Journal of Neuro-Ophthalmology, March 1998, Volume 18, Issue 1

Ocular Neuromyotonia

The objective of this article was to evaluate the etiologies, findings, and treatment of ocular neuromyotonia (ONM) in three case reports. The etiologies of ONM were determined by the histories, neuroradiologic tests, or biopsies. Clinical observations, videotaping, and electronic eye movement recordings documented the eye movement abnormalities. Intermittent diplopia developed several years after myelography with thorium dioxide (Thorotrast), radiation treatment for a pituitary tumor, and radiotherapy for medulloblastoma of the posterior fossa. All of the patients had intermittent, variable tropias that occurred spontaneously or were induced by eccentric gaze. One patient had a partial third nerve palsy, and another had a unilateral internuclear ophthalmoplegia (INO). ONM involved the paretic third nerve, extraocular muscles, and ipsilateral lateral rectus muscle in one patient, the paretic medial rectus muscle (INO) in one patient, a lateral rectus muscle (INO) in one patient, and a lateral rectus muscle in the last patient. Eye movement recordings were consistent with spasms of the involved muscles. Carbamazepine (Tegretol) abolished the ONM in two patients. The other patient had been taking carbamazepine for seizures and developed ONM when the dose was decreased. Increasing the dose abolished the ONM. ONM is an unusual cause of intermittent diplopia and strabismus, but its distinctive history and signs identify it easily. Damage to the peripheral cranial nerves might produce segmental demyelination, axonal hyperexcitability, and a self-perpetuating, reverberating circuit that causes spasms of the extraocular muscles.

Journal of Neuro- Ophthalmology 18( 1): 1- 8, 1998. © 1998 Lippincoll- Raven Publishers, Philadelphia Ocular Neuromyotonia: Three Case Reports With Eye Movement Recordings Robert D. Yee, M. D., F. A. C. S., and Valerie A. Purvin, M. D. The objective of this article was to evaluate the etiologies, findings, and treatment of ocular neuromyotonia ( ONM) in three case reports. The etiologies of ONM were determined by the histories, neuroradiologic tests, or biopsies. Clinical obser­vations, videotaping, and electronic eye movement recordings documented the eye movement abnormalities. Intermittent dip­lopia developed several years after myelography with thorium dioxide ( Thorotrast), radiation treatment for a pituitary tumor, and radiotherapy for medulloblastoma of the posterior fossa. All of the patients had intermittent, variable tropias that oc­curred spontaneously or were induced by eccentric gaze. One patient had a partial third nerve palsy, and another had a uni­lateral internuclear ophthalmoplegia ( INO). ONM involved the paretic third nerve, extraocular muscles, and ipsilateral lateral rectus muscle in one patient, the paretic medial rectus muscle ( INO) in one patient, a lateral rectus muscle ( INO) in one patient, and a lateral rectus muscle in the last patient. Eye movement recordings were consistent with spasms of the in­volved muscles. Carbamazepine ( Tegretol) abolished the ONM in two patients. The other patient had been taking carbamaze­pine for seizures and developed ONM when the dose was de­creased. Increasing the dose abolished the ONM. ONM is an unusual cause of intermittent diplopia and strabismus, but its distinctive history and signs identify it easily. Damage to the peripheral cranial nerves might produce segmental demyelina-tion, axonal hyperexcitability, and a self- perpetuating, rever­berating circuit that causes spasms of the extraocular muscles. Key Words: Ocular neuromyotonia- Eye movement record­ings. Ocular neuromyotonia ( ONM) produces transient, in­voluntary spasm of an extraocular muscle, intermittent diplopia, and strabismus. Clark described the first patient with this disorder in 1966 ( 1), but Ricker and Mertens were the first to use the term " ocular neuromyotonia" in a second case report in 1970 ( 2). ONM typically begins Manuscript accepted July 25, 1997. From the Department of Ophthalmology, Indiana University School of Medicine ( R. D. Y., V. A. P.), and Methodist Hospital ( V. A. P.), India­napolis, Indiana, U. S. A. Address correspondence and reprint requests to Dr. Robert D. Yee, Department of Ophthalmology, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, U. S. A. Two of the three case reports in this study were presented at the annual meeting of the American Ophthalmological Society in Asheville, NC, on May 21, 1996. months to years after radiotherapy for a tumor in the sellar and parasellar areas. It is a rare disorder that has been described infrequently ( 1- 13). However, its char­acteristic clinical features are striking and, once recog­nized, readily lead to its diagnosis and an effective drug therapy. We describe three patients with ONM. These cases are unusual because of their documentation with eye movement recordings, the identification of thorium dioxide ( Thorotrast) myelography as an etiology, the co­existence of internuclear ophthalmoplegia and ONM af­fecting the same extraocular muscle, and the likelihood that treatment with carbamazepine for seizures masked ONM until the dose was decreased. METHODS The patients were referred to the authors for neuro-ophthalmic consultations. Each patient gave their in­formed written consent to participate in the research pro­tocol approved by the institutional review board for hu­man subjects at the Indiana University School of Medicine. Videotaping and magnetic scleral search coils recorded the eye movements. The latter method has been described previously in detail ( 14,15). In brief, several turns of fine wire are embedded in an annulus made of soft contact lens material, which adheres tightly to the perilimbal sclera. The subject's head is centered in a cube made up of three sets of 6- foot diameter coils that induce a weak magnetic field within the cube. Rotation of the eyes and their contact lenses induce an electrical current that is amplified. The electronic and digital re­cording system can accurately record eye movements as small as 0.1 degree. The system's linear range is ± 20 degrees horizontally and vertically, and its bandwidth is 0- 100 Hz. The target is a bright red spot produced by a helium- neon laser. The laser light is reflected by a mirror galvanometer and is backprojected onto a translucent screen in front of the subject. CASE REPORTS Case 1 A 72- year- old man developed low back pain, weak­ness, and numbness of his legs 50 years ago. Forty years 2 R. D. YEE AND V. A. PURVIN ago, he had myelography with a contrast dye. Neither he nor his current physicians knew what dye had been used. Several months after his myelography, he had a severe infection. He did not recall the infection's location but remembered that he was treated with large doses of peni­cillin and streptomycin. Soon thereafter he had marked bilateral hearing loss. Over the ensuing years, he had six back surgeries for lumbar disk disease, but his back and leg symptoms slowly progressed. Several years ago, he developed incontinence of bladder and bowels. His phy­sicians thought that he had a chronic arachnoiditis and a cauda equina syndrome caused by iophendylate. Six years ago, he complained of episodes of intermit­tent diplopia that occurred several times each day and persisted for a few to many seconds. Three years ago, his ophthalmologist found limited abduction of the right eye and thought that he had a partial, right sixth nerve palsy. One year ago, the ophthalmologist detected pupillary di­lation, ptosis, and limitation of supraduction and infra-duction in the right eye, consistent with a right, partial, third nerve palsy. Neurologic examination showed mod­erately severe, bilateral leg weakness and loss of DTR's, proprioception and vibratory sensation in both legs. Per­ception of touch and pin also were decreased in both legs. Neuro- ophthalmic examination showed 15 prism di­opters of right esotropia and 15 prism diopters of right hypotropia in primary gaze. The right pupil was 6 mm in diameter and had decreased reactions to direct light stimulation and to near effort. The left pupil was 4 mm, and had normal reactions. There was 2- 3 mm of right, upper lid ptosis. The range of eye movements in the left eye was full. In the right eye, abduction was decreased to 40 degrees, supraduction to 20 degrees, and infraduction to 20 degrees. Gaze to the right for a few seconds caused a gradual increase in the right esotropia in primary gaze to 45 prism diopters and the right hypotropia to 45 prism di­opters over a few seconds. After about 30 s, the right esotropia and right hypotropia gradually returned to their initial measurements over 10 s. A return to right gaze immediately afterward did not induce a similar, transient increase in strabismus. However, right gaze 2- 3 min later did cause increased strabismus. During the tran­siently increased right esotropia, there was retraction of the right upper lid, but there was no change in the right pupil. Left gaze for a few seconds produced 20 prism diopters of right exotropia in the primary position. The right exotropia persisted for - 15 s. Magnetic search coil recordings showed only slightly decreased peak velocities of horizontal and vertical sac-cades in the right eye. In our laboratory, the mean peak velocity of 20 degrees, horizontal, and vertical saccades is - 400 ± 50 deg/ s (± 1 SD). The peak velocities of 20 degree up and down saccades in the right eye were 360 and 320 deg/ sec, respectively. In the left eye the veloc­ities were 400 and 390 deg/ sec for up and down sac­cades, respectively. Figure 1 shows vertical saccades for unpredictable target jumps across the center of the orbit. 10deg FIG. 1. Vertical saccades across center of orbit in case 1. Top, left eye; bottom, right eye. Deflections up are upward. Both eyes had postsaccadic drifts downward for 80 ms after most upward and downward saccades. The peak velocities of 20 degree right and left saccades were 380 and 370 deg/ sec, respectively, Figure 2 shows horizontal saccades across center. Leftward saccades in the right eye have overshooting waveforms. After rightward sac­cades, both eyes show convergence movements. Figure 3 shows horizontal saccades during target jumps from cen­ter to left 15 degrees. After several seconds, the right eye has a decelerating intersaccadic drift toward the left ( ad­duction) of initially 5 deg/ sec and a progressive decrease in amplitudes of saccades. Magnetic resonance imaging ( MRI) of the spinal cord showed abnormal clumping and enhancement of the cauda equina. MRI of the head showed abnormal wid­ening of the cerebral sulci, dilation of the lateral ven­tricles, old bilateral cortical infarcts, and extensive le­sions in subcortical periventricular, brain stem, basal ganglia, and thalamic areas, consistent with ischemia. There was diffuse pial enhancement, sometimes nodular in pattern, throughout the cerebral cortex and promi­nently in the basilar cisterns. The enhancement also in­volved the structures in the pineal region and the superior vermis. Figure 4 shows abnormal pial enhancement along the right temporal lobe, extending to the right cav­ernous sinus. The peripheral portion of the third nerve in the right cavernous sinus enhanced abnormally. A cis­ternal tap showed normal opening pressure, cytology, and chemistry of the cerebrospinal fluid ( CSF). How­ever, after the tap, the patient and his wife reported that his memory, alertness, and energy improved transiently, suggesting that he had normal pressure hydrocephalus. A ventriculoperitoneal shunt was placed into the right lateral ventricle, and a biopsy of the leptomeninges and the right frontal cortex was performed. The biopsy showed thickening and fibrosis of the leptomeninges and gliosis of the cortical molecular layer and underlying white matter. There were small foci of mononuclear in­flammatory cells in the leptomeninges, some of which contained brown pigment. The brown pigment was also free in the extracellular space. Iron and Fontana stains were negative. Transmission electron microscopy showed that the pigment was amorphous, dense osmio-philic granules in the cytoplasm of macrophages. The ./ Neiim- Ophllwlmol, Vol. 18, No. I, 1998 OCULAR NEUROMYOTONIA 3 10deg FIG. 2. Horizontal saccades across center of orbit in case 1. Top, left eye; bottom, right eye. Deflections up are to the right. Arrows, artifacts from eyelid blinking. h-' osmiophilic granules were membrane bound. Scanning electron microscopy and x- ray energy dispersive analysis showed that the pigment was thorium. Figure 5 shows thorium's major peak at 2.996 KeV and its minor peak at 12.967 KeV. This finding proved that the myelographic contrast dye was thorium dioxide ( Thorotrast). The pa­tient developed a chronic, diffuse arachnoiditis, induced by this agent, that eventually produced a cauda equina syndrome, normal pressure hydrocephalus, a partial right third nerve palsy, and ONM. Chronic arachnoiditis or streptomycin might have caused the bilateral hearing loss. The patient was treated with carbamazepine 200 mg orally twice daily. Within 1 day, the diplopia and ONM resolved. The ONM returned when the drug treatment was stopped 2 months later and resolved when the treat­ment was restarted. Case 2 A 66- year- old woman had been diagnosed with a pi­tuitary tumor and acromegaly 30 years ago. She under­went 19 radiation treatments and developed intermittent horizontal and occasionally vertical diplopia after the treatments. The episodes worsened over the past 5 months. They lasted several seconds and occurred many times each day. An MRI of the head showed an enlarged, empty sella with a small residual pituitary gland and a few lesions in the periventricular white matter of the cerebral hemispheres, consistent with ischemia. Proton and T2- weighted scans showed a small area of increased signal in the left medial longitudinal fasciculus in the pons. Results of magnetic resonance angiography were normal. She complained of imbalance while walking during the past year. Neurologic examination showed mild dysmetria on finger- to- nose testing and mild dys-diadochokinesia of the left arm and hand. Her gait had a normal base, but she could not walk in tandem. Neuro- ophthalmic examination showed a left inter-nuclear ophthalmoplegia ( INO). The range of eye move­ments was full, except for limitation of adduction in the left eye to 40 degrees. Abducting nystagmus of the right eye was present in right gaze, and rightward saccades in the left eye were slow. Left gaze produced a mild, gaze-evoked nystagmus. Smooth pursuit was mildly impaired, and fixation did not normally suppress vestibular nystag­mus induced by rotation of her chair. There was no phoria in center gaze. Right gaze pro­duced three prism diopters of exotropia, and left gaze eight prism diopters of esotropia. Several episodes of marked esotropia of the left eye were observed, as the right eye maintained fixation. They lasted 45- 80 s. These episodes were induced by right gaze and up gaze, but sometimes occurred while fixation was maintained in primary gaze. No pupillary constriction was observed during the esotropia. Treatment with carbamazepine 200 mg orally twice daily was begun. The episodes of dip­lopia resolved within a few days. Magnetic scleral search coil recordings were made while the patient was taking carbamazepine and 10 days after stopping the drug. During both sessions, marked slowing of rightward saccades in the left eye due to the left INO were found ( Fig. 6). For example, the mean peak velocity of 20 degree rightward sac­cades in the right eye was 390 deg/ s, but that of the rightward saccades in the left eye was only 110 deg/ s. Leftward and vertical saccades in the left eye, as well as horizontal and vertical saccades in the right eye, had normal peak velocities. A small- amplitude ( 1 de­gree) right- beating, jerk nystagmus was found in pri­mary gaze in the right eye, and a large- amplitude, ab- FIG. 3. Horizontal saccades between primary gaze and 15 deg left gaze in case 1. Top, left eye; bottom, right eye. At end of tracing, the right eye channel saturates in left gaze. J Nairo- Ophllialmal, Vol. / « , No. 1. 1998 4 R. D. YEE AND V. A. PURVIN FIG. 4. Coronal MRI of head with gadolinium in case 1. Arrow, enhancement of right third nerve in cavernous sinus. ducting nystagmus of the right eye was present in right gaze. No ONM was present during the session while carba-mazepine was taken. After the medication was stopped, videotaping and search coil recordings documented the ONM. Episodes of esotropia occurred spontaneously during fixation in primary gaze and after return to pri­mary gaze from right gaze and gaze up- and- right gaze. Their durations were 4- 7 s, peak velocities 5- 9 deg/ s, and amplitudes 4- 9 degrees. In Fig. 6, the left eye is covered, and the right eye is fixing the target. After re­turn to primary gaze from right gaze, a left esotropia developed, lasting 7 s. The amplitude and duration of the left medial rectus spasms had been much greater before carbamazepine was initially given. Case 3 A 47- year- old man developed imbalance and vertigo 5 years ago. A partial excision of a cerebellar medulloblas- 320- 1 Thorium ( 314) 240- O CD • « a 160- c 3 5.00 10.00 15.00 20.00 KeV FIG. 5. X- ray energy dispersive analysis in case 1. Probe cen­tered on intracytoplasmic, dense material in macrophage. Major and minor peaks identify material as thorium. toma was performed, and he received radiotherapy and chemotherapy. Three years ago, he had grand mal sei­zures and was placed on carbamazepine 200 mg orally four times daily because of an allergic reaction to diphe-nylhydantoin. He had no subsequent seizures. The dose was decreased to 200 mg three times daily 1 year ago because of a mild decrease in the white blood cell count. He began to have episodes of intermittent, binocular, horizontal diplopia 3 months ago. The episodes were often brought on by turning of his head to the left, but also occurred without a head turn or conscious change of gaze. They occurred three times to several times each day and persisted for 5 s to 20 min. MRI studies of the head had been performed every 6 months and showed no signs of recurrence of the tumor. His general neurologic examination was normal, except for mild gait ataxia. Neuro- ophthalmic examination showed two prism di­opters of right esotropia in center gaze. If the eyes were placed in 45 degrees of right gaze for 20 s and then returned to primary gaze, he had 10 prism diopters of right exotropia that persisted for 10- 20 s. Magnetic scleral search coil recordings showed the right exotropia on return to primary gaze from right gaze. After 10- 15 s there was a very low velocity, leftward drift of the right eye to the primary position as the right exotropia de­creased. The range of eye movements were full in both eyes. The peak velocities of horizontal and vertical reflex saccades were symmetrical between both eyes and within the normal limits for our laboratory. The remain­der of the eye movement recordings was also normal, except for a mild symmetrical decrease in horizontal pur­suit gain. A complete blood count and platelet count were normal while the patient was taking carbamazepine 200 mg orally three times daily, and the blood level was 9.5 jjim/ ml ( therapeutic range for epilepsy, 4- 12 | xm/ ml). The episodes of ONM ceased after the dose was in­creased to 200 mg orally four times daily. His blood tests have remained normal and/ or in the therapeutic range. DISCUSSION Differential Diagnosis Many disorders cause intermittent diplopia and stra­bismus. Those that produce diplopia and strabismus in primary gaze include decompensated phorias, conver­gence spasm, myasthenia gravis, restrictive orbitopathies ( Graves' ophthalmopathy), superior oblique myokymia, and congenital oculomotor palsy with cyclic spasms. Diplopia and strabismus occurring only in eccentric gaze are created by ocular myopathies ( myasthenia gravis), cranial nerve palsies, restrictive orbitopathies, and INO. ONM is a rare cause of intermittent diplopia and strabis­mus. Only 26 patients, including ours, have been de­scribed in the literature ( 1- 13). However, the clinical history and the examination of ocular motility are dis­tinctive. Because many patients with ONM have had radiotherapy for pituitary tumors, the onset of diplopia and strabismus suggests that there might be recurrence of the tumor with cranial nerve palsies. Recognizing the distinctive features of ONM can reassure the clinician and patient that a tumor has not recurred. ./ Neiira- Ophlhaliiwl, Vol. IS, No. I, 1998 OCULAR NEUROMYOTONIA 5 10deg 10deg FIG. 6. Horizontal eye movements in case 2. Top, left eye; bottom, right eye. Right eye is fixing tar­get, which moved from left 15 degrees, to right 15 degrees, and to center. Deflections up are to right. In right eye, note abducting nystagmus in right gaze, and low- amplitude, right- beating nys­tagmus in primary gaze. In left eye note slow ad-ducting saccade and transient esotropia after re­turn to primary gaze. Extraocular muscle spasm occurs in other disorders, but these can be readily differentiated from ONM. In cyclic oculomotor palsy, the paretic muscles have peri­ods of spasm. However, the underlying extraocular muscle paresis persists between episodes, producing limitation of ductions and slowing of saccades. In addi­tion, the oculomotor palsy is usually congenital. The ages of onset of reported cases of ONM range from 6 to 74 years, but the majority of patients are adults. In each instance, ONM was an acquired disorder. Superior ob­lique myokymia causes diplopia and monocular oscillop-sia. There are tonic, large- amplitude contractions of the superior oblique, as well as high- frequency, small-amplitude contractions of the muscle. Although ONM has involved the superior oblique muscle in several pa­tients, none of them have had monocular, torsional os­cillations. Convergence spasm produces intermittent es­otropia and diplopia. However, the other components of the near reflex ( miosis and accommodation) are usually present. Gaze- Induced and Spontaneous ONM In ONM, intermittent spasms of extraocular muscles create strabismus and diplopia in primary gaze. Eccentric gaze often induces spasm of an agonist muscle that per­sists on return to primary gaze. For example, in case 1, left gaze produced spasm of the right medial rectus and right inferior rectus so that the right esotropia and right hypotropia increased on return to primary gaze. Right gaze caused spasm of the right lateral rectus and a right exotropia in primary gaze. In case 2, right gaze and up­ward gaze produced left medial rectus spasm and left esotropia in primary gaze. In case 3, right gaze caused spasm of the right lateral rectus and right exotropia on return to primary gaze. The effects of eccentric gaze were documented in 24 of the 26 reported cases. Eccentric gaze evoked extraocu­lar muscle spasms in 17 of the 24 patients. It was nec­essary to maintain eccentric gaze for several seconds to a few minutes. ONM will be missed if prolonged periods of eccentric gaze are not used. In case 1 periodic voli­tional saccades into left gaze every 1.5 seconds also were sufficient to induce extraocular muscle spasms. In this patient, a refractory period was found after an episode of gaze- induced ONM. Return to right gaze did not induce another episode of ONM for 2- 3 min. Helmchen and colleagues used electro- oculography to record ONM of the left lateral rectus in a patient ( 8). Repetitive saccades into left gaze also induced episodes of ONM. The au­thors documented whether or not the spasms occurred spontaneously in primary gaze without prior eccentric gaze in 18 patients. Spasms were spontaneous in 15 pa­tients, including case 2. The patient's history sometimes indicates that the ONM is gaze induced. For example, patient 3 reported that diplopia occurred after head turn to the left that induces gaze toward the right and activation of the af­fected right medial rectus muscle. However, the history alone cannot differentiate gaze- induced from spontane­ous ONM, because the patient might not be aware that a reflex or voluntary change in gaze precedes the diplopia. Therefore, the clinician must observe the eyes in primary gaze and after many seconds of eccentric gaze. Spasm of Extraocular Muscles Versus Ophthalmoplegia Detailed examination shows that the strabismus in ONM results from extraocular muscle spasm rather than from extraocular muscle paresis. In the reported cases, the spasms and deviations persisted for several seconds to a few minutes. Every extraocular muscle, except the inferior oblique, has been affected in ONM. In the 26 reported cases, the medial rectus was involved in 13, superior rectus in five, inferior rectus in five, lid levator in five, lateral rectus in 11, and superior oblique in six. The iris sphincter muscle was affected in two patients ( 5,13). ONM has been unilateral in every patient, except for bilateral involvement of third nerve, extraocular muscles in one patient ( 12). Extraocular muscle spasm in ONM can be distin­guished from paresis resulting from a cranial nerve palsy. Slowing of saccades in ONM is usually slight, but the decrease in peak saccadic velocity is marked in cranial nerve palsies. Right sixth and third cranial nerve palsies were thought to be present in case 1 because of the limitation of eye movements. However, the electronic eye movement recordings indicated that the limitations of abduction, supraduction, and infraduction in the right eye were probably caused by cocontraction of antagonist muscles. The peak velocities of horizontal and vertical J Neuro- Oplilhalmol, Vol. 18, No. I, 1998 6 R. D. YEE AND V. A. PURVIN saccades in the right eye were only slightly decreased, compared with the velocities of saccades in the left eye. These findings can be explained by the lack of inhibition of antagonist muscles and a slight decrease in force gen­erated by agonist muscles that are tonically contracted ( spasm). Extraocular muscle paresis would cause much larger decreases in peak velocities. Frohman and Zee ( 11) recorded eye movements in a patient with ONM of the inferior rectus, superior rectrus, and medial rectus muscles of the right eye. After sus­tained left gaze, postsaccadic drift to the left at the end of leftward saccades increased, and the peak velocities of leftward saccades decreased slightly in the right eye. These changes were consistent with tonic contraction of the right medial rectus. The baseline right esotropia and right hypotropia in primary gaze in case 1 were probably also produced by tonic spasms of the right medial rectus and right inferior rectus. Morrow et al. ( 12) recorded saccades and found slowing in all directions in a patient with bilateral ONM involving muscles innervated by the third nerve. They attributed the slowing to impaired pha­sic firing of agonist muscles and tonic contraction of antagonist muscles. Between episodes of ONM, the peak velocity of saccades was only slightly decreased. ONM and cranial nerve palsy can affect the same extraocular muscles ( 5,6,13) ( case 1), and aberrant regeneration of the third nerve can also be present ( 5,13). However, a peripheral nerve that is damaged enough to markedly decrease saccadic velocities might not be able to dem­onstrate ONM. In case 2 the peak velocities of leftward saccades in the left eye were markedly slow because of the left INO. This is the first reported association of ONM and INO. In addition, the patient had other eye movement abnormali­ties ( gaze- evoked nystagmus in left gaze, impaired smooth pursuit and impaired suppression of vestibulo-ocular responses by fixation) found with disorders of the cerebellum and brain stem. The left MLF lesion found on MRI and the left INO could have been caused by isch­emia secondary to the radiotherapy. However, the INO and other eye movement abnormalities do not contribute to the ONM. The MLF lesion blocks the normal recruit­ment of oculomotor neurons during conjugate, versional eye movements but does not damage the motor neurons or their axons. Thus, the latter can participate in the phenomenon of ONM. In case 3 the peak velocities of saccades were normal. Among our cases, the ONM was least severe in this patient, probably because carbamaz-epine was ameliorating some of its effects when the eye movement testing was performed. Saccadic velocities can be normal in ophthalmoplegia caused by myasthenia gravis and restrictive orbitopa-thies, such as Graves' ophthalmopathy. However, pa­tients with ONM do not have the other associated ocular and systemic signs of these disorders. Causes of ONM In 16 of the 26 cases of ONM, radiotherapy had been given for a tumor in or around the sella. The tumors included pituitary adenomas, craniopharyngiomas, an ethmoid carcinoma, a thalamic glioma, a chondrosar­coma, and a rhabdomyosarcoma. The total radiation dos­ages ranged from 20 to 77 Gy, and the symptoms of ONM began several months to 17 years later. Patient 2 had undergone radiotherapy for a pituitary adenoma and acromegaly 30 years earlier. Patient 3 had undergone radiation treatment to the posterior fossa for a cerebellar medulloblastoma, but the sellar area probably also re­ceived radiation. Ten previously reported patients did not have radiation to the sellar and parasellar areas. Two of these patients had compressive lesions, including a clivus chordoma ( 4) and a supraclinoid carotid artery aneurysm ( 13). One patient had a radical mastectomy and local irradiation for breast adenocarcinoma without evidence of metastasis by CSF examination or computed tomog­raphy ( 5). The seven remaining patients had no known disord^ that might have been associated with ONM. In one of these patients, alcohol ingestion induced ONM ( 13). Shults et al. stated briefly that one of them had examined four other patients with ONM involving the third nerve ( three postradiation for tumors, one idio­pathic) and that they believed another patient described by other investigators had ONM of the third nerve caused by a supraclinoid aneurysm ( 5,16). Case 1 is unique because chronic arachnoiditis caused by thorium dioxide myelography is the most likely eti­ology of the ONM. Thorium dioxide was used as an x- ray contrast dye from 1928 to the mid- 1950s in Europe and the United States ( 17- 19). Thorotrast was a 25% colloidal suspension of thorium dioxide. It was used for angiography and to fill body cavities. Neuroradiologic applications included cerebral angiography, ventriculog­raphy, myelography, and opacification of brain ab­scesses. Unfortunately, severe complications, including malignancies, were not identified until 1947 ( 20). After administration, thorium dioxide is preferentially stored in reticuloendothelial cells in the liver, spleen, bone mar­row, and lymph nodes. Malignant tumors of the liver, leukemias, blood dyscrasias, and asplenism have been reported after thorium dioxide injection. Extravasated material around the injection site produced chronic, in­flammatory granulomas ( thorotrastomas), especially in the neck when the dye was used for cerebral angiogra­phy- Thorium 232 is a radioactive alpha emitter that has a physical half- life of 1.39 x 1010 years and a biologic half- life of 400 years ( 21). Each gram of thorium delivers about 890 cGy to the body each year. Its radioactive daughters are beta and alpha emitters, which deliver an­other 890 cGy each year. Secondary neoplasia and chronic inflammation are probably due to radiation. In­jection of thorium dioxide into brain abscesses and into a subdural hematoma has caused local granulomas, a gliosarcoma, and a meningioma ( 22- 24). Myelography has produced a meningioma, a schwannoma, chronic arachnoiditis, and a cauda equina syndrome ( 25- 30). The patient described by Kaplan et al. ( 26) had severe, dif­fuse arachnoiditis, multiple cranial nerve palsies, right J Natro- Ophllialmol, Vol. IS, No. I, 1998 OCULAR NEUROMYOTONIA 7 optic atrophy, bilateral neurosensory hearing loss, a cauda equina syndrome, and " external ophthalmople­gia." Our patient and his current physicians suspected that iophendylate ( Pantopaque) had been used for his myelography 40 years ago. This material can also cause chronic arachnoiditis ( 31- 33). However, scanning elec­tromyography and x- ray energy dispersive analysis de­finitively showed that thorium dioxide had actually been used. Mechanism of ONM Myotonia is an abnormal delay in relaxation of muscle fibers caused by disorders of the muscle membrane. Neu-romyotonia is a delayed muscle relaxation caused by repetitive firing in peripheral nerves triggered by an im­pulse. Disorders that damage peripheral nerves have caused neuromyotonia in limb muscles. Interestingly, these disorders include peripheral neuropathy, traumatic peripheral neuropathy, and radiation- induced damage to the brachial plexus ( 34- 38). Histopathologic examina­tion of peripheral nerves in these disorders have shown segmental demyelination, degeneration of axons, axonal sprouting, and remyelination. Electromyography of limb muscles have shown continuous motor unit firing, fibril­lations, fasciculations, and myokymia. Hemifacial spasm might be caused by compression of the peripheral facial nerve at its root entry zone in the brain stem ( 39,40). The mechanism of ONM might be similar. For ex­ample, Ricker and Mertens ( 2) and Papst ( 3) found ab­normalities in electromyography of extraocular muscles between episodes of ONM, that they interpreted as neu­rogenic in origin. Many cases of ONM followed radia­tion for tumors in the sellar and parasellar areas. This observation suggests that damage to the peripheral nerves in or near the cavernous sinus sets the stage for ONM. The patient described by Ricker and Mertens ( 2) and our case 1 had ONM of muscles innervated by ip-silateral sixth and third cranial nerves, suggesting that these nerves had been damaged in or near the cavernous sinus. The patient described by Helmchen et al. ( 8) and case 1 had ONM of the lateral rectus and ipsilateral, partial third nerve palsies. MRI in case 1 demonstrated a third nerve lesion in the cavernous sinus. Ephaptic transmission ( axon- to- axon crosstalk) has been proposed as a mechanism in limb neuromyotonia, ONM, hemifacial spasm, and the misdirection syndrome of third nerve palsy ( 39- 42). In a previously damaged part of the peripheral nerve, neural signals transmitted through axons that are demyelinated and hyperexcitable might spread to adjacent axons. The extraocular muscle spasm in ONM persists for many seconds even when a change of gaze would not normally excite the involved muscles. A self- perpetuating, reverberating circuit in which axons are reinnervated might sustain the contrac­tion. Other explanations for these phenomena have been proposed, including reorganization of neurons in the brain stem nuclei secondary to retrograde degeneration, ephaptic transmission in the nuclei, and reorganization of patterns of motor output in the nuclei ( 42- 44). Treatment Of the 26 documented cases of ONM, only one patient experienced spontaneous resolution ( 9). Sixteen patients were treated with carbamazepine. The ONM resolved or significantly decreased with treatment in 14 of these pa­tients. In most patients, dosages of carbamazepine of 200 mg twice daily to 200 mg three times daily were effec­tive. The treatment for one patient was stopped after 1 month, but the ONM did not recur. 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