Journal of Pediatric Ophthalmology and Strabismus

Original Article 

A Cluster of Cyclic Esotropia: White Matter Changes on MRI and Surgical Outcomes

Kimberly Merrill, CO; Jill Anderson, MD; Daniel Watson, MD; Raymond G. Areaux Jr., MD

Abstract

Purpose:

To report a series of patients with cyclic esotropia, their surgical outcomes, and incidental findings.

Methods:

The medical records of five patients with cyclic esotropia presenting over 17 months were reviewed. Age at onset, ocular and motility examinations, brain magnetic resonance imaging (MRI), acetylcholine receptor antibodies, thyroid hormone levels and antibodies, calendars documenting phases, surgical treatments, postoperative alignment, and fusion were documented.

Results:

Three boys and two girls presented at 3 to 4 years old in 2015–2016. Typical periodicity followed a 48-hour cycle. Duration of cycling varied from 1 to 9 weeks. Mean maximum deviation was 37 prism diopters (PD) of esotropia (range: 35 to 40 PD of esotropia). All patients had normal laboratory studies. MRIs showed an abnormal white matter signal in the frontal lobes in 2 patients and were normal in the others. Bilateral medial rectus recessions for the maximum angle were successful in 4 patients at a minimum follow-up of 13 months; the other patient required reoperation for a residual esotropia. Fusion was present in 4 patients preoperatively and all postoperatively. Stereopsis was stable or improved in all postoperatively.

Conclusions:

This is the first report of frontal white matter changes occurring in the setting of cyclic esotropia. MRI with attention to frontal lobe white matter might be considered in the work-up of cyclic esotropia to determine if this is a common finding. Bilateral medial rectus recessions can restore fusion in these patients.

[J Pediatr Ophthalmol Strabismus. 2019;56(3):178–182.]

Abstract

Purpose:

To report a series of patients with cyclic esotropia, their surgical outcomes, and incidental findings.

Methods:

The medical records of five patients with cyclic esotropia presenting over 17 months were reviewed. Age at onset, ocular and motility examinations, brain magnetic resonance imaging (MRI), acetylcholine receptor antibodies, thyroid hormone levels and antibodies, calendars documenting phases, surgical treatments, postoperative alignment, and fusion were documented.

Results:

Three boys and two girls presented at 3 to 4 years old in 2015–2016. Typical periodicity followed a 48-hour cycle. Duration of cycling varied from 1 to 9 weeks. Mean maximum deviation was 37 prism diopters (PD) of esotropia (range: 35 to 40 PD of esotropia). All patients had normal laboratory studies. MRIs showed an abnormal white matter signal in the frontal lobes in 2 patients and were normal in the others. Bilateral medial rectus recessions for the maximum angle were successful in 4 patients at a minimum follow-up of 13 months; the other patient required reoperation for a residual esotropia. Fusion was present in 4 patients preoperatively and all postoperatively. Stereopsis was stable or improved in all postoperatively.

Conclusions:

This is the first report of frontal white matter changes occurring in the setting of cyclic esotropia. MRI with attention to frontal lobe white matter might be considered in the work-up of cyclic esotropia to determine if this is a common finding. Bilateral medial rectus recessions can restore fusion in these patients.

[J Pediatr Ophthalmol Strabismus. 2019;56(3):178–182.]

Introduction

Cyclic esotropia was first described in 1845.1 The incidence is 1 in 3,000 to 5,000 cases of strabismus.1 It occurs most frequently in children 3 to 4 years of age.2 When it occurs in adults, onset is usually rapid.3–5 Patients present with alternating periods of orthophoria and esotropia (typically 40 to 50 prism diopters [PD]), no amblyopia, insignificant refractive error, and a normal anatomical eye examination.1,2,6 Other types of heterophoria have been reported.7,8 Periodicity often follows a 48-hour cycle (24 hours of orthophoria, followed by 24 hours of esotropia).1 Cycling has been reported to be as short as 2 weeks to as long as years before becoming a constant deviation.9 Patients usually struggle with depth perception, but diplopia is not usually reported, possibly due to age.10 A strong family history of other types of strabismus has been reported.1 It is important to differentiate this rare phenomenon from other types of acquired esotropia, including sixth nerve palsy, convergence spasm, myasthenia gravis, migraine-related phenomenon, decompensated microtropia or phoria, and intermittent accommodative esotropia.

We report a series of five patients with of cyclic esotropia who presented within a period of 10 months in 2015–2016 at our institution.

Patients and Methods

This study was approved by the institutional review board of our institution and conformed to the requirements of the United States Health Insurance Portability and Accountability Act. We obtained informed consent from parents of all patients to report de-identified medical information. We identified five patients who presented to our clinic with cyclic esotropia. History of onset, ocular examination, motility examination, brain magnetic resonance imaging (MRI) results, results of laboratory studies (acetylcholine receptor antibodies, thyroid hormone levels and antibodies), and calendars documenting cyclic phases were collected for all patients. Parents were asked questions about behavior on esotropic versus orthophoric days. Patients were observed for motility stability, fusion ability (Worth four-dot test, stereopsis measured with the Titmus test), and amblyopia.

Results

Patient characteristics are presented in Table 1. All patients had normal laboratory results (myasthenia gravis panel 5/5, thyroid panel was completed in 4/5 and negative).

Patient Characteristics

Table 1:

Patient Characteristics

Brain MRIs were abnormal in two of the five cases, with both showing abnormal white matter signal in the frontal lobes. These two patients were fraternal twins. Specific MRI description was: T2 hyperintensities in frontoparietal white matter at the level of the basal ganglia and superior, which seem to be consistent with prenatal infectious processes such as cytomegalovirus. Neither twin was cytomegalovirus positive at birth. The twins were delivered at 38 weeks, 1 day and weighed 5 pounds 0.8 ounces and 6 pounds 5 ounces, respectively. One twin was breech and required conversion to caesarian section. Subsequently he developed respiratory distress; chest x-ray performed demonstrating bilateral pneumothoraces and pneumomediastinum. Pneumothoraces resolved without intervention. Further testing was indicated by a pediatric neurologist due to the abnormal white matter signals in the frontal lobe. Subsequent laboratory evaluation for myasthenia gravis and adrenoleukodystrophy were unrevealing. Targeted laboratory studies in these two patients revealed no metabolic disease or genetic abnormality. Testing included leukocyte lysosomal enzyme screen, very long chain fatty acids, urine organic acids, carbohydrate deficient transferrin, genetic testing including karyotyping and next generation sequencing of leukodystrophy-associated genes, and whole exome gene sequencing. MRIs and genetic testing were both repeated 12 months later on both twins. The MRIs remained stable with no further white matter changes. Repeat genetic testing was normal.

Three of the five patients complained of diplopia, irritability, or distress when esotropic. No patient had signs or symptoms of encephalopathy. All but one (M3) had a family history of strabismus. Typical periodicity followed a 48-hour cycle (24 hours orthophoric, 24 hours esotropic).

Details of preoperative alignment and surgical outcomes are provided in Table 2. Fusion was present in all but one patient preoperatively and in all patients postoperatively. The cyclic phase varied from 1 to 9 weeks, and the mean maximum angle of deviation was 37 PD of esotropia. Bilateral medial rectus recessions for the maximum measured angle of esotropia were successful in all five patients; however, one (F1) required a second surgery for a residual esotropia.

Alignment, Surgery, and Outcomes

Table 2:

Alignment, Surgery, and Outcomes

Hyperopic spectacles were prescribed for three of the five patients preoperatively (F1, F2, and M3). Two patients (F1 and F2) had a minimal accommodative component to their esotropia. One patient (M3) had a low hyperopic correction and spectacles were discontinued when the angle of deviation and cyclic pattern did not change. One patient (F2) remained in spectacles postoperatively. This patient still has an accommodative component to her esotropia, showing 100 arc sec of stereoacuity with spectacles. Patient M1 had a residual variable microtropia for 6 months with progressively elongating periods of orthophoria. For the past 8 months, no esotropia has been noted at home and his examinations have shown orthophoria to a small exophoria of 2 to 6 PD over the past 15 months.

Discussion

Case reports of cyclic esotropia have been described in the literature, but only two large case series have been reported. Helveston6 surveyed 61 ophthalmologists to search for cases of cyclic esotropia. His survey had 40 respondents, of which only seven had ever seen a patient with cyclic esotropia. He found characteristics that resembled accommodative esotropia, average age of onset was 3 to 4 years old, average angle of deviation was 35 PD, and cyclic phase was every 48 hours. The other large report by Roper Hall and Yapp11 reported on 12 cases of cyclic esotropia in the United Kingdom. Six of the patients in Roper Hall and Yapp's series described “behavioral problems,” with two of those patients showing behavior changes when they had a manifest strabismus. Abnormal electroencephalograms were also shown on those two patients with recurring alternate day phases. We describe five patients with cyclic esotropia, three of whom were symptomatic when in their esotropic phase. These children were not the ones with frontal lobe changes on brain MRI. It is unclear why these two patients were not symptomatic when tropic.

Cyclic esotropia is thought to result from an aberration of the biological clock.5 Periodic biological phenomena are numerous. For example, temperature, sweating, pulse, salivation, and mood are known to cycle.1 A case report of a child whose cyclic esotropia pattern changed after traveling across six times zones has been reported.2 The biological clock is believed to reside in the hypothalamus. One case of normal extensive testing and imaging of the hypothalamichypophyseal axis in a patient with cyclic esotropia has been reported.12 Other theories include cyclic abducens palsy,13 ocular myotonia,8 and cerebral adaptation to a peripheral visual field defect.5

Bilateral medial rectus recession for the maximum measured angle of esotropia was successful in all five patients. Four of five of our patients had progressed to constant manifest deviations when surgery was performed. Only one patient (M3) had surgery while still in the cyclic phase. All seven patients described by Helveston responded well to surgical correction with bilateral medial rectus recessions or recess-resect procedures. One of these patients required three surgeries. Six of these patients responded to spectacles and one to spectacles with hydroxyzine.6 Eight of the 12 patients in Roper Hall and Yapp's series11 were treated surgically with slightly different surgical techniques but all had functional outcomes. Cahill et al.16 reported a recurrence of cyclic esotropia. The patient remained orthophoric for 16 months, then became cyclic esotropia, cycled for another 18 months, and then repeated surgery.

Other findings have been associated with cyclic esotropia. It has been reported after surgery for intermittent exotropia.17,18 Surgeries, including intraocular lens implantation after a traumatic cataract and scleral buckling for a retinal detachment, have also been reported precipitating cases of cyclic esotropia.3,4,17,18 Kee and Hwang19 reported a decompensated accommodative esotropia that become cyclic. Other neurological associations that have been reported include optic atrophy, brain tumor, seizure disorders, craniofacial surgery, mild cerebral palsy, third ventricular astrocytoma resection, and cerebellar lesions.4,20,21 This is the first report of frontal lobe white matter changes associated with cyclic esotropia. This may be a coincidental finding, especially since the patients are twins.

Conjugate contralateral eye movements originate in the frontal eye fields.22 Frontal eye field lesions in humans have shown to cause an increased in latency of saccades. The role of the frontal eye fields in generating voluntary saccades has been shown in humans and rhesus monkeys.23 Likewise, cognitive mechanisms shown to be related to sleep function are part of the frontal lobe function.24 We theorize that white matter lesions in the frontal lobe may have disrupted eye movements and/or sleep cycles that could have resulted in cyclic esotropia in our two patients with frontal lobe lesions.

Non-surgical treatments for cyclic esotropia have been suggested. Botulinum toxin A has been reported to break the cycle, with the patient remaining esophoric for more than 1 year.25 Another patient reported temporary relief with two injections of botulinum toxin A, but then developed a constant esotropia 2 months after the second injection.26 One case report included spontaneous resolution after 1.5 years.21 Another report noted that the cycle was broken after prescribing prisms for the esophoric deviation on days without a manifest deviation.27 Finally, adults with electromyographic findings suggestive of neuromyotonia have been reported to show a response to carbamazepine and gabapentin.8

Limitations of our study include the small sample size, retrospective nature of this review, and short-term follow-up. Two patients did not demonstrate “classic” cyclic esotropia patterns. Patient F2 presented with a partially accommodative esotropia and a convincing cyclic phase of 6 weeks. Patient M1 had a short cyclic phase, but we believe moderate amblyopia drove him to become constant sooner than his twin.

This is the largest case series of cyclic esotropia reported in North America at a single institution. In our patients, cycles usually repeated every 2 to 3 days, the duration of the cyclic phase varied from 1 to 9 weeks, and there were family histories of strabismus. Non-specific white matter changes were found in two fraternal twins. Future studies may determine whether this is a common finding occurring in association with cyclic esotropia. The mean maximum angle of deviation was 37 PD of esotropia, and fusion (central or peripheral) was maintained postoperatively in all cases. Amblyopia occurred in three patients. It is possible that an initial cycling pattern is present with some frequency in later-onset esotropia and may facilitate the family's delay to clinical evaluation until a constant tropia is manifest. Finally, we are unsure what caused this surge of cyclic esotropia at this institution.

References

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Patient Characteristics

PatientAge at Presentation (y)Cyclic PatternOnsetFamily History of StrabismusMRILab StudiesAmblyopiaFusion on Straight DaysBehavior on ET Day
F1324 hrs ET, 24 hrs orthotropicMay 2016Maternal aunt-exotropia, MGF-strabismusNormalNormalMildW4D–presentTantrums, upset, monocular eyelid closure
M13.5VariedSept 2015Fraternal twin-cyclic ETFrontal lobe changesNormalModerateNANormal
M23.524 hrs ET, 24 hrs orthotropicJune 2015Fraternal twin-cyclic ETFrontal lobe changesNormalMildStereo-100″Normal
F2424 hrs ET, 24 hrs orthotropicOct 2016Fraternal twin-AETNormalNormalAbsentStereo-100″Diplopia complaints
M3324 hrs ET, 48 hrs orthotropicOct 2016AbsentNormalNormalAbsentStereo-100″Tired/upset

Alignment, Surgery, and Outcomes

PatientLargest Angle (PD)No. of Visits Prior to SurgeryPattern Prior to SurgerySurgeryAlignment and Sensory Statusa

3–5 Mo PostopLast Visit (Mo After Surgery)
F135 ET61st week ET on alternate days; 2nd week ½ days; 3rd week variable; 4th week constantAug 2016: BMRc 5.3, RIOc; Feb 2017: BMRc reoperate to 11.5 mm from limbus, LIOccc: ortho, ortho'; stereo: 80″17 mo: sc: ortho, ortho'; stereo: 50″
M140 ET91st 4 weeks intermittent ET; 5th week cyclic ET; next 16 weeks constant ETJune 2016: BMRc 6.0sc: ortho, ortho'; stereo: 100″20 mo: sc: X6, ortho'; stereo: 60″
M235 ET101st week constant ET; 2nd week ortho; next 4 weeks cyclic ET; next 20 weeks constant ETMay 2016: BMRc 6.0sc: X6, X'4; W4D: fuses d/n; stereo: nil21 mo: sc: ortho, ortho'; stereo: 60″
F235 ET41 yr accommodative ET; 6 weeks cyclic ET; next 5 weeks constant ETFeb 2017: RMRc 6.0, LMRc 5.5cc: E(T)6, E(T)'10, add ortho'; stereo: 100″13 mo: cc: E4, E'10; stereo: 100″; sc: ET'25, ET 30
M340 ET91 to 2 weeks intermittent ET; next 9 weeks cyclic ET; surgery in cyclic phaseFeb 2017: BMRc 6.5sc: ortho, E'1; stereo: 40″15 mo: sc: ortho, ortho'; stereo: 40″
Authors

From the Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota.

Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York.

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: Kimberly Merrill, CO, 701 25th Ave. South, Suite 300, Minneapolis, MN 55454. E-mail: kmerrill@umphysicians.umn.edu

Received: November 20, 2018
Accepted: January 24, 2019

10.3928/01913913-20190211-01

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