What is juvenile myasthenia gravis, its typical presentation, diagnosis, treatment, and management in children and adolescents under 18 years old?

Juvenile Myasthenia Gravis: Comprehensive Overview

Definition and Epidemiology

Juvenile myasthenia gravis (JMG) is an autoimmune disorder affecting the neuromuscular junction in children under 18 years of age, characterized by fluctuating muscle weakness that worsens with activity and improves with rest. 1, 2

• JMG is rare, with an incidence of 0.04 to 5 per 100,000 children per year 3
• Ethnicity influences incidence, clinical presentation, and disease course 2
• Female predominance is observed (58.6% in one large series) 4
• Age of onset ranges from 11 months to 17 years 4
• African American children represent a significant proportion of cases (50% in some cohorts) 4

Pathophysiology

Antibodies attack acetylcholine receptors at the postsynaptic membrane, preventing normal nerve signal transmission to muscles. 3, 2

• Acetylcholine receptor (AChR) antibodies are found in 84% of JMG patients, though rates are lower in prepubertal children 4, 5
• Muscle-specific tyrosine kinase (MuSK) antibodies represent a distinct subtype with different treatment responses 1
• Extraocular muscles are particularly susceptible due to their twitch fiber composition and fewer acetylcholine receptors 3
• The disorder is B-cell mediated, with antibodies inhibiting rather than stimulating the neuromuscular junction 3

Clinical Presentation

Ocular Manifestations (Most Common Initial Presentation)

• Ptosis (drooping eyelids) is often the first symptom, appearing unilateral or bilateral, worsening with prolonged upgaze 3, 6
• Diplopia (double vision) from extraocular muscle weakness is highly variable 3, 6
• Variable strabismus and slow ocular saccades are characteristic 7
• 50% of patients initially present with isolated ocular symptoms 3, 2
• Isolated ocular symptoms are particularly frequent at disease onset in children 2

Generalized Manifestations

• 65% of JMG patients present with generalized myasthenia gravis at onset 4
• Proximal muscles are affected more than distal muscles 6, 7
• Dysarthria (slurred speech) and dysphagia (difficulty swallowing) are common bulbar features 6, 7
• Facial muscle weakness causes reduced facial expressions 6
• Neck weakness leads to difficulty holding up the head 6, 7
• Respiratory muscle weakness represents the most life-threatening manifestation 6, 7

Age-Specific Presentations

Very young children (under 6 years) present with atypical features that frequently delay diagnosis: 8, 2

• Poorly localized pain and refusal to bear weight 8
• Irritability and meningism 8
• Unsteady gait 8
• Generalized muscle weakness can appear as early as the second year of life 2
• Antibodies may be only slightly elevated or even negative in very young children 2

Disease Progression

• 50-80% of patients with initial ocular symptoms develop generalized MG within a few years 3, 7
• Spontaneous remission or intermittent symptoms can occur over longer periods, particularly in children 2
• Fluctuating weakness worsens with continued activity and improves with rest 6, 7
• Symptoms characteristically worsen as the day progresses (fatiguability) 6

Diagnosis

Clinical Examination

Diagnosis is confirmed by demonstrating fluctuating muscle weakness with characteristic fatigability patterns. 1, 5

• Ice pack test shows temporary improvement of ptosis 3
• Pupils are NOT affected—pupillary involvement suggests alternative diagnoses like third nerve palsy 8
• Reflexes are typically preserved (unlike Guillain-Barré syndrome) 8
• Variable presentation during examination is typical 6

Electrodiagnostic Studies

• Repetitive nerve stimulation demonstrates decremental response 3, 5
• Single fiber EMG shows increased jitter and blocking 5
• These studies are essential when antibodies are negative 5

Serological Testing

Acetylcholine receptor antibodies are positive in 84% of JMG patients but are frequently absent in prepubertal children. 4, 5

• MuSK antibodies should be tested in seronegative patients 3
• Lipoprotein-related protein 4 (LRP4) antibodies are another alternative in seronegative cases 3
• Antibody negativity does not exclude diagnosis, especially in very young children 2

Additional Investigations

• Chest CT is mandatory to screen for thymoma (present in 10-15% of patients) 3
• Pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) is essential for respiratory assessment 3, 6
• Thymic hyperplasia is found in 21% of patients undergoing thymectomy 4
• Thymoma is rare but occurs in approximately 6% of surgical cases 4

Classification

The Myasthenia Gravis Foundation of America (MGFA) classification guides management: 3, 7

• Class I: Ocular symptoms only (ptosis, diplopia) 7
• Class II: Mild generalized weakness 7
• Class III: Moderate generalized weakness 7
• Class IV: Severe generalized weakness 7
• Class V: Myasthenic crisis requiring intubation and ventilatory support 7

Treatment Approach

First-Line Symptomatic Management

Pyridostigmine (acetylcholinesterase inhibitor) is first-line symptomatic treatment for generalized JMG. 1

• Dosing: 0.4-1.0 mg/kg per dose, typically given 3-6 times daily 1
• Works by increasing acetylcholine concentration in the synaptic cleft to overcome receptor blockade 3
• MuSK-positive JMG shows poor response to pyridostigmine 1
• Overdosage can cause cholinergic crisis with worsening weakness 9

Critical warning from FDA labeling: Overdosage may result in cholinergic crisis characterized by increasing muscle weakness that can lead to respiratory failure and death. 9

• Differentiation between myasthenic crisis (needs more treatment) and cholinergic crisis (needs drug withdrawal) is essential 9
• Edrophonium chloride testing may be required for differentiation 9
• Atropine is used for cholinergic crisis but can mask signs of overdosage 9

First-Line Immunosuppression

Early use of oral prednisolone is important when good control is not achieved with pyridostigmine alone. 1

• Initiate immunosuppression early to avoid long-term physical and psychosocial morbidity 1
• Appropriate prevention and monitoring of steroid side effects is essential in growing children 1, 2
• Potential long-term effects on the growing organism must be considered 2

Second-Line Immunosuppression

Consider azathioprine or mycophenolate when: 1

• No response to steroids after adequate trial 1
• Inability to wean to a reasonable minimum effective dose 1
• Intolerable side effects from steroids 1

For MuSK-positive JMG, rituximab should be considered as second-line immunosuppression based on anecdotal evidence. 1

Thymectomy Indications

Thymectomy is indicated in any patient with a thymoma. 1

• For AChR-positive generalized JMG, thymectomy should be considered after allowing time for spontaneous remission 1
• 59% of patients experience good improvement (Millichap and Dodge scale B level) after thymectomy 4
• 75% experience a drop in Osserman classification by at least one level 4
• Thymectomy is well tolerated in children 4
• The benefit is less clear in ocular JMG 1
• Thymectomy is NOT advised in MuSK-positive JMG 1
• Clinical remission is achieved in the majority of patients with current treatment methods 5

Management of Ocular JMG

Management is similar to generalized JMG but requires close ophthalmology involvement in young children to prevent amblyopia. 1

• Pyridostigmine as first-line symptomatic treatment 1
• Immunosuppression with prednisolone if symptoms interfere with visual development 1
• Regular ophthalmologic monitoring is essential 1

Myasthenic Crisis Management

Children experiencing myasthenic crisis require urgent hospital admission with intensive care unit access. 1

• Plasma exchange (PLEX) is preferred over IVIG due to rapid onset of action 1
• This preference must be balanced with feasibility in very young children 1
• Close monitoring of respiratory function with pulmonary function tests is critical 3, 6
• Respiratory muscle weakness can rapidly progress to respiratory failure 6, 7

Critical Medications to Avoid

The following medications can precipitate or worsen myasthenic weakness and must be avoided: 3, 6

• Beta-blockers 3, 6
• Intravenous magnesium 3, 6
• Fluoroquinolones 3, 6
• Aminoglycosides 3, 6
• Macrolide antibiotics 3, 6

Concurrent Conditions to Monitor

JMG may occur with myositis and/or myocarditis, requiring evaluation with: 3

• CPK and aldolase levels 3
• Troponin T 3
• ECG and echocardiography if respiratory insufficiency or elevated CPK is present 3

Prognosis

The prognosis of JMG is generally good with current treatment methods. 5

• Clinical remission is achieved in the majority of patients 5
• Spontaneous remission occurs more frequently in children than adults 2
• Recovery can continue for more than 3 years after onset 8
• Long-term physical and psychosocial morbidity can be avoided with early appropriate treatment 1

Key Clinical Pitfalls

Failure to recognize early respiratory involvement can be fatal—all grades of JMG warrant thorough evaluation given potential for progression to respiratory compromise. 3, 7

• Atypical presentations in very young children frequently cause diagnostic delay 8, 2
• Antibody negativity in prepubertal children should not exclude diagnosis 2, 5
• Cholinergic crisis from pyridostigmine overdosage can mimic myasthenic crisis 9
• Certain medications can precipitate crisis and must be avoided 3, 6