Visual and Systemic Outcomes in Pediatric Ocular Myasthenia Gravis




Purpose


To evaluate visual and systemic outcomes in pediatric patients with purely ocular myasthenia gravis (OMG) treated at the Children’s Hospital of Philadelphia.


Design


Retrospective chart review.


Methods


Pediatric patients with OMG seen at a single institution over a 16-year period with a minimum follow-up of 1 year were reviewed. Associations of demographic and clinical characteristics with disease resolution, amblyopia, and development of generalized symptoms of myasthenia gravis were analyzed.


Results


Thirty-nine patients were identified, with a mean age of 5.4 ± 4.8 years and mean follow-up of 4.8 ± 4.3 years. Fifteen patients were treated with pyridostigmine only, 19 (49%) also received steroids, and 15 (38%) underwent thymectomy. Four patients (10%) received steroid-sparing immunosuppressive therapy. Resolution occurred in 10 patients, and generalized symptoms eventually occurred in 9 patients. Although 10 patients were treated for amblyopia, only 1 had amblyopia at the final visit. There was no correlation between sex or age with amblyopia or development of generalized symptoms. Thymectomy, when performed before the onset of generalized symptoms, showed a trend toward protection from the development of generalized symptoms ( P = .07).


Conclusions


In our series, 24% of patients had disease resolution and 23% had generalized symptoms. Our larger cohort confirms previous findings that treated and untreated pediatric patients with OMG have a relatively low risk of developing generalized symptoms and that related amblyopia is readily reversible. Although our treatments were more aggressive than those previously reported, our rates of amblyopia and development of generalized symptoms are comparable.


Myasthenia gravis is an acquired autoimmune disorder in which acetylcholine receptors (AChRs) within the neuromuscular junction of skeletal muscle are targeted by autoantibodies. This results in disrupted neuromuscular transmission and symptoms of fluctuating and fatigable weakness. Myasthenia gravis is relatively uncommon in the pediatric population, with children accounting for approximately 10% to 15% of cases annually. Approximately 90% of children with myasthenia gravis will have ophthalmic features, such as ptosis or ophthalmoplegia, in isolation, or in association with other systemic weakness. In 10% to 15% of children, weakness is strictly limited to the extraocular muscles, resulting in a diagnosis of ocular myasthenia gravis (OMG). One group has suggested that in 50% of pediatric patients with OMG, systemic or bulbar symptoms will develop within 2 years.


Data regarding the treatment and prognosis of children with OMG at initial presentation is limited. There are a few case series, of fewer than 25 patients, that specifically describe the characteristics and outcomes of relatively small cohorts of pediatric patients with OMG. Because we have seen a relatively larger number of children with OMG at the Children’s Hospital of Philadelphia and many of our patients have undergone more aggressive treatment regimens than those published by previous groups, we sought to compare our outcomes with those previously reported. Finally, we set out to evaluate risk factors for the development of undesirable outcomes, such as amblyopia and development of generalized symptoms.


Methods


Records were reviewed for all patients 1 to 18 years of age with at least 1 year of follow-up and a diagnosis of OMG who were seen by one of the coauthors (G.T.L.) from July 1993 through September 2009 at the Children’s Hospital of Philadelphia. Pediatric OMG is also often referred to as juvenile OMG to differentiate it from congenital myasthenic syndromes and neonatal myasthenia. To meet inclusion into the study, patients had to satisfy all of the criteria described in Table 1 for the diagnosis of pediatric OMG. Children with congenital or neonatal myasthenia (with an onset less than 6 months of age) were excluded. Our criteria represent a modification of the Myasthenia Gravis Foundation of America clinical classification and other published criteria for adults. Modifications were based on differences in evaluating children and adults with OMG, for example, relative difficulty in obtaining single-fiber electromyography in children. Patients were excluded from this retrospective review if they had systemic or bulbar weakness preceding ocular symptoms.



TABLE 1

Criteria for Diagnosing Pediatric Ocular Myasthenia Gravis a







  • 1

    One of the following must be present:



    • a

      Ptosis in one or both upper lids not resulting from local disease, with or without fatigability and recovery with rest, by history or examination.


    • b

      Extraocular muscle weakness, with or without fatigability and recovery with rest, and the absence of an alternative explanation for the duction abnormality, often including negative neuroimaging in questionable cases.



  • 2

    No pupillary abnormalities except from prior ocular disease, surgery, or physiologic anisocoria.


  • 3

    Positive results from 1 of the following confirmatory tests:



    • a

      Fatigue of the affected muscle with worsening of ptosis after prolonged upward gaze, or worsening of duction abnormality after prolonged gaze using the affected extraocular muscle,


    • b

      Recovery of ptosis or ductional deficits after prolonged rest,


    • c

      Positive edrophonium test,


    • d

      Abnormal repetitive nerve stimulation,


    • e

      Abnormal acetylcholine receptor binding antibody level.



  • 4

    Age at presentation between 1 and 18 years.


  • 5

    Lack of generalized symptoms at disease onset.


a Modification of previously published criteria for adult ocular myasthenia gravis.



In general at our institution, pediatric patients suspected of having OMG first undergo AChR antibody testing as a confirmatory test. If the antibody level is within normal limits, patients often are sent for repetitive nerve stimulation testing. In the pediatric population, single-fiber electromyography of the orbicularis oculi usually is not tolerated; therefore, repetitive nerve stimulation of the upper extremity often is performed. If both of the preceding tests demonstrate negative results, patients may undergo edrophonium testing, in which edrophonium is injected intravenously, and then measurements of eyelid position, ocular ductions, and alignment are repeated in attempt to evaluate for improvement. Finally, if diagnostic testing shows negative, equivocal, or unobtainable results, an improvement in ptosis or extraocular muscle weakness after a period of rest (i.e., a so-called rest test) often is used as a confirmatory test. After the diagnosis of pediatric OMG is established, the first step in our treatment protocol is to determine whether any treatment is indicated. In general, children are treated if their ptosis or ophthalmoplegia is potentially amblyogenic. Therefore, if the ptosis is observed by us, or a parent, to be occluding the visual axis at any time, or if the child has any degree of manifest strabismus, treatment is initiated. However, if reliable visual acuity measurements can be obtained and visual acuity is symmetric between both eyes, then we might consider a period of careful observation. Additionally, anomalous head postures attributed to ptosis or strabismus and diplopia are indications for treatment. Those with mild ptosis and normal ocular alignment in primary gaze usually are left untreated and are observed.


All patients requiring treatment initially are started on pyridostigmine (2 to 4 mg/kg/day in divided doses). Depending on the severity of the symptoms, children are followed up approximately 1 to 8 weeks later. Additionally, a chest magnetic resonance imaging examination usually is ordered to evaluate for thymic hyperplasia or thymoma. If the symptoms do not improve, or if there is any worsening of the symptoms, steroids are recommended. If thymus abnormalities are found, a thymectomy is considered at this time. After the symptoms are controlled by steroids, an attempt to wean the steroids often is undertaken. If the symptoms cannot be controlled on a low dose of steroids, then other immunosuppressants are introduced, and thymectomy is considered. At our institution, thymectomies for younger children with myasthenia gravis are performed transthorascopically without a sternotomy, and in older children, they are performed transcervically. Because these procedures are considered relatively safe and leave minimal scars, we have a low threshold for noninvasive thymectomy, even in children with solely OMG, as a means by which to reduce the amount of medication required, to minimize chronic steroid side effects, and possibly to decrease the risk of generalized symptoms.


For each patient, data were recorded from the first clinic visit, including: the age at presentation, ocular and systemic symptoms, visual acuity, stereoacuity, ocular ductions, ocular alignment, and the presence of ptosis. For verbal children, visual acuity was measured using projected optotypes appropriate for age (ie, Snellen letters, H-O-T-V, or Lea symbols). For preverbal testing, Teller acuity was measured. If Teller acuity could not be measured, then fixation behaviors were tested. Subsequent visits were reviewed for changes in visual acuity, ptosis, strabismus, ocular alignment, and ductions. In addition, data regarding various treatments initiated, onset of new symptoms (including generalized ones), or resolution of symptoms was noted. As a rule, we tend to use the term generalized symptoms instead of systemic generalization because we can not be sure whether systemic generalization is masked by treatment. Generalized symptoms include muscular weakness, generalized fatigue, or bulbar symptoms (difficulty breathing, swallowing, or chewing). Disease remission was diagnosed in patients who were completely asymptomatic and had not received any treatments for at least 1 year, without ptosis, extraocular muscle weakness, strabismus, or generalized symptoms. Amblyopia was defined as a 2-line or more difference in best-corrected visual acuity between each eye. In preverbal children in whom Teller acuity testing was not performed, amblyopia was defined as a failure to hold fixation with either eye. Additionally, any treatment-related complications were noted. The patient’s disease status at the final visit was classified using a modification of the Myasthenia Gravis Foundation of America postintervention status categories. Patients were categorized into one of the following final outcomes: complete stable remission, ocular minimal manifestations (MMs) with medications, ocular MM without medications, or persistent generalized symptoms.


Logistic regression models were created to evaluate for associations between disease outcomes (resolution, generalized symptoms, and amblyopia) and individual patient characteristics (age, sex, follow-up length, diagnostic test responses, and treatment type). Analysis was carried out using Stata-10 statistical software (StataCorp, College Station, Texas, USA). A P value of .05 or less was considered a statistically significant association.




Results


A summary of patient characteristics is presented in Table 2 . Thirty-nine patients meeting the study inclusion criteria were identified. Eighteen patients (46%) were male, and the mean age at presentation was 5.4 ± 4.8 years (range, 1 to 17 years), with 7 patients (18%) who were 12 years of age or older at the time of presentation. The age distribution is presented in the Figure . The mean follow-up time was 4.8 ± 4.3 years (range, 1 to 17 years).



TABLE 2

Patient Characteristics for Pediatric Ocular Myasthenia Gravis





































Characteristic Values
Gender 18 male, 21 female
Age at onset (yrs) 5.4 ± 4.8 (range, 1 to 17)
Follow-up (yrs) 4.8 ± 4.3 (range, 1 to 17)
Abnormal AchR antibody level 15/31 abnormal results (48%)
Positive edrophonium test 16/18 positive results (88%)
Abnormal repetitive nerve stimulation 2/7 abnormal results (29%)
Generalized symptoms 9/39 (23%)
Disease resolution 10/39 (26%)
Amblyopia diagnosis at any time 10/39 (26%)
Amblyopia at final visit 1/39 (3%)

AChR = acetylcholine receptor.



FIGURE


Bar graph showing the distribution of patient ages at the time of presentation with ocular myasthenia gravis. Shaded areas indicate the number of patients who experienced generalized symptoms at any point during their clinical course.


On presentation, all of our cases had ptosis. Strabismus in primary position was present in 22 (56%) patients, and ocular duction deficits were present in 20 (51%) patients. AChR antibody testing was performed in 31 patients, 15 of whom had an abnormally high level (48% sensitivity). Repetitive nerve stimulation was performed in 7 patients, with 2 patients showing an abnormal response (29% sensitivity). Finally, edrophonium testing was performed in 18 patients, 16 of whom had a positive response with improvement in ptosis or ophthalmoplegia (88% sensitivity). Characteristics of patients who had abnormal versus normal results of AChR antibody testing are presented in Supplemental Table (Supplemental Material at AJO.com ).


Generalized symptoms developed in 9 (23%) patients, manifested by generalized hypotonia (n = 1), bulbar symptoms (n = 6), and extremity weakness (n = 2). The mean time to generalized symptoms was 0.75 ± 0.6 years (range, 1 month to 2 years). The age distribution for those patients who experienced generalized symptoms is depicted by shading in the Figure . Ten subjects (26%) had complete resolution of symptoms without medication for at least 1 year. The mean time to resolution was 2.3 ± 1.5 years (range, 3 months to 5 years). At the final follow-up visit, of those patients whose disease had not resolved, 7 had MM without any medications, 21 had MM with medication, and 1 patient had generalized symptoms (systemic weakness). During the follow-up period, 10 patients (26%) were treated for amblyopia with occlusion therapy. At the final visit, 1 patient (3%) had residual amblyopia (> 2 lines difference in visual acuity). The age of OMG onset for patients treated for amblyopia ranged from 1 to 6 years. At the final follow-up visit, 6 (15%) had manifest strabismus, and 18 (46%) had some degree of ptosis. Two cases had thymic hyperplasia. One case of thymic hyperplasia was identified on preoperative magnetic resonance imaging (enlarged thymus), and the second case was identified in the postthymectomy pathologic analysis (follicular hyperplasia). No thymomas (epithelial cell tumor of the thymus) were identified in our series.


A summary of treatment regimens in our cases is presented in Table 3 . Medical treatment was initiated in all but 5 cases. All untreated cases were considered too mild to warrant therapy. The remaining 34 patients initially were treated with pyridostigmine. Steroid treatment was added to pyridostigmine in 19 cases. In addition, 15 patients underwent thymectomy. Finally, 4 patients received long-term steroid-sparing agents such as azathioprine (n = 1), cyclosporine (n = 1), mycophenolate mofetil (n = 1), or monthly intravenous immunoglobulin (n = 4). All of the cases that received long-term steroid-sparing treatments had generalized symptoms before initiation of the agent. The reason for proceeding to thymectomy in those patients who underwent thymectomy was either a lack of symptomatic improvement on pyridostigmine and steroids (n = 8), generalized symptoms (n = 6), or thymic hyperplasia with failure to improve with pyridostigmine (n = 1). There were no reported complications of treatment other than diarrhea associated with pyridostigmine.



TABLE 3

Treatment Outcomes for Pediatric Ocular Myasthenia Gravis



















































































Treatment Amblyopia at Any Time during Follow-up Generalized Symptoms at Any Time during Follow-up Outcome at Most Recent Follow-up
CSR MM without Medications MM with Medications Generalized Symptoms Amblyopia
No treatment (n = 5) 0 0 2 3 0 0 0
Pyridostigmine (n = 15) 1 1 4 2 9 0 0
Pyridostigmine + steroid (n = 3) 1 1 2 0 1 0 0
Pyridostigmine + steroid, other immunosuppressive (n = 1) 0 1 0 0 0 1 (systemic weakness) 0
Pyridostigmine + steroid + thymectomy ± other immunosuppressive (n = 15) 8 6 2 2 11 0 1
Generalized + amblyopia = 4



  • Generalized only = 2



  • Amblyopia only = 4

Total 10 9 10 7 21 1 1

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Jan 17, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Visual and Systemic Outcomes in Pediatric Ocular Myasthenia Gravis
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