• Neuro-Ophthalmology

    This chapter was reviewed for currency and updated by its author in December 2020.

    Establishing the diagnosis

    A 2-year-old Vietnamese girl was struck on the right cheek. The following day she was noted to have a "droopy" right eyelid. It was noted on subsequent days that the eyelid would open very widely immediately upon awakening in the morning and after a nap, with contralateral eyelid "droopiness," followed by the right eyelid becoming progressively "droopy" over the course of several minutes, with the left eyelid raising to a normal position. She was taken to a local eye care provider who thought she may have had an infection. A referral was made, and she was evaluated by 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. Computed tomography (CT) of the chest revealed no abnormality, specifically no thymoma. Acetylcholine receptor 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   A population based study found an incidence rate of 22 per million person years for myasthenia gravis, with ocular myasthenia gravis occurring at a rate of 11.3 per million person years.5  Incidence of myasthenia gravis appears to be rising over time in patients over the age of 65.6  In the pediatric population the incidence is estimated to be between 1.0 and 5.0 cases per million person years.3  A recent population based study found the incidence of juvenile myasthenia gravis to be 1.2 per million person years.7  It is estimated that between 10% and 15% of all cases of myasthenia occur in the pediatric population.8  This proportion may be higher in Asian populations.9,10  Two main subtypes of autoimmune MG exist, the generalized subtype and ocular subtype.

    Pathophysiology

    In normal neuromuscular transmission, 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 which attach 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.11-13 This interferes with post-synaptic transmission and leads to early fatigability.  

    Presentation

    Ocular

    Ocular myasthenia gravis (OMG) accounts for approximately 10%-35% of cases of MG in childhood.1,14  A higher proportion of children present with OMG in Asian populations.9,10  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.15 MG was present in patients with ptosis at an odds ratio of 26.7, compared to aged matched controls without ptosis.15 Variability of measurements and mimicry of cranial nerve palsies are possible. In one study of children from Thailand with OMG, 97% of patients presented with ptosis, and 45% had some duction limitation.16 Of those with duction limitations, the most common presentation (in 24%) of those children was complete ophthalmoparesis.16 Pupils are not affected in MG. Patients presenting with the ocular subtype may convert to generalized myasthenia gravis.  

    Generalized

    Up to 90% of patients with MG will have the extraocular muscles and levator palpebrae affected.7 However, the factor that distinguishes ocular from generalized MG is the involvement of any other non-ophthalmic skeletal muscle. Patients may develop 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 as patients may develop respiratory failure and require intubation.1,12

    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 present after birth to a mother with 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.17,18 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.18 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 in the congenital myasthenic syndromes.  

    Juvenile Myasthenia Gravis

    Juvenile myasthenia gravis (JMG) is an autoimmune disorder that presents before the age of 19 years and is not transient like NMG, and is not due to a structural disorder leading to a congenital myasthenic syndrome.19 Patients who have the purely ocular form of MG are less likely to have positive autoantibodies (for AchR or MUSK) when measured in the serum.  Some patients do not have detectable autoantibodies to AchR or MUSK and are labeled as double seronegative MG. However, these children may be positive for antibodies to other substrates such as agrin, cortactin, or low-density lipoprotein receptor-related protein 4 (LRP4), which are present in the neuromuscular junction.20,21   JMG may be associated with other autoimmune diseases such as Hashimoto disease and autoimmune polymyositis.22 

    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.23  These patients have a non-immune-mediated cause for their symptoms in which a structural alteration at the NMJ itself leads to fatigability, such as changes in the acetylcholine receptor itself, or in endplate development and maintenance.24  Genetic analysis of patients with CMS is necessary to identify the pathologic mutation as the specific treatment for one mutation may be harmful for another mutation, and treatment must be tailored to the specific cause of CMS.24  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 tested for include binding, blocking, and modulating antibodies to the AchR.12 Positive antibody testing makes the diagnosis of MG near certain.12,25 An additional antibody may be tested for, anti-MuSK. This autoantibody is positive in about 40% of patients with negative antibodies to the AchR, although the rate of positivity specifically in children is not clear and may be dependent upon region and/or race.12,13,25  Children with a positive anti-MuSK antibody have a similar course and presentation as adults who are positive, with respiratory crises being common, and with varied response to therapy, in comparison to AchRAb positive JMG.26  Recent evaluations of autoantibody status at diagnosis in JMG found 41%-61% positive rate in those presenting with ocular symptoms only, and a 72%-74% positive rate in those with generalized disease.7,27  One study found that 41% of patients who were initially antibody negative became antibody positive with at least 2 years of follow-up but did not clinically worsen except for a single patient, and patients who converted from antibody positive to antibody negative were associated with disease remission.27 Another study in an Asian JMG population found that patient who were negative for AchR antibodies were more likely to have clinical remission at 2 years.28  Rates of conversion from OMG to GMG have been reported to involve 36% of patients, but vary between studies.2

    Pharmacologic testing

    The classic test for diagnosing MG is the edrophonium 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, as other diseases may show improvement after administration, and some patients fail to respond to edrophonium.1 The test may need 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 the use of a trial of pyridostigmine, with the response to drug administration observed over a much longer period of time.  

    Electrophysiologic testing

    Repetitive nerve stimulation is one test which 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. 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.29 Results of stimulated single fiber EMG have been found to be sensitive for neuromuscular junction disorders, including JMG.30,31

    Other clinical tests

    A simple test that can be performed in the office for ocular features of MG is to look for fatigability in sustained upgaze. The patient has their palpebral fissure height and motility examined first. Then the patient is asked to look at a target above them 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 overelevate 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 pack test. In this test, an ice pack or ice-filled glove is placed over 1 or both eyes for 2 minutes, and then removed. Improvement of ptosis by 2 mm or greater is considered to be a positive result, and is approximately 80% sensitive.32,33  A similar test that can easily be performed is the rest test, in which the patient closes their eyes and rests for 30 minutes, followed by repeat examination.34 This test may not be as sensitive as the ice test.35

    Patient management: treatment and follow-up

    Treatment

    Pyrodistigmine

    Pyridostigmine 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.36 The side effect profile is similar to that of other acetylcholinesterase inhibitors (see edrophonium above).

    Oral agents

    Oral steroids are often the initial immunosuppressive agent used in controlling MG and decreases autoantibody circulation.18,37 The conversion from OMG to generalized MG may be prevented or delayed by the use of steroids.38 Azathioprine has been used as an immunosuppressant agent for MG; however, it can cause leucopenia and pancytopenia, and is considered carcinogenic, which should be taken into account when being prescribed to children. Azathioprine's treatment effect is delayed from initial dose by several months.39

    Immunomodulatory agents

    Other immunomodulatory agents have been used in MG to control symptomatology. Rituximab has been reported in several case reports and small series to improve symptoms and to reduce or eliminate the need for steroids.40-42 Eculizumab has been approved for use in AChR antibody positive GMG in adults and can be considered for use in severe refractory cases.43,44 Mycophenolate mofetil is another medication that has been used for MG.39 Tacrolimus has also been reported as a steroid-sparing agent in children for MG.45

    Other treatment modalities

    Both plasmapheresis and intravenous immune globulin (IVIG) have been suggested and used for acute exacerbations of GMG.46-48 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.49 Appropriate use of these modalities for OMG is not well defined.50 

    Thymectomy

    Thymomas are associated with MG in 10%-15% of all adult cases. Cases of thymoma in children associated with MG are exceedingly rare, but have been reported.51  Thymectomy for adults with GMG associated with positive AChR antibodies has been reported in the MGTX randomized trial to reduce myasthenia symptoms and the dose of prednisone needed.51,52  Thymectomy may have a role, especially in children who have generalized disease that is unresponsive to traditional therapies within 1 year of diagnosis; however, the long-term consequences of thymectomy in children remain unclear.1,36,54,55 Additionally, there may be a protective effect from thymectomy on development of generalized symptoms in children, and it may control OMG as well.11,56 However, there are no randomized controlled trials evaluating the effectiveness and safety of thymectomy for children with myasthenia gravis.55 Retrospective studies comparing thymectomy to nonoperative management have conflicting results.55 

    Ophthalmic outcomes

    Patients in the amblyopic age range must be monitored for the development of amblyopia from ptosis or strabismus and treated appropriately. Amblyopia may develop in between 25% and 50% of patients who have OMG.56,57 However, when amblyopia is aggressively treated in patients with OMG, final outcomes can reduce residual amblyopia to 3%.56 Rates of residual strabismus at final visits are between 15% and 57%. Ptosis may be present following stabilization of disease in between 46% and 66% of patients.56,57 Complete resolution of manifestations of OMG can occur in between 13% and 50%, and may occur in 31% of all juvenile myasthenia patients.7,56 Once the underlying disease is stabilized strabismus surgery and ptosis surgery can be considered, with a 56% long-term success rate found in 1 study for strabismus surgery.58  Patients and their parents should be counseled about the possibility of multiple surgeries and possible treatment failure due to their underlying disease.

    References 

    1. Andrews PI. Autoimmune myasthenia gravis in childhood. Semin Neurol. 2004;24:101-110.
    2. Mullaney P, Vajsar J, Smith R, Buncic JR. The natural history and ophthalmic involvement in childhood myasthenia gravis at the Hospital for Sick Children. Ophthalmology. 2000;107:504-510.
    3. McGrogan A, Sneddon S, de Vries CS. The incidence of myasthenia gravis: A systematic literature review. 2010;34:171-183.
    4. Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurology. 2010;10:46.
    5. Hendricks TM, Bhatti T, Hodge DO, Chen JJ. Incidence, epidemiology, and transformation of ocular myasthenia gravis: A population-based study. Am J Ophthalmol. 2019;205:99-105.
    6. Maddison P, Ambrose PA, Sadalage G, Vincent A. A prospective study of the incidence of myasthenia gravis in the East Midlands of England. Neuroepidemiology. 2019;53:93-99.
    7. Mansukhani SA, Bothun ED, Diehl NN, Mohney BG. Incidence of ocular features of pediatric myasthenias. Am J Ophthalmol. 2019;200:242-249.
    8. Phillips LH, Torner JC, Anderson MS, Cox GM. The epidemiology of myasthenia gravis in central and western Virginia. Neurology. 1992;42:1888-1893.
    9. Zhang X, Yang M, Xu J, Zhang M, et al. Clinical and serological study of myasthenia gravis in HuBei Province, China. J Neurol Neurosurg Psychiatry. 2007;78:386-390.
    10. Chiu HC, Vincent A, Newsome-Davis J, Hsieh KH, Hung T. Myasthenia gravis: Population differences in disease expression and acetylcholine receptor antibody titers between Chinese and Caucasians. Neurology. 1987;37:1854-1857.
    11. Gadient P, Bolton J, Puri V. Juvenile myasthenia gravis: three case reports and a literature review. J Child Neurol. 2009;24:584-590.
    12. Liew WKM, Kang PB. Update on juvenile myasthenia gravis. Curr Opin Pediatr. 2013;25:694-700.
    13. Pal J, Rozsa C, Komoly S, Illes Z. Clinical and biological heterogeneity of autoimmune myasthenia gravis. J Neuroimmunol. 2011;231:43-54.
    14. Castro D, Derisavifard S, Anderson M, Greene M, Iannaccone S. Juvenile myasthenia gravis: A twenty-year experience. J Clin Neuromusc Dis. 2013;14:95-102.
    15. Nemet AY, Segal O, Mimouni M, Vinker S. Associated morbidity of pediatric ptosis - a large, community based case-control study. Graefes Arch Clin Exp Ophthalmol. 2014;252:1509-1514.
    16. Vanikieti K, Lowwongngam K, Padungkiatsagul T, Visudtibhan A, Poonyathalang A. Juvenile ocular myasthenia gravis: Presentation and outcome of a large cohort. Pediatr Neurol. 2018;87:36-41.
    17. Téllez-Zenteno JF, Hernández-Ronquillo L, Salinas V, Estanol B, da Silva O. Myasthenia gravis and pregnancy: clinical implications and neonatal outcome. BMC Musculoskelet Disord. 2004;5:42.
    18. Namba T, Brown SB, Grob D. Neonatal myasthenia gravis: Report of two cases and review of the literature. Pediatrics. 1970;45:488-504.
    19. Evoli A. Acquired myasthenia gravis in childhood. Curr Opin Neurol. 2010;23:536-540.
    20. Cortés-Vicente E, Gallardo E, Martínez MA, et al. Clinical characteristics of patients with double-seronegative myasthenia gravis and antibodies to cortactin. JAMA Neurol. 2016;73:1099-1104.
    21. Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol. 2016;263:826-834.
    22. Tsao CY, Mendell JR, Lo WD, Luquette M, Rennebohm R. Myasthenia gravis and associated autoimmune diseases in children. J Child Neurol. 2000;15:767-769.
    23. Kinali M, Beeson D, Pitt MC, et al. Congenital myasthenic syndromes in childhood: diagnostic and management challenges. J Neuroimmunol. 2008;201-202:6-12.
    24. Engel AG, Shen XM, Selcen D, Sine SM. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015;14:420-434.
    25. Della Marina A, Trippe H, Lutz S, Schara U. Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. Neuropediatrics. 2014;45:75-83.
    26. Skjei KL, Lennon VA, Kuntz NL. Muscle specific kinase autoimmune myasthenia gravis in children: A case series. Neuromuscul Disord. 2013;23:874-882.
    27. Anlar B, Şenbil N, Köse G, Değerliyurt A. Serological follow-up in juvenile myasthenia: clinical and acetylcholine receptor antibody status of patients followed for at least 2 years. Neuromuscul Disord. 2005;15:355-357.
    28. Chou CC, Su IC, Chou IJ, et al. Correlation of anti-acetylcholine receptor antibody levels and long-term outcomes of juvenile myasthenia gravis in Taiwan: a case control study. BMC Neurology. 2019;19:170.
    29. Pitt M. Neurophysiological strategies for the diagnosis of disorders of the neuromuscular junction in children. Dev Med Child Neurol. 2008;50:328-333.
    30. Verma S, Lin J. Stimulated jitter analysis for the evaluation of neuromuscular junction disorders in children. Muscle Nerve. 2016;53:471-472.
    31. Bhatia S, Quinlan H, McCraken C, et al. Serial stimulated jitter analysis in juvenile myasthenia gravis. Muscle Nerve. 2018;58:729-732.
    32. Golnik KC, Pena R, Lee AG, Eggenberger ER. An ice test for the diagnosis of myasthenia gravis. Ophthalmology. 1999;106:1282-1286.
    33. Sethi KD, Rivner MH, Swift TR. Ice pack test for myasthenia gravis. Neurology. 1987;37:1383-1385.
    34. Odel JG, Winterkorn JM, Behrens MM. The sleep test for myasthenia gravis. A safe alternative to Tensilon. J Clin Neuroophthalmol. 1991;11:288-292.
    35. Kubis KC, Danesh-Meyer HV, Savino PJ, Sergott RC. The ice test versus the rest test in myasthenia gravis. Ophthalmology. 2000;107:1995-1998.
    36. Andrews PI. A treatment algorithm for autoimmune myasthenia gravis in childhood. Ann N Y Acad Sci. 1998;841:789-802.
    37. Ionita CM, Acsadi G. Management of juvenile myasthenia gravis. Pediatr Neurol. 2013;48:95-104.
    38. Kupersmith MJ. Ocular myasthenia gravis: treatment successes and failures in patients with long-term follow-up. J Neurol. 2009;256:1314-1320.
    39. Haines SR, Thurtell MJ. Treatment of ocular myasthenia gravis. Curr Treat Options Neurol. 2012;14:103-112.
    40. Wylam ME, Anderson PM, Kuntz NL, Rodriguez V. Successful treatment of refractory myasthenia gravis using rituximab: A pediatric case report. J Pediatr. 2003;143:674-677.
    41. Stieglbauer K, Topakian R, Schäffer V, Aichner FT. Rituximab for myasthenia gravis: Three case reports and review of the literature. J Neurol Sci. 2009;280:120-122.
    42. Iorio R, Damato V, Alboini PE, Evoli A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol. 2015;262:1115-1119.
    43. Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2020: epub ahead of print.
    44. Howard JF Jr., Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomized, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16:976-986.
    45. Mori T, Mori K, Suzue M, Ito H, Kagami S. Effective treatment of a 13-year-old boy with steroid-dependent ocular myasthenia gravis using tacrolimus. Brain Dev. 2013;35:445-448.
    46. Feasby T, Banwell B, Benstead T, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. 2007;21:S57-S107.
    47. Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann Neurol.1997;41:789-796.
    48. Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology.2011;76:2017-2023.
    49. Liew WKM, Powell CA, Sloan SR, et al. Comparison of plasmapheresis and intravenous immunoglobulin as maintenance therapies for juvenile myasthenia gravis. JAMA Neurol. 2014;71:575-580.
    50. Fisher K, Shah V. Pediatric ocular myasthenia gravis. Curr Treat Options Neurol. 2019;21:46.
    51. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375:511-522.
    52. Wolfe GI, Kaminski HJ, Aban IB, et al. Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial. Lancet Neurol. 2019;18:259-268.
    53. Nikolic DM, Nikolic AV, Lavrnic DV, Medjo BP, Ivanovski PI. Childhood-onset myasthenia gravis with thymoma. Pediatr Neurol. 2012;46:329-331.
    54. Sauce D, Larsen M, Fastenackels S, et al. Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest. 2009;119:3070-3078.
    55. Madenci AL, Li GZ, Weil BR, et al. The role of thymectomy in the treatment of juvenile myasthenia gravis: a systematic review. Pediatr Surg Int. 2017;33:683-694.
    56. Pineles SL, Avery RA, Moss HE, et al. Visual and systemic outcomes in pediatric ocular myasthenia gravis. Am J Ophthalmol. 2010;150:453-459.
    57. Ortiz S, Borchert M. Long-term outcomes of pediatric ocular myasthenia gravis. Ophthalmology. 2008;115:1245-1248.
    58. Peragallo JH, Velez FG, Demer JL, Pineles SL. Long-term follow-up of strabismus surgery for patients with ocular myasthenia gravis. J Neuroophthalmol. 2013;33:40-44.