Strabismus Surgery in Patients With Ocular Neuromyotonia: Potential Unmasking of the Condition and Effective Management Tool

Classically defined as bilateral, symmetric, and progressive ophthalmoparesis with myopathic ptosis, chronic progressive external ophthalmoplegia (CPEO) rarely has been reported in the absence of ptosis. We describe 2 patients with CPEO and without ptosis who presented with binocular diplopia related to small-angle esodeviations, poor fusional amplitudes, and slow saccades. In both cases, hematological studies and neuroimaging ruled out alternative etiologies, whereas muscle biopsy showed findings of mitochondrial myopathy.

Original Contribution Strabismus Surgery in Patients With Ocular Neuromyotonia: Potential Unmasking of the Condition and Effective Management Tool J. Anna Kim, MD, Federico G. Velez, MD, Stacy L. Pineles, MD Background: Ocular neuromyotonia (ONM) is a rare motility disorder in which paroxysms of tonic extraocular muscle contraction from abnormal ocular motor nerve firing result in episodic diplopia and strabismus. Medical therapy with membrane-stabilizing agents has varied success. A surgical approach to treatment has not yet been described. We report the outcomes of strabismus surgery in patients with ONM. Methods: We describe 3 patients with sixth nerve paresis and ONM of the affected lateral rectus muscle who underwent strabismus surgery. All patients had a history of radiation therapy for intracranial tumors. Ophthalmologic and orthoptic examinations were performed with appropriate medical and neuroradiologic evaluation. Preoperative and postoperative data are presented and analyzed. Results: Two patients were noted to have ONM after their first strabismus surgery for a sixth nerve palsy. Patients 1 and 2 had 3 surgeries, whereas Patient 3 had 1 operation. Extraocular muscles operated on included the medial rectus and lateral rectus. Preoperative primary gaze baseline esotropia ranged from 35 to 75 prism diopters (D). All patients achieved improvement in ocular alignment and motility. Postoperative primary gaze deviations ranged from orthotropia to 20D of esotropia. Abduction deficits were unchanged or improved. The follow-up period ranged from 15 months to 2 years. Conclusions: Patients with ONM of a paretic rectus muscle can achieve binocular fusion with strabismus surgery. ONM may manifest postoperatively in patients with a sixth nerve palsy and a contractured medial rectus who, preoperatively, were not noted to have ONM. Journal of Neuro-Ophthalmology 2016;36:259-263 doi: 10.1097/WNO.0000000000000371 © 2016 by North American Neuro-Ophthalmology Society Jules Stein Eye Institute and Department of Ophthalmology, University of California, Los Angeles. S. Pineles grant support: NIH/NEI K23EY021762, Knights Templar Eye Foundation, Research to Prevent Blindness (RPB), Velez grant support: RPB unrestricted grant. The remaining authors report no conflicts of interest. Address correspondence to Stacy L. Pineles, MD, Stein Eye Institute, 100 Stein Plaza, David Geffen School of Medicine at UCLA, Los Angles, CA 90095-7002; E-mail: [e-mail] Kim et al: J Neuro-Ophthalmol 2016; 36: 259-263 O cular neuromyotonia (ONM) is a rare motility disorder characterized by episodic diplopia and strabismus due to involuntary, tonic extraocular muscle contraction, and delayed relaxation from brief repetitive firing of an ocular motor nerve. The paroxysms may occur spontaneously or be triggered by sustained gaze in the direction of the affected muscle (1). Treatment with membrane-stabilizing agents, such as carbamazepine and gabapentin, is frequently limited by pharmacological intolerance, recurrence on discontinuation, or a failed therapeutic response (2,3). Spontaneous resolution of ONM is uncommon (3-7). Surgical correction of an underlying deviation is challenging because the ocular alignment can vary at baseline and between the spasmodic and relaxation phases. In addition, the effect of strengthening or weakening procedures on an extraocular muscle with neuromyotonia is not predictable. We report the outcomes in patients who underwent strabismus surgery for esotropia secondary to sixth nerve paresis with abducens neuromyotonia. METHODS A retrospective medical record review was conducted on all patients diagnosed with ONM of the lateral rectus muscle who underwent strabismus surgery at the Stein Eye Institute between 2009 and 2014. All patients underwent a complete ophthalmologic examination and were diagnosed with ONM during the strabismus evaluation. Diagnosis was based on a clinical finding of lateral rectus muscle spasm triggered by sustained gaze and causing restriction to adduction, in addition to medical history identifying known risk factors, such as cranial irradiation. There were no exclusion criteria. The study was approved by the University of California-Los Angeles Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. The following preoperative and postoperative characteristics were recorded from the patients' charts: age at surgery, best-corrected visual acuity, preoperative motor alignment 259 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution at distance and near and in the cardinal positions of gaze, and an assessment of ocular ductions. Ocular ductions were measured using a standard 4-point scale. Forced duction testing was performed intraoperatively and graded on a scale of 0 to 24 (8). In addition, details of the surgical procedure, adjustment amount (if required), and postoperative ocular alignment and ductions were recorded. Any postoperative complications were recorded. RESULTS Characteristics of 3 patients with ONM who underwent strabismus surgery are summarized in Table 1. All patients had a history of an intracranial neoplasm treated by resection and irradiation and demonstrated abducens neuromyotonia in the setting of a sixth nerve paresis. The mean delay in onset of neuromyotonia after radiation was 10.3 years (range: 6-13 years). Medical management failed to control the spasms in all patients. Patients 1 and 2 had 3 surgeries. Patient 3 underwent 1 operation. In 2 cases, the ONM was diagnosed after strabismus surgery. In both of these cases, forced duction testing revealed restriction to abduction intraoperatively. All patients underwent recession of the ipsilateral medial rectus in combination with a strengthening procedure of the affected lateral rectus muscle. Two patients underwent bilateral surgery. Primary gaze deviations ranged from 35 to 75 prism diopters (D). All patients achieved improvement in ocular alignment and motility. Postoperative primary gaze deviations ranged from orthotropia to 20D of esotropia. Lateral incomitance was reduced in all patients. The follow-up period ranged from 15 months to 2 years. CASE REPORTS Patient 1 A 44-year-old woman underwent 3 surgeries for removal of a pituitary adenoma with extension into the left cavernous sinus followed by stereotactic radiosurgery. Six months later, she developed diplopia due to a right sixth nerve palsy. Positron emission tomography showed no evidence of tumor recurrence, but fluid-attenuated inversion recovery and T2 magnetic resonance imaging demonstrated evidence of radiation necrosis in the medial aspect of both temporal lobes. Seven months after onset of diplopia, the patient was documented to have an esotropia of 35D. She underwent a 7.5 mm right lateral rectus resection and a 5.0 mm left medial rectus recession. This resulted in an undercorrection, so a second surgery was performed consisting of 7.0 mm left lateral rectus resection and a 4.0-mm right medial rectus recession. Five years later, the patient returned with complaints of horizontal diplopia at distance and near, which had been 260 progressively worsening over a 2-year period. She had an esotropia of 18D in central and right gaze and was orthotropic in left gaze. Ocular rotations showed mild limitation to abduction bilaterally. After sustained lateral gaze to either side, the patient developed a large angle exotropia with significant limitation to adduction in the abducted eye (22 to 23). Her presentation was consistent with bilateral abducens ONM with bilateral sixth nerve palsies. Serologic testing for myasthenia gravis and Graves disease was negative, and neuroimaging showed no evidence of tumor recurrence. Treatment with carbamazepine failed to resolve her symptoms. She elected to undergo strabismus surgery for her esotropia. Intraoperative forced duction testing was positive in abduction (21) bilaterally. Both medial rectus muscles were recessed from 12 to 15 mm posterior to the limbus. Postoperatively, the patient was orthotropic in central gaze and had a 4D exophoria in left gaze and a 4D esophoria in right gaze. Prolonged eccentric gaze did not elicit neuromyotonia. Over 2 years, ocular motility and alignment here remained stable. Patient 2 A 56-year-old woman with a 12-year history of diplopia due to nasopharyngeal carcinoma had undergone craniotomy, chemotherapy, and radiotherapy. On examination, alignment was highly variable. The largest amount of esotropia measured 75D at distance and 85D at near. There were also times she was completely orthotropic or even slightly exotropic. Ocular rotations demonstrated significant limitation to abduction in the right eye and very slow abducting saccades. During sustained right gaze, abduction improved and the esotropia resolved. With return to central gaze, there was limited adduction of the right eye, but after sustained gaze to the left, the patient regained full adduction. Treatment with carbamazepine (200 mg twice daily) yielded no improvement in alignment or in reducing the frequency and severity of spasms. During strabismus surgery, forced duction testing was normal, and both medial rectus muscles were recessed 5.5 mm. Postoperatively, the esotropia measured 14D at distance and 35D at near. It was not clear why there was a much larger deviation at near, but we speculated it could be due either to innervational imbalance or mild subclinical neuromyotonia of the medial rectus muscles. Initially, the patient reported significant improvement in her ability to control the spasms with longer periods of orthotropia. However, gradually there was an increase in diplopia and, once again, carbamazepine was ineffective. Therefore, both medial recti were recessed to a position 15 mm posterior to the limbus. In addition, a posterior fixation suture on the right lateral rectus muscle at 8 mm from the insertion to reduce the exotropia in lateral gaze. Postoperatively, there was an esotropia of 2D at distance, orthotropia at near, and the Kim et al: J Neuro-Ophthalmol 2016; 36: 259-263 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Kim et al: J Neuro-Ophthalmol 2016; 36: 259-263 TABLE 1. Clinical features of patients with ocular neuromyotonia undergoing strabismus surgery Case 1 2 3 Diagnosis Preoperative Preoperative Preoperative Resting Resting Neuromyotonia Deviation (D)* Rotations Preoperative Spasmodic Deviation Preoperative Spasmodic Rotations Surgeries Performed BLR paresis (invasive pituitary adenoma) BLR paresis (nasopharyngeal carcinoma) BLR ET 18 ortho, Limited LG ET9 12 adduction (21)‡ OU Large angle XT Limited adduction OU (22) RLR Limited RET 75, RET9 85, RET abduction 45, LG RET (25) OD 100, RG Large angle XT LLR paresis (clival chordoma) LLR LET 30, LHT 4,Limited LET9 16, abduction (23) OS LHT9 2 n/a§ Limited abduction (22) and limited adduction (21) OD n/a§ FDT Postoperative Alignment and Motility Followup† (mo) RMRc 3.0 mm 21 to Ortho distance, ortho near, 24 (12-15 mm PTL), abduction rotations unchanged, LMRc 3.0 mm OU no OMN elicited/reported (12-15 mm PTL)║ 8.5 Ortho distance, ortho to X(T)' #1: BMRc 5.5 mm, 0 25, improved abduction (21) #2: BMRc 5.0 OD, limited adduction (21) mm, RLR faden 8 OU, reduced OMN episodes¶ mm, #3: RLR plication LET 12, ortho near, rotations LMRc 5.5 mm with 21 to unchanged, reduced OMN abduction inferior episodes¶# OS transposition,║ LLR plication║ 8 261 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution *Gaze incomitance of $10D noted when present. † Postoperative follow-up from last strabismus surgery. ‡ Previous history of strabismus surgery: left medial rectus recession 5.0 mm and right lateral rectus resection 7.5 mm, right medial rectus recession 4.0 mm on adjustable suture and left lateral rectus resection 7.0 mm. § OMN presented after strabismus surgery. ║ Muscle placed on an adjustable suture. ¶ Reduced frequency and magnitude of ocular deviation. # On treatment with carbamazepine. BLR, bilateral lateral rectus; BMRc, bilateral medial rectus recession; FDT, forced duction test; LET, left esotropia; LG, left gaze; LHT, left hypertropia; LLR, left lateral rectus; LMRc, left medial rectus recession; OD, right eye; OMN, ocular neuromyotonia; OS, left eye; OU, both eyes; PTL, posterior to limbus; RET, right esotropia; RG, right gaze; RHT, right hypertropia; RLR, right lateral rectus; RMRc, right medial rectus recession; XT, exotropia. Original Contribution patient reported single vision most of the time. ONM could still be elicited, but the resultant deviation was greatly reduced. Over the next 4 months, the patient had an intermittent esotropia that varied from a small phoria to 25D in primary position with lateral incomitance in right gaze. A third surgical procedure involved take down of the posterior fixation suture and a right lateral rectus plication of 3.5 mm. Postoperatively, she was orthotropic in all gaze positions, and the abduction deficit improved to full rotation. At 9-month follow-up, ocular alignment and motility remained stable, and the patient noted only rare recurrence of spasms. Patient 3 A 77-year-old woman with a history of a clival chordoma status after resection, radiation, and gamma knife treatment 15 years prior was evaluated for a 2-year history of binocular horizontal diplopia. She had 30D of left esotropia and 4D of left hypertropia at distance, 16D of left esotropia and 2D of left hypertropia at near, and exhibited a left face turn of 10°. Ocular rotations were full except for limited abduction of the left eye (22). Maddox rod testing revealed no evidence of ocular torsion, and there was no change in eye position after sustained eccentric gaze. The patient underwent a left medial rectus recession of 5.5 mm with a 2.0 mm inferior transposition and a left lateral rectus plication of 6.0 mm. Intraoperative forced duction testing revealed mild restriction to abduction (21). Postoperatively, she was orthotropic in all gaze positions except in left lateral gaze where she measured 8D of esotropia. Abduction was improved but not full (21). Four months after surgery, she returned with complaints of recurrent diplopia. On examination, she demonstrated a greater limitation to abduction of the left eye (22) and a left esotropia of 20D increasing in left gaze. With sustained left gaze, she developed an exotropia in primary position with significant limitation to adduction of the left eye, consistent with a left abducens ONM. Carbamazepine did help to reduce the spasms but was discontinued because of hyponatremia. At 15 months after surgery, her deviation measured 20D of esotropia and the ONM could no longer be elicited. DISCUSSION In our review of the literature, 50% of reported cases of ONM had ocular misalignment in primary gaze (1-3, 5- 36). There are 4 single case reports of strabismus surgery in patients with ONM and an additional case series of strabismus surgery in 3 patients with a cyclic vertical deviation that the authors describe as a "forme fruste ocular neuromyotonia" (3,6,7,30,36). All 7 patients had undergone recession of the neuromyotonic muscle with resolution of paroxysms postoperatively. 262 These results suggest that weakening the neuromyotonic muscle may ameliorate spasms by reducing the resting tension or the force that the muscle is able to generate. If the converse is true of strengthening procedures, a resection or plication might exacerbate the paroxysms. This presents a dilemma for the surgeon when trying to correct esotropia due to a sixth nerve palsy, but the paretic muscle also demonstrates neuromyotonia. In 2 of our patients, recession of the medial rectus and resection of the lateral rectus was performed as the initial operation, and ONM did not appear until 4 months and 2 years in Patients 3 and 1, respectively. This phenomenon has been reported previously. De Saint Sardos et al (30) described a 15-year-old girl with parasellar metastasis of a medulloblastoma who developed right abducens ONM 10 months after bilateral medial rectus recessions. Much et al (7) documented a 35-year-old woman who had transsphenoidal surgery, external beam radiotherapy, and radiosurgery for pituitary tumor with cavernous sinus invasion. She developed exotropia from a left third nerve palsy and underwent left lateral rectus recession and left medial rectus resection. One year later, she developed left medial rectus neuromyotonia. One explanation for this finding is that restriction by a contractured antagonist muscle may have prohibited ocular rotation, masking the spasms preoperatively. Delayed onset of ONM is another possibility. Tightening the neuromyotonic muscle, by plication in Patient 2, did not alter the spasms. In Patient 2, a faden operation on the spastic lateral rectus reduced the amount of deviation during a neuromyotonic episode. When lateral incomitance needs to be addressed, a faden procedure can be performed on either the spastic muscle or the contralateral yoke muscle. Theoretically, this should worsen the spasms due to fixation duress yet, interestingly, this did not occur in our patient. In planning surgery for patients with neuromyotonia, we believe that surgeons should correct the deviation present in primary position, and not the deviation where the spasm is occurring even if the spasm is occurring frequently. If the forced duction test is positive, surgeons should recess the tight muscle. In our experience, the spasms seem to worsen if a tight antagonist is recessed or if the spasmodic muscle is resected if fixation duress is created. Our approach to these patients includes the use of recess/resect procedure on the paretic eye provided there is lateral rectus function present. For lateral incomitance, surgery on the fellow eye can be considered as either a faden procedure or a standard recess/ resect operation. Faden procedures not only potentially diminish the spasms associated with neuromyotonia, but they may reduce lateral incomitance in cases of palsied muscles. It is unclear if plication procedures have a similar effect on neuromyotonia. In Case 2, our results were somewhat unexpected after plication. It is possible that enesthesial disruption plays a role in lessening Kim et al: J Neuro-Ophthalmol 2016; 36: 259-263 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution neuromyotonia and, therefore, it may be that plication procedures lead to in different results. This possibility deserves further study. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Kim, F. Velez, and S. L. Pineles; b. Acquisition of data: A Kim; c. Analysis and interpretation of data: A. Kim, F. Velez, and S. L. Pineles. Category 2: a. Drafting the manuscript: A. Kim, F. Velez, and S. L. Pineles; b. Revising it for intellectual content: F. Velez and S. L. Pineles. Category 3: a. Final approval of the completed manuscript: A. Kim, F. Velez, and S. L. Pineles. REFERENCES 1. Ezra E, Spalton D, Sanders MD, Graham EM, Plant GT. Ocular neuromyotonia. Br J Ophthalmol. 1996;80:350-355. 2. Chung SM, Lee AG, Holds JB, Roper-Hall G, Cruz OA. Ocular neuromyotonia in Graves dysthyroid orbitopathy. Arch Ophthalmol. 1997;115:365-370. 3. Roper-Hall G, Chung SM, Cruz OA. Ocular neuromyotonia: differential diagnosis and treatment. Strabismus. 2013;21:131-136. 4. Lessell S, Lessell IM, Rizzo JF III. Ocular neuromyotonia after radiation therapy. Am J Ophthalmol. 1986;102:766-770. 5. Choi KD, Hwang JM, Park SH, Kim JS. 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