• Neuro-Ophthalmology

    Establishing the diagnosis

    A 2-year-old Vietnamese girl was struck on the right cheek. The following day she was observed to have a "droopy" right eyelid. It was noted on subsequent days that the eyelid would open very widely immediately after the child awoke in the morning and after a nap, with contralateral eyelid "droopiness." This was followed by the right eyelid becoming progressively "droopy" over the course of several minutes, and the left eyelid raising to a normal position. She was taken to a local eye care provider who indicated that she might have had an infection.  She was referred to an oculoplastic specialist who noted a right hypotropia, limitation of elevation of the right eye, and right ptosis. She was referred to a pediatric neurologist who diagnosed her clinically with ocular myasthenia gravis. Mestinon and a short course of steroids were started. Her hypotropia resolved, and ptosis improved but did not completely resolve. CT of the chest revealed no abnormality, specifically no thymoma. Acetylcholine receptor (AChR) antibodies were negative.  She has been followed to ensure amblyopia does not develop. She remains orthophoric. No symptoms of generalized myasthenia gravis have developed. 

    Introduction

    Myasthenia gravis (MG) is an autoimmune disorder involving the neuromuscular junction (NMJ) in which there is fatigue of the skeletal musculature, which is potentially life threatening.1,2 Weakness of the muscles tends to fluctuate. The extraocular muscles and levator palpebrae tend to be involved. Estimates of incidence vary in the literature, between 1.7-30.0 cases per million person years, with a prevalence of 77.7 cases per million persons.3,4  In the pediatric population the incidence is estimated to be between 1.0 and 5.0 cases per million person years.3  It is estimated that between 10% and 15% of the cases of myasthenia occur in the pediatric population.5 This proportion may be higher in Asian populations.6,7 Two main subtypes of autoimmune MG exist; the generalized subtype and the ocular subtype.

    Pathophysiology

    Depolarization of a motor neuron propagates to the axon terminal, where acetylcholine is released into the synapse. Synaptic transmission in the NMJ is dependent upon the release of acetylcholine from the presynaptic terminal, followed by binding to the acetylcholine receptor at the postsynaptic terminal. Once acetylcholine binds its receptor at the postsynaptic terminal, an ion channel is opened, allowing the cell to depolarize. In the majority of MG cases, autoantibodies are created that bind to the acetylcholine receptor (AchR) in the NMJ. Once the autoantibodies are bound to the AchR, complement binds to the site, leading to immune-mediated injury, endocytosis of the AchR, and subsequent degradation of the AchR.8-10 This interferes with postsynaptic transmission and leads to early fatigability.  

    Presentation

    Ocular

    OMG accounts for approximately 10-35% of cases of MG in childhood.1,11 A higher proportion of children present with OMG in Asian populations.6,7 In OMG, only the extraocular muscles and levator palpebrae are involved. Patients may present with ptosis, diplopia, or strabismus as their initial symptoms or findings. A community-based case-control study found that MG was present in 0.81% of pediatric patients with ptosis.12 MG was present in patients with ptosis at an odds ratio of 26.7 compared to aged-matched controls without ptosis.12 Variability of measurements and mimicry of cranial nerve palsies are possible. The pupils are not affected in MG.  

    Generalized

    Up to 90% of patients with MG will have involvement of the extraocular muscles and levator palpebrae.. The factor that distinguishes ocular from generalized MG is the involvement of any other nonophthalmic skeletal muscle. Patients may develop difficulty and early fatigue with running or walking. Talking may become affected, including a change in voice. Facial weakness and difficulty swallowing may occur. The most troubling sign is difficulty breathing when the diaphragm becomes involved. This is an emergency, because patients may develop respiratory failure and require intubation.1,9 

    Subtypes of MG in childhood

    Neonatal Myasthenia Gravis

    Neonatal myasthenia gravis (NMG) is an immune-mediated disorder distinct from juvenile myasthenia gravis and the congenital myasthenic syndromes. NMG is a transient disorder that presents after birth in an infant with a mother who has autoimmune MG. The mechanism of disease in these patients is transfer of maternal autoantibodies to the fetus through the placenta.  Between 5% and 30% of children born to mothers with autoimmune MG will have NMG.13,14  Features of neonatal myasthenia include difficulty feeding, hypotonia, respiratory distress, weak cry, and poor facial expression, as well as involvement of the extraocular muscles and ptosis.14 Respiratory support may be necessary, and treatment options include neostigmine and plasma exchange. Once the antibodies are cleared from the infant's body, the adverse effects are no longer present, and the transient nature of the myasthenia is clear, as opposed to the congenital myasthenic syndromes where the symptoms persist.  

    Juvenile Myasthenia Gravis

    Juvenile myasthenia gravis (JMG) is an autoimmune disorder that presents before the age of 19 years of age and is not transient like NMG, and is not due to a structural disorder leading to a congenital myasthenic syndrome.15 Patients who have the purely ocular form of MG are less likely to have positive autoantibodies (for AchR or MUSK) in their serum.  Some patients  do not have detectable autoantibodies and are labeled as seronegative MG. JMG may be associated with other autoimmune diseases such as Hashimoto's disease and autoimmune polymyositis.16 

    Congenital Myasthenic Syndromes

    There is a collection of syndromes known as the Congenital Myasthenic Syndromes  (CMS) which are distinct entities from autoimmune MG.  Onset is usually between birth and early childhood.  Fatigable ptosis and weakness occur in these patients as well.  A high index of suspicion may be necessary to distinguish these disorders from myopathies or other neurogenic disorders.17 These patients have a non-immune-mediated cause for their symptoms in which structural alterations at the NMJ itself lead to fatigability such as changes in the acetylcholine receptor itself, or in endplate development and maintenance.18 Genetic analysis of patients with CMS is necessary to identify the pathologic mutation as the specific treatment for one mutation may be harmful to patients with another mutation, and treatment must be tailored to the specific cause of CMS.18  Distinguishing autoimmune JMG from CMS may be difficult in the absence of a known pathological genetic mutation and the absence of autoantibodies.

    Diagnostic Considerations  

    Laboratory testing

    Acetylcholine receptor (AchR) antibody testing is commercially available and should be performed in patients suspected of having MG.  The three antibodies generally evaluated are the binding, blocking, and modulating antibodies to the AchR.9 Positive antibody testing confirms the diagnosis of MG in most cases..9,19 The Anti-MuSK autoantibody is positive in about 40% of patients with negative antibodies to the AchR, although the rate of positivity in children is not clear and may be dependent upon region and/or race.9,10,19  Children with a positive anti-MuSK antibody have a course and presentation similar to that of adults with a positive Anti-MuSK antibody who are positive; respiratory crises are common and have a varied response to therapy in comparison to AchRAb positive JMG.20  One recent evaluation of autoantibody status at diagnosis in JMG found a 41% positive rate in those presenting with ocular symptoms only, and a 72% positive rate in those with generalized disease.21 They also found that 41% of patients who were initially antibody negative became antibody positive with at least two years of follow-up, but did not clinically worsen (except for a single patient). Patients who converted from antibody positive to antibody negative were associated with disease remission.21  This fact is in contrast to previous reports of conversion to generalization in 36% of patients.2 

    Pharmacologic testing

    The classic test for diagnosing MG is the edrophonium (Tensilon) test. Edrophonium is a short-acting inhibitor of acetylcholinesterase. It effectively increases the amount of acetylcholine within the synapse, allowing acetylcholine to bind to its receptor for a longer period of time.  Edrophonium is administered intravenously in a monitored setting. The patient should have some aspect of MG that can be monitored (photographs are helpful) for confirmation of a positive test.  An intravenous test dose should be given first for possible supersensitivity. Escalating doses are given, and the patient is observed. Side effects can include salivation, hypotension, diarrhea, flushing, sweating, nausea, and bradycardia. The test should be administered in a facility with resuscitation equipment and atropine available, due to the risk of severe bradycardia and asystole. Edrophonium testing may not be sensitive or specific, because other diseases may show improvement after administration, and because some patients fail to respond to edrophonium.1 The test may have to be repeated if the results are equivocal. Neostigmine can be used as an alternative to edrophonium in young patients. Another possible alternative pharmacologic test to edrophonium is a trial of pyridostigmine, with the response to drug administration observed over time.  

    Electrophysiologic testing

    Repetitive nerve stimulation is one test that can be used to aid in diagnosing MG. Low-frequency stimuli are given, and a decrease in response from the first to the fifth response of 10% is considered pathologic. It is not specific for MG, however.  Single-fiber electromyography (EMG) is considered to be the most sensitive method to detect abnormal neuromuscular transmission; however, the patient must be cooperative for the test.1 Stimulation single fiber EMG of the orbicularis oculi can be performed on conscious children.22 

    Other clinical tests

    A simple test to perform in the office for ocular features of MG is to look for fatigability in sustained upgaze.  The patient's palpebral fissure height and motility are examined first. Then the patient is asked to look at a target above primary gaze for a prolonged period of time. Observation during this period may reveal a gradual increase in ptosis or a change in ocular alignment. Following this period of sustained upgaze, the palpebral fissure height and motility examination can be repeated, with a change in measurements confirming fatigability. Also suggestive of MG is the Cogan lid twitch, in which the eyelids over-elevate following a period of downgaze and return to primary position. This phenomenon is due to a period of relative rest for the levator palpebrae muscles.  

    An alternative test suggestive of MG that can be performed in the office is the ice test. In this test, an ice pack or ice-filled glove is placed over one or both eyes for two minutes, and then removed. Improvement of ptosis by 2 mm or greater is considered to be a positive result, and is approximately 80% sensitive.23,24  Another test that can easily be performed is the rest test, in which the patient rests for 30 minutes, followed by repeat examination.25 This test may not be as sensitive as the ice test.26 

    Patient management: treatment and follow-up

    Treatment

    Pyrodistigmine

    Pyrodistigmine is considered a mainstay of treatment for MG. It is an acetylcholinesterase inhibitor that has a longer half-life than edrophonium. Despite treatment, symptoms may persist.27 The side effect profile is similar to that of other acetylcholinesterase inhibitors (edrophonium) described above.  

    Oral agents

    Oral steroids are often the initial immunosuppressive agent used in controlling MG, and they work by decreasing autoantibody circulation.14,28  The conversion from OMG to generalized MG may be prevented or delayed by the use of steroids.29 Azathioprine has been used as an immunosuppressant agent for MG; however, it can cause leucopenia, pancytopenia, and is considered carcinogenic, which should be taken into account when it is prescribed to children.   Azathioprine's treatment effect is delayed from the initial dose by several months.30 

    Immunomodulatory agents

    Other immunomodulatory agents have been used in MG to control symptomatology. Rituximab has been reported in several cases to improve symptoms and to reduce or eliminate the need for steroids.31,32 Mycophenolate mofetil is another medication that has been used for MG.30 Tacrolimus has also been used as a steroid-sparing agent in children who have MG.33 

    Other treatment modalities

    Use of plasmapheresis has been reviewed, and little evidence has been found supporting or refuting its use in MG, despite studies examining this treatment modality.34 In contrast, intravenous immune globulin (IVIG) has been suggested and used for acute exacerbations of MG.35 A comparison of IVIG to plasmapheresis as maintenance therapy for MG in pediatric patients found that both modalities had high response rates, but plasmapheresis had a more consistent response.36 

    Thymectomy

    Thymomas are associated with MG in 10-15% of all adult cases. In children, cases of thymoma  associated with MG have been reported but are exceedingly rare,.37 Thymectomy may have a role, especially in children who have generalized disease that is unresponsive to traditional therapies within one year of diagnosis. The long-term consequences of thymectomy in children remain unclear.1,27,38  Additionally, there may be a protective effect from thymectomy on development of generalized symptoms in children, and it may control OMG as well.8, 39 However, there are no randomized controlled trials evaluating the effectiveness of thymectomy in patients without a thymoma.40 

    Ophthalmic outcomes

    Patients in the amblyopic age range must be monitored for the development of amblyopia from ptosis or strabismus and treated appropriately. Amblyopia develops in 25-50% of patients who have OMG39,41 However, when amblyopia is aggressively treated in patients with OMG, final outcomes can reduce residual amblyopia to 3%.39 Rates of residual strabismus at final visits are between 15% and 57%. Ptosis may be present following stabilization of disease in 46%-66% of patients.39,41 Complete resolution of manifestations of OMG occurs in between 13-50%.39 Upon stability of the underlying disease, strabismus surgery and ptosis surgery can be considered with a 56% long-term success rate found in one study for strabismus surgery.42 Patients and their parents should be counseled about the possible need for multiple surgeries and the possibility of treatment failure due to the child’s underlying disease.

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