defective AChR clustering (DOK7 mutation), and synaptic (COLQ mutation) cases.3 3,4-diaminopyridine increases the content of ACh at the synapse through delayed degradation and increased rate of release; subsequently, it should be considered for trial in all patients. For the slow channel syndrome, drugs that block the acetylcholine receptor ion channel when in the open state should be beneficial (fluoxetine and quinidine).3
  • For JMG, first line treatment includes anti-AChEs, such as pyridostigmine, +/- corticosteroids. Immunosuppressive agents, such as azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, rituximab may also be considered. IVIG may be implemented in higher acuity cases or crisis.5
  • Thymectomy is an option if pharmacological treatment fails or in AChR-Ab positive generalized JMG patients; however, there is a lack of large prospective cohort studies for data to standardize this treatment for JMG.5

At different disease stages

  • Myasthenic crisis is a rare, life-threatening condition often triggered by fever, infection, and stress. Other causes include adverse effect to medications, especially anti-epileptics, and insufficient intake of anti-AChE. Myasthenic crisis should be differentiated from cholinergic crisis, which, in contrast, is caused by excess intake of Anti-AChE.
  • Any child with MG exhibiting dyspnea or drowsiness must be evaluated for a potential acute myasthenic crisis, which could lead to respiratory failure. Admission to an ICU setting is required for these children until their respiratory status is stabilized.
  • Treatment for myasthenic crisis may include ventilatory support, plasma exchange, and intravenous immunoglobulin. Anti-AChEs are rarely helpful during crisis and should be withheld during this time.
  • Treatment for cholinergic crisis may include mechanical ventilation and antimuscarinic drugs, such as atropine.
  • To prevent crisis, individuals should avoid the crisis triggers and be especially cautious when using new medications.

Coordination of care

  • A referral to speech therapy may benefit those with dysphagia and dysphonia.
  • Respiratory weakness may necessitate involvement of a respiratory care team.
  • Dietary intervention is useful for individuals with significant weight loss or avoidance of significant obesity related to inactivity.
  • Daytime somnolence or other signs of sleep apnea should prompt consideration of polysomnography.

Patient & family education

Both child and parent education are essential.

Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally-based.

N/A

Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

N/A

Cutting Edge/Emerging and Unique Concepts and Practice

In 2021, the FDA approved efgartigimod (Vyvgart), an antibody fragment which reduces pathogenic IgG antibodies, for adults with MG via fast track and orphan drug designation. Pediatric trials are ongoing.12

As gene therapy is believed to be the future for many genetic neuromuscular conditions, it has not yet been available as an option for CMS. Likely, the heterogeneity of gene defects amongst the mutation variants accounts for a barrier in advancement of this type of therapy. Theoretically, strengthening well-defined, postsynaptic signaling pathways would be helpful. Postsynaptic cholinergic function might also be improved by specific monoclonal antibodies or peptides.1

Controversies and Gaps in the Evidence-Based Knowledge

There is no consensus in the literature regarding the role, timing, or approach for thymectomy in patients with JMG and it remains controversial. Despite the lack of prospective studies evaluating thymectomy in JMG, it is generally accepted that thymectomy is considered a part of the initial management in patients with abnormal thymus pathology, typically thymoma or thymus hyperplasia.5

References

  1. Gilhus NE. Myasthenia gravis and congenital myasthenic syndromes. Handb Clin Neurol. 2023;195:635-652. doi:10.1016/B978-0-323-98818-6.00010-8
  2. Bardhan M, Dogra H, Samanta D. Neonatal Myasthenia Gravis. [Updated 2023 Jan 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558935/
  3. Henehan L, Beeson D, Palace J. Congenital myasthenic syndromes. Practical Neurology. 2024;24(3):185-187. https://proxy1.library.jhu.edu/login?url=https://www.proquest.com/scholarly-journals/congenital-myasthenic-syndromes/docview/3065822645/se-2. doi: https://doi.org/10.1136/pn-2024-004098
  4. Estephan EP, Zambon AA, Thompson R, et al. Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis. Eur J Neurol. 2022; 29: 833–842. doi:10.1111/ene.15173
  5. Lin Y, Kuang Q, Li H, et al. Outcome and clinical features in juvenile myasthenia gravis: A systematic review and meta-analysis. Front Neurol. 2023;14:1119294. Published 2023 Mar 8. doi:10.3389/fneur.2023.1119294
  6. Prior DE, Ghosh PS. Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features. J Child Neurol. 2021;36(8):610-617. doi:10.1177/0883073820987755
  7. Andrews PI. Autoimmune Myasthenia Gravis in Childhood. Seminar in Neurology, Volume 24, Number 1, 2004.
  8. Chiang LM, Darras BT et al. Juvenile Myasthenia Gravis. Muscle Nerve 39: 423-431, 2009.
  9. Marina, AD et al. Long Term Follow-Up on Pediatric Cases With Congenital Myasthenic Syndromes—A Retrospective Single Centre Cohort Study. Front. Hum. Neurosci., 2020 | https://doi.org/10.3389/fnhum.2020.560860
  10. Arroyo HA, Torres AR. Spontaneous remission in juvenile myasthenia gravis: A cohort of 13 cases and review of the literature. Neuromuscul Disord. 2022;32(3):213-219. doi:10.1016/j.nmd.2021.11.014
  11. Ware T, Ryan M et al. Autoimmune myasthenia gravis, immunotherapy and thymectomy in children. Neuromuscular Disorders 22 (2012) 118-121.
  12. Heo YA. Efgartigimod Alfa in Generalised Myasthenia Gravis: A Profile of Its Use [published correction appears in CNS Drugs. 2023 May;37(5):475. doi: 10.1007/s40263-023-01003-w.]. CNS Drugs. 2023;37(5):467-473. doi:10.1007/s40263-023-01000-z

Original Version of the Topic

Frank S. Pidcock, MD, Christina Kokorelis, MD. Myasthenic Syndromes. 9/14/2015

Previous Revision(s) of the Topic

Melissa Trovato, MD, William Ide, MD. Myasthenic Syndromes. 9/14/2019

Anton Dietzen, MD, Melissa Trovato, MD. Myasthenic Syndromes. 5/19/2022

Author Disclosure

Kristen Courtney, DO
Nothing to Disclose

Melissa Trovato, MD
Nothing to Disclose