A 54 year old man with intermittent diplopia
Digital Journal of Ophthalmology 2005
Volume 11, Number 8
April 1, 2005
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Kathy Lee, B.Sc. | University of British Columbia
Nipat Aui-Aree, M.D. | University of British Columbia
Duncan P Anderson, M.D., F.R.C.S.C. | University of British Columbia


History
A 54 year old Chinese man who presented with complaints of binocular horizontal distance diplopia, more on side gazes to both directions. He details that the images are sometimes close together but sometimes they are far apart. The diplopia is only periodic and worsens when he is concentrating hard or tired like after a long drive. He does not have other symptoms suggestive of amaurosis fugax.

He had an epidermoid nasopharyngeal cancer about eighteen years ago in 1985 that was irradiated with resulting necrosis of brainstem and lower cranial nerves. Staging work-up revealed this to be Stage I disease, Ho’s classification. He was treated with a radical course of radiotherapy from November 4, 1985 to December 14, 1985. 5950 rads were delivered to the nasopharynx and 4550 rads prophylactically to the neck. Post-radiotherapy nasopharyngeal biopsies have all been negative. He is otherwise healthy.

He is not on any regular medications. He is a non-smoker but a social drinker with about 5 drinks a month. Except for liver cancer in his mother who died at 63 years old, there is no other history of cancer or ocular diseases in the family. His four siblings are alive and well. He came to Canada in 1988 and had no recent travel history.

Examination
He was wearing OD: -5.50-1.75x67 and OS: -5.00-1.75x95. Visual acuity was 20/20 OD and 20/25 OS that corrects to 20/20 with pinhole. Dilated fundus examination was unremarkable with no ischemic signs. Colour vision was 17/17 Ishihara plates. Pupils reacted from 4 to 3mm with light bilaterally. There was no relative afferent defect noted. Stereopsis was normal at 40 seconds of arc. Retinal artery pressures are 50/15 on the right and 55/12 on the left. Lids were symmetrical. Slit lamp examination and intraocular pressure readings were normal.

Orthoptics testing noted an underaction of the both lateral rectus muscles of -1 in the left and -0.5 in the right. Examination with Hess confirmed the bilateral lateral rectus palsy. In primary position, the esotropia was 10 prism diopter (PD) and the hypotropia was 2 PD at distance with his corrective lenses. At near, the esotropia was only minimal at 1 PD without any hypotropia. On sustained right gaze, the tiny esotropia broke into an exotropia of 35-40 PD (Video). The deviations did not change in any other sustained directions of gaze. After he broke into the exotropia, he had trouble recovering control and the exotropia persisted in all gaze positions for approximately one minute. The same esotropia transforming to a large exotropia was observed in left gaze.

Cranial nerve V and VII was normal as tested by facial sensation and lid closure strength respectively. However, left hearing was decreased compared to the right. The rest of his physical examination was unremarkable.

Video (requires Windows Media Player to view)
 The eye movements show esotropia in all positions. However, after eccentric gazes he developed a large angle of exotropia which gradually returned to his resting state of alignment.

Ancillary Testing
Radiographic Studies
MRI following an infusion of gadolinium showed cystic areas in the right and left temporal lobes consistent with radiation necrosis. There is minimal progression in the necrotic changes since the MRI in January 1996. There is no mass effect and no other definite focal lesions in the rest of the brain. The is no evidence of recurrence of the nasopharyngeal cancer. Goldman visual field was unremarkable.

Treatment
The refractive error was corrected with new glasses prescription and removable base out prisms of 10 PD was prescribed for distance vision only. Because of the variable nature of his deviations, permanent corrections like strabismic surgery were not suggested. Furthermore, neuromyotonia can resolve completely.1

Differential Diagnosis
- ocular neuromyotonia
- ocular myasthenia
- demyelinizing diseases
- decompensating phorias
- convergence spasms
- early stages of Graves’ disease
- cyclic oculomotor paresis
- superior oblique myokymia
- cyclic esotropia
- transient ischemia attack

Diagnosis and Discussion
Ocular neuromyotonia (ONM) is a rare disorder that most commonly involves the oculomotor nerve followed by the abducens nerve and then the trochlear nerve (3). It was first described by Clark in 1966 (4), but Ricker and Mertens coined the term “ocular neuromyotonia.” (5) It is characterized by(6):
1. intermittent diplopia lasting seconds to minutes
2. The amount and direction of intermittent angles of deviation may vary without any pattern.
3. Provocation of these episodes by changes in the gaze direction or after holding eccentric gaze (7)..
4. Phases characterized by overaction of isolated single muscles.

Previous radiation to the sellar or parsellar regions is the most common cause (8,9). This is the most likely etiology of ONM in our patient, however, recurrence of his nasopharyngeal tumour with metastasis to the cerebrum cannot be ruled out without the proper imaging. ONM have been attributed to other causes like supraclinoid aneurysms, infectious cavernous sinus thrombosis, alcohol abuse, arachnoiditis, basilar artery dolichoectasia, and Graves’ disease (10-13). Other cases of OMN resulting from radiotherapy of nasopharyngeal cancer have been documented (14-15). The latency between radiation and onset of diplopia varies between 2 months and 18 years (6).

Although the exact pathogenesis of OMN is unknown, there is wide acceptance of the segmental demyelination hypothesis (16). The membrane potential traveling within the axons which is normally insulated from the surrounding by the myelin sheath is exposed due to damage from causes mentioned above to result in atypical patterns of neural transmission and muscle activation – ephaptic transmission (lateral or “cross-talk”); reflection (reversal of transmission); and proximal branching of sprouting axons. The growth of axons within a damaged fiber (sprouting) may conduct orthodromic impulses which are reflected and conducted in an anti-dromic fashion. This mechanism can establish a reverberating nerve circuit. The speed, number and specific connections of the sprouting fibers dictate the degree and specifics of the response, giving the dynamic nature of ONM (17). Supporting this hypothesis is electrophysiologic testing revealing neuronal degeneration and impaired nerve conduction after radiation therapy(18,19). In addition, eye movement recordings were consistent with spasms of the involved muscles (20).

Spontaneous firing of neurons supplying a muscle may spread to the other neurons supplying the other extraocular muscles or ephaptic transmissions between the axons may result in the co-contraction of the other extraocular muscles. Abdulla and Eustace described a case where oculomotor nerve neuromyotonia was replaced by optic nerve neuromyotonia (21). In this 48 year old woman, phasic constrictions of the pupil developed after surgery for a giant aneurysm of the internal carotid artery in the cavernous sinus. Two years later this was replaced by intermittent involuntary cyclic spasms elevating the ptotoc lid which were not elicietd with any eye movement or by increased accomodation.

In our patient with the bilateral VI nerve palsy, the weak VI nerves resulted in the small esotropia. However, on sustained lateral gazes to both directions, the overfiring of the lateral rectus resulted in the large exotropia. Radiation may be a relatively effective way to achieve the unique a pattern of nerve injury without cell death that gives the potential to develop ONM (17). A combination of impaired phasic firing in agonist muscles and tonic contraction of the antagonist muscles explains the paroxysms of eye movement limitation in this disorder (22). With horizontal muscle weakness there may be a small amount of intermittent hypotopia, especially when the vertical and oblique muscles cannot compensate in the primary position.

Following the trial of prism glasses, carbamazepine will be suggested. The pharmacological effect of neural membrane stabilization to inhibit inappropriate action potential transmission effective in treatment of ocular neuromyotonia helps to support the pathogenesis. (6) Alternatively, eye muscle exercises may help as Safran and Magistris reported a case where the patient with fourth nerve neuromyotonia discovered that each episode of tonic ocular depression could be terminated by forcefully directing her gaze upwards. (23) Further stretching an abnormally innervated muscle, as is the case with ONM, may eventually cause some crease in the force generated by the stretched muscle. (24) Although not apparent on clinical history and examination, thyroid studies should be ordered to rule out Graves’ disease as this may be an easily reversible cause of GL’s ONM.(13)

In patients presenting with intermittent diplopia, it is important to rule out benign disorders like ocular neuromyotonia that may respond to conservative treatment and not perform strabismic surgery given the variable nature of the deviations. Furthermore, serious pathology leading to the ocular neuromyotonia needs to be ruled out.

References
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