Myasthenic Syndromes

Definition

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

Etiology

1. Neonatal myasthenia gravis (NMG) results from the transfer of AChR antibodies from mother to fetus.
2. Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders.
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.

Epidemiology including risk factors and primary prevention

1. NMG is a transient disorder, occurring in 10-15% of babies born to mothers with MG. The primary risk factor is maternal myasthenia.
2. CMS has a prevalence of somewhere between 1:100,000, and 1: 500,000, or about one-tenth of the incidence and prevalence of autoimmune MG. More than 20 subtypes have been described. Many cases present with symptoms at birth, but delayed onset in infancy or childhood can also occur. In rare cases of autosomal dominant transmission, the primary risk factor is a parent with similar symptoms attributable to CMS. In autosomal recessive transmission, family history is usually negative, unless there is significant consanguinity or the prior birth of a child with CMS. Ethnicities with increased risk for genetic inheritance of a CMS include Roma, Central and Western European, and Mahgreb populations.
3. MG has a prevalence of 1:10,000, with an incidence of 1:500,000. In North America, onset of disease before age 20 accounts for 10-15% of all individuals with MG¹. In Asian populations, JMG represents almost half of all cases of MG². Risk factors include having an autoimmune disorder and being female.

Patho-anatomy/physiology

1. NMG results from transplacental transfer of AChR antibodies from a myasthenic mother to her fetus.
2. CMS results from defective or absent presynaptic, synaptic or post-synaptic proteins required for neuromuscular transmission and is marked by the absence of AChR antibodies. Approximately 75% of cases are due to post-synaptic (acetylcholine receptor) defects; these are classified further into fast and slow channel syndromes. Acetylcholinesterase deficiency and pre-synaptic deficiency also occur.
3. MG results from the production of AChR antibodies at the NMJ. In binding to the AChR, antibodies accelerate receptor degradation while also preventing acetylcholine (ACh) from binding to the receptors, thus disrupting normal neuromuscular transmission.

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

1. Characteristic clinical features include weakness that improves with rest, ptosis, dysphagia, proximal muscle weakness, fatigue, and respiratory involvement. There is no sensory, bowel, or bladder involvement.
2. NMG symptoms appear within hours of birth and include hypotonia, feeding difficulties, and respiratory weakness, which may require mechanical ventilation. Generally, symptoms improve within 2 weeks and recovery is achieved by 2 months.
3. CMS has a variable presentation but may include hypotonia, dysphagia, scoliosis, and respiratory difficulties including episodic apnea.  The first myasthenic symptoms typically occur in the first two years of life, in some phenotypes as late as the second or third decade³.
4. MG 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.

Specific secondary or associated conditions and complications

1. 80% of MG cases involve the thymus. In JMG, the thymus is generally hyperplastic, producing AChR antibodies. Thymomas, which occur in 10% of adult cases, are not typical of JMG.
2. Myasthenic Crisis is a life-threatening condition, triggered by stress or infection, during which weakness becomes severe enough to require intubation.

History

1. All patients will present with a history of weakness, which improves with rest. History may also reveal diplopia, dysphagia, respiratory problems, and difficulty with overhead activities and stairs.
2. In NMG, there is a history of MG in the mother.
3. In CMS, there may be a positive family history of a similar disorder in autosomal dominant cases.
4. In JMG, there is a higher rate of autoimmune disorders in these individuals and their relatives⁴.
5. The differential diagnosis includes: mitochondrial neuromuscular disorders, Lambert Eaton Syndrome, Tick Paralysis, Botulism, Acute Inflammatory Demyelinating Polyradiculoneuropathy, Motor Neuron Diseases, brainstem tumors, Guillain-Barre syndrome, and diphtheria.

Physical examination

Patients present with variable degrees of ptosis, facial weakness, hypotonia, and proximal muscle weakness. Dropped head, inability to whistle, and difficulty raising arms above the head may be noted. In some familial cases there is proximal lower extremity weakness as well. Weakness intensifies with repetitive activity and improves with rest. There is no 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.

Laboratory studies

1. 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 ⁵_. Muscle-specific kinase (MuSK) antibodies are present in 40% of seronegative individuals⁴.
2. In CMS, AChR antibodies are absent, and the specific diagnosis instead depends on genetic testing. Panels are available for the most common genes, and genetic etiologies of cases with atypical findings may be found through whole exome sequencing.

Imaging

Although thymomas are relatively rare compared to the adult population, chest imaging with MRI or CT should be considered, particularly in generalized JMG⁶.

Supplemental assessment tools

1. In the Tensilon Test, improvement in fatigued muscle is seen with administration of endrophonium, 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.
2. In the Ice Pack Test, placing ice over an eyelid for minutes can improve ptosis since lower temperatures facilitate neuromuscular transmission.
3. Electrodiagnostic studies aimed at the affected muscles may demonstrate a decrement with repetitive stimulation. A decreased response of at least 10% by the 4^th or 5^th 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.
4. Single-fiber EMG has the highest sensitivity and is useful in diagnosing seronegative MG.
5. 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

1. In NMG, complete resolution of symptoms is seen within weeks to months.
2. CMS has a variable prognosis depending on the subtype. Typically, symptoms improve over time. Longevity is not generally affected.
3. In MG, children exhibit a higher rate of remission than adults³, with 44% of those with pre-pubertal onset achieving remission⁷.

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

1. 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.
2. 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.
3. 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 specialists⁸.

Off-label use of medications such as steroids and immunosuppressants has been employed to manage MG. This should be explained carefully to families in order to avoid misunderstandings if pharmacists question their use.

Available or current treatment guidelines

1. For NMG, treatment is supportive and symptoms are self-limiting.  Assistance with breastfeeding may be the only treatment required.  When indicated, low doses of pyridostigmine or neostigmine are recommended as first-line agents for symptomatic treatment.  Exchange transfusions or intravenous immunoglobulin are reserved for rare cases of severely affected babies⁹.
2. For CMS, treatment depends on the subtype. Pyridostigmine and other anti-AchEs often work well for the fast-channel post-synaptic conditions, though they will typically worsen or not help the slow channel post-synaptic conditions and acetylcholinesterase deficiency (synaptic) cases. Pre-synaptic or combination conditions may respond to the potassium channel blocker 3,4-diaminopyridine (3,4-DAP) though this may not be safe for fast-channel conditions; ephedrine, pseudoephedrine, or albuterol; or other drugs such as fluoxetine or quinidine.
3. For MG, first line treatment includes anti-AChEs, such as pyridostigmine. If symptoms persist following anti-AChEs, other options include immunosuppressants, such as steroids, azathioprine, cyclosporine, and cyclophosphamide.
4. Thymectomy is an option if pharmacological treatment fails. Thymectomy within two years of diagnosis results in a higher rate of remission¹⁰. A review of retrospective data noted a 77% post-operative improvement in JMG severity with 29% complete sustained remission¹¹.  The largest, most recent cohort study of patients with JMG undergoing thymectomy at a single tertiary referral center reported 50% clinical improvement through 3.5 years¹².
5. Exercise programs including scheduled rest breaks, energy-conserving techniques, and muscle training can be beneficial.
6. One small study of adults with MG undergoing thymectomy demonstrated efficacy of a pre-operative and post-operative structured rehabilitation program in reducing morbidity, rates of post-operative intensive care, and length of hospital stay¹³.

At different disease stages

1. 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.
2. 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.
3. 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.
4. Treatment for cholinergic crisis may include mechanical ventilation and antimuscarinic drugs, such as atropine.
5. To prevent crisis, individuals should avoid the crisis triggers and be especially cautious when using new medications.

Coordination of care

1. Outcomes improve when children are managed by a pediatric neuromuscular expert².
2. A referral to speech therapy may benefit those with dysphagia and dysphonia.
3. Respiratory weakness may necessitate involvement of a respiratory care team.
4. Dietary intervention is useful for individuals with significant weight loss or avoidance of significant obesity related to inactivity.

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.

Not Applicable

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

Not Applicable

In the largest review of thymectomies in pediatric MG¹⁴, open sternotomy approach to thymectomy (OT), used predominantly prior to 2006, was compared to the newer, minimally invasive approach, used predominantly since 2006. The most common minimally invasive approach, known as video-assisted thoracoscopic surgery (VATS), requires only 3-4 subcentimeter intercostal incisions. Perioperatively, the VATS group experienced fewer overall complications and a significantly shorter hospital stay than OT. Furthermore, there was no difference in postoperative disease severity between the two groups, suggesting that VATS is not an inferior approach to thymectomy.

The majority of CMS cases associated with AChR deficiency are due to mutations within the CHRNE gene, which encodes the adult-specific Ɛ subunit of the AChR. While these subjects typically respond favorably to acetylcholinesterase inhibitors and 3,4-DAP, patients with severe phenotypes have been observed to respond incompletely.  Recent evidence suggests that the addition of oral salbumatol or ephedrine in patients with AChR deficiency due to CHRNE mutations taking pyridostigmine results in marked improvement in muscle strength and functional ability¹⁵.

While thymectomy is indicated in peripubertal and postpubertal children with severe AChR-positive MG, it is controversial in prepubertal and seronegative forms. Not only is premature immunosuppression a concern, but in prepubertal children, remission rate was lower after thymectomy (5). Similarly, there was no significant difference after thymectomy in six seronegative children¹⁶.

There is no consensus in the literature regarding the role, timing, or approach for thymectomy in patients with JMG¹². Although existing data regarding thymectomy for seropositive JMG is favorable, it is based off of limited and retrospective studies.  A prospective multicenter controlled trial of thymectomy in JMG has been recommended by investigators^11,12.