Pediatrics

Myasthenia gravis

Overview: What every practitioner should know

Are you sure your patient has myasthenia gravis? What are the typical findings for this disease?

Myasthenia gravis (MG) is the most common autoimmune neuromuscular junction disorder in children and in adults. It typically presents with ocular and bulbar symptoms, followed by limb weakness. MG is also associated with thymoma. MG is diagnosed based on clinical features, antibody testing and electrophysiological studies (repetitive nerve stimulation and single fiber EMG).

MG responds to anticholinesterase agents and corticosteroids (prednisone) or other oral immunosuppressive agents. IVIG and plasma exchange are commonly used in the management of MG crises, but also may be used for maintenance therapy in refractory patients and to prepare patients for thymectomy. Thymectomy is recommended in children with acetylcholine receptor antibody positive MG who do not respond to anticholinesterase agents alone, and in all children with thymoma.

Typical Clinical Findings:

The most common clinical finding in MG is ptosis, frequently accompanied by external ophthalmoparesis. Ptosis can be unilateral at onset but generally spreads to the other eye in most patients. Weakness of facial and oropharyngeal muscles will produce dysarthria, dysphagia, and difficulty chewing. Proximal weakness is a prominent feature on limb examination. Myasthenic crisis involves respiratory failure secondary to weakness of diaphragm or intercostal muscles, or the failure of airway protection because of pharyngeal muscle weakness.

In most children, ocular symptoms are seen at the onset of disease, but generalized weakness with or without ocular involvement may be encountered. Children with a pure ocular presentation of MG may progress to generalized forms later. Fatigable weakness is a unique feature of MG and is easily demonstrable with ptosis or other forms of ocular or bulbar weakness. Deep tendon reflexes, sensory function, and cognitive examination remain normal in children with MG.

Key symptoms and signs of MG:

Ptosis

Oculomotor weakness

Bulbar, facial and neck weakness

Proximal limb weakness

Fatigability: A typical history of progressive weakness with repeated action that improves after rest suggests fatigability. This feature can be elicited on history and can be confirmed on examination.

Neonatal Myasthenia Gravis

Acquired autoimmune MG can present during the neonatal period or later in childhood. Neonatal MG is a transient disease seen in infants born to mothers with either acetylcholine receptor or MuSK antibody positive MG. The transient weakness is secondary to passive placental transfer of maternal antibodies. Most affected neonates present with a weak cry, hypotonia, decreased spontaneous movements and respiratory difficulty. Acute manifestations such as respiratory difficulty and hypotonia generally resolve in a few hours to days, but facial weakness and difficulty swallowing might persist for longer periods. Close monitoring during pregnancy and childbirth, and general awareness of this potential issue for children born to mothers with MG can limit harm to the infant.

Juvenile Myasthenia Gravis

MG during childhood presents with most of the common manifestations listed earlier. Onset of disease usually tends to cluster around puberty. Ptosis followed by oculomotor weakness is the most common manifestation followed by facial, bulbar and limb weakness. Neck flexion and proximal limb weakness are seen with generalized MG.

MG Classification

MG has been classified based on clinical presentation, antibody status and Myasthenia Gravis Foundation of America (MGFA) Classification system.

Overall clinical classification is based on the distribution of weakness, either purely ocular or generalized MG. MG can be also classified based on the presence of acetylcholine receptor (AChR) antibody, muscle specific kinase (MuSK) antibody, and seronegative MG.

MGFA classification:

Class I: Any ocular muscle weakness. Other muscles are normal.

Class II: Mild weakness affecting muscles other than the ocular muscles. Class II is further subdivided into IIa: predominantly axial or limb muscle weakness, and Class IIb: predominantly oropharyngeal or respiratory muscle weakness.

Class III: Moderate weakness affecting muscles other than the ocular muscles. Class III is further subdivided into IIIa: predominantly axial or limb muscle weakness, and Class IIIb: predominantly oropharyngeal or respiratory muscle weakness.

Class IV: Severe weakness affecting muscles other than the ocular muscles. Class IV is further subdivided into IVa: predominantly axial or limb muscle weakness, and Class IVb: predominantly oropharyngeal or respiratory muscle weakness.

Class V: Requirement for intubation with or without mechanical ventilation.

What other disease/condition shares some of these symptoms?

Differential diagnosis:

1. Congenital myasthenic syndromes

2. Botulism

3. Lambert Eaton myasthenic syndrome

4. Mitochondrial myopathy

5. Various types of cranial neuropathies can also cause ptosis and oculomotor weakness.

What caused this disease to develop at this time?

There are no known factors that generate the onset of autoimmune MG; however, multiple factors may precipitate severe weakness in MG patients. These include infections, using medication that can worsen MG (see below) and non-compliance with medication. Surgery can also precipitate weakness, and myasthenic symptoms may worsen during pregnancy.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Lab and electrodiagnostic testing:

1. Anti- AChR antibodies: Elevated AChR antibodies are diagnostic of acquired MG. However, negative results do not exclude MG. In most facilities, antibody results take a few days to return and the clinician will need to rely on clinical features and electrodiagnostic studies to guide initial management.

2. If testing for AChR antibodies is negative, anti-MuSK antibodies should be tested. Recently, autoantibodies to lipoprotein-related protein 4 (LRP4)have been detected in small subpopulation of MG patients who are for the most part seronegative for the other two antibodies.

3. Electrophysiological testing, specifically repetitive nerve stimulation: Repetitive nerve stimulation is performed by stimulating one nerve (ulnar, spinal accessory and facial nerves are commonly tested). A significant decrement in the compound muscle action potential amplitude or area (>10%) on slow rates (2-3 Hz) of repetitive nerve stimulation suggests a defect in neuromuscular transmission. It is not specific for MG, however. Repetitive nerve stimulation can be a painful procedure, and most infants will need to be sedated. Older children and teenagers are usually able to tolerate the procedure with reassurance. Routine nerve conduction studies and most aspects of electromyography are normal in MG.

4. Single-fiber electromyography: Single-fiber EMG is the most sensitive test for MG, however it can be technically challenging and requires significant cooperation from the patient. In our experience, this test should be performed in children only after exploring the above laboratory options.

5. Tensilon testing: Tensilon (edrophonium bromide) is a short-acting acetylcholinesterase inhibitor and can be used to detect a transient improvement in ptosis or ocular movements. Tensilon testing requires close monitoring because of the possibility of bradycardia, and atropine should be on hand for such settings.

6. All children should tested for thyroid dysfunction because of its frequent association with MG.

Would imaging studies be helpful? If so, which ones?

All children with MG should undergo chest imaging to look for thymoma. Imaging can be either a chest computed tomography (CT) or magnetic resonance imaging (MRI). Contrast enhanced imaging is not routinely needed. MRI of the chest would be preferable if there is concern for radiation exposure to the child.

If you are able to confirm the patient has myasthenia gravis, what treatment should be initiated?

Initial treatment for most children is with acetylcholinesterase inhibitors, specifically pyridostigmine. The maximum recommended dose is 7mg/kg/day. Pyridostigmine is usually given in 4-6 divided doses a day. It is available in syrup form (60mg/5ml) or in tablet form (60mg). Very rarely intravenous pyridostigmine may be used if the child cannot take medication orally (oral 60mg dose is equal to 2mg intravenous form).

Prednisone is widely felt to be the most effective and commonly used immunosuppressive agent in MG. It is usually started at a dose of 1mg/kg daily and can be changed to alternate daily dosing to decrease side effects after several weeks. There is a possibility of short-term worsening of MG with the above regimen, and the child may need to be admitted to the hospital for a few days to monitor respiratory function while starting high-dose prednisone. Lower dose regimens that may start with alternate-day administration have been developed for less severe or ominous presentations of MG.

Thymectomy is standard procedure in a child with thymoma. Even in children without thymoma, thymectomy is used. Thymectomy might increase the chances of remission, but the clinical effect of thymectomy may take several years to become apparent. Thymectomy does not guarantee disease remission.

Other immunosuppressive agents used include azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide and tacrolimus.

For acute exacerbations, we recommend either intravenous immunoglobulin (IVIG) therapy or plasma exchange. IVIG has been used extensively for various neuromuscular disorders. For acute exacerbations, the standard induction dose is 2gm/kg divided over 2-5 days. IVIG has also been used for maintenance therapy and is given at a dose of 0.5 to 1gm/kg every 2 to 4 weeks. Plasma exchange can be used in myasthenic crisis; it usually requires support from the transfusion/pathology services at the hospital. IVIG or plasma exchange are also used to prepare children for thymectomy and to hasten post-thymectomy recovery if needed.

What are the adverse effects from the treatment options you've recommended?

Pyridostigmine: Most of the side effects are due to muscarinic effects of the drug. These include diarrhea and abdominal cramps. Oral loperamide or glycopyrrolate may be used to help with these side effects.

Prednisone: Numerous side effects from prednisone or other corticosteroids are well recognized, including diabetes, weight gain, hypertension, growth retardation, depression and osteopenia. Alternate-day dosing may decrease the incidence of these side effects.

Thymectomy: Thymectomy can be performed via a transsternal approach, transcervical approach or more recently using video-assisted thoracoscopic surgery (VATS). VATS-assisted thymectomy boasts a shorter post-operative stay and less morbidity compared to transsternal approaches.

Azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide, and tacrolimus can all cause to varying degrees renal or hepatic toxicity, bone marrow suppression and rarely malignancies.

IVIG is well tolerated. Its most notable side effects are headache, renal impairment, venous thrombosis, and rarely anaphylaxis. Children should be adequately hydrated to prevent any renal impairment.

Plasma exchange is restricted to centers with appropriate support staff and a transfusion department. Most children will need a central venous access or PICC line. Fluid, electrolytes and coagulation parameters need to be closely monitored during plasma exchange.

What are the possible outcomes of myasthenia gravis?

In most instances, myasthenic symptoms are well controlled with treatment. Children with thymectomy have a higher chance of remission (42% in one study) compared to children who did not have thymectomy. We believe that all AChR antibody-positive children should be offered the option of thymectomy, outlining potential benefits and complications with the parents or guardians. A VATS procedure may be preferred because of cosmetic issues, especially in girls, and shorter hospital stays.

Spontaneous remission is also possible, but generally occurs only after several years of therapy, usually requiring immunosuppression. A small proportion of children with MG will require prolonged aggressive immunosuppresive therapy. In most cases, medications can be tapered over time.

What causes this disease and how frequent is it?

MG is known to have a prevalence of 125 cases per million and between 10-20 of these cases will develop MG as a child or during adolescence.

MG is more common in girls.

Different HLA antigens are common in certain ethnic groups (for example, HLA DQ8 and DR3 in Caucasians).

MG, being an autoimmune disease, can be associated with other autoimmune disorders including thyroid disease, diabetes, and connective tissue diseases such as lupus or rheumatoid arthritis.

MG is an antibody-mediated disease caused by IgG antibodies directed against the AChR of the postsynaptic membrane of the neuromuscular junction. These antibodies cause complement mediated damage to the AChR and ultimately lead to functional loss of AChRs on the postsynaptic membrane. It is believed that antibodies directed against MuSK cause MG by impairing the clustering of AChR on the postsynaptic membrane.

Drugs that may worsen or unmask MG

Anesthetic Agents:

1. Neuromuscular blocking agents

2. Procaine and lidocaine

Antibiotic Agents:

1. Aminoglycosides

2. Telithromycin

3. Erythromycin

4. Tetracycline

5. Penicillins

6. Fluoroquinolones

7. Sulfonamides

8. Clindamycin

Cardiovascular Agents:

1. Beta blockers

2. Procainamide

3. Quinidine

Rheumatological Agents:

1. D-Penicillamine

Others:

1. Lithium

2. Corticosteroids

3. Phenytoin

What complications might you expect from the disease or treatment of the disease?

Complications from MG and treatment of MG

Themost important complication of MG is myasthenic crisis secondary torespiratory muscle weakness or inability to protect the airway. Mostpatients develop MG crises during the first few years of MG or as aresult of secondary underlying infections. Children in MG crisis willneed to be admitted to a hospital for ICU monitoring and might requireintubation. Functional vital capacity below 20ml/kg or expiratory forceless than 40cm suggest that either non-invasive ventilation orintubation is required. These respiratory measures might only beobtainable in older children.

Similar tomanagement of other neuromuscular causes of respiratory failure, oneshould not wait for hypoxia to develop before initiating respiratorysupport, as this is a late feature. Most children will require treatmentwith IVIG or plasma exchange for MG crises. Underlying infection shouldbe treated aggressively with appropriate antibiotics - avoidingaminoglycosides, fluoroquinilones and telithromycin if possible - andany offending drugs should be stopped.

How can myasthenia gravis be prevented?

There are no known preventive measures for acquired MG.

Obstetricians and pediatricians should be aware of and be ready to manage neonatal MG when an expectant mother has MG or if another sibling had neonatal MG.

Genetic counseling would be important in cases of congenital MG which can be inherited in either autosomal recessive or dominant patterns.

Drugs known to worsen MG should be avoided if possible.

What is the evidence?

Because MG is a relatively rare disease in children, most treatment recommendations are based on case series or controlled studies performed in the adult population.

The reader is directed to the following reviews and publications:

Meriggioli, MN, Sanders, DM. "Autoimmune myasthenia gravis: Emerging clinical and biological heterogeneity". Lancet Neurol. vol. 8. 2009. pp. 475-490.

Seybold, ME. "Thymectomy in childhood myasthenia gravis". Ann NY Acad Sci. vol. 841. 1998. pp. 275-282.

Barohn, RJ. "Treatment and clinical research in myasthenia gravis: how far have we come?". Ann NY Acad Sci.. vol. 1132. 2008. pp. 225-232.

Ongoing controversies regarding etiology, diagnosis, treatment

Although little controversy exists regarding the pathogenesis and diagnosis of MG, there remain questions regarding the benefits of thymectomy beyond medical treatment alone in non-thymomatous MG, and there is ongoing debate regarding the best initial and long-term approach to immunotherapy.

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