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Show Journal of Nemo- Oplillialmolagy 18( 4): 277- 280, 1998. & 1998 Lippincoll Williams & Wilkins, Philadelphia Bilateral Internuclear Ophthalmoplegia Related to Chronic Toluene Abuse Jennie Hunnewell, M. D., and Neil R. Miller, M. D. A 36- year- old woman exhibited slurred speech, progressive ataxia, blurred vision, and oscillopsia. Examination showed dysconjugate torsional nystagmus and bilateral internuclear ophthalmoplegia ( INO). Further investigation revealed evidence of chronic toluene abuse. The neurologic findings in toluene abuse and the causes of bilateral INO are discussed. Key Words: Ataxia- Internuclear ophthalmoplegia- Nystagmus- Oscillopsia- Toluene. Toluene is an organic solvent commonly present in glues, paints, paint thinners, and other industrial products. It is often inhaled to achieve acute euphoria and alteration in consciousness. Solvent abuse typically begins in childhood and adolescence in a population that is not cognizant of the long- term consequences. This insidiously toxic substance is cheap and widely available to people of all ages. Patients who are exposed to toluene for a prolonged period can exhibit a variety of neurologic manifestations, including ataxia, tremor, anosmia, sensorineural hearing loss, dementia, corticospinal tract dysfunction, abnormal brainstem auditory- evoked potentials, and epileptic seizures ( 1- 4). Abnormal magnetic resonance imaging findings include generalized cerebral, cerebellar, and brainstem atrophy; atrophy of the corpus callosum; loss of gray- white matter discrimination; multifocal high signal intensity in the cerebral white matter; and hypointensity of the thalami on T2- weighted images ( 5,6). Toluene is highly lipophilic, with a high affinity for myelin and cell membranes; however, the exact pathophysiologic mechanism for toxicity is unknown. Neuro- ophthalmologic manifestations can also develop in patients with chronic toluene toxicity. These include pendular nystagmus, ocular flutter, opsoclonus ( 1- 3,7), and optic neuropathy ( 8,9). We report what we consider to be a new manifestation of toluene toxicity, bilateral internuclear ophthalmoplegia ( INO). Manuscript received January 8, 1998; accepted April 29, 1998. From the Neuro- Ophthalmology Unit of the Wilmer Eye Institute, The Johns Hopkins Hospital, Baltimore, Maryland. Address correspondence and reprint requests to Dr. Neil R. Miller, Neuro- Ophthalmology Unit of the Wilmer Eye Institute, The Johns Hopkins Hospital, Maumenee B- 109, 600 North Wolfe Street, Baltimore, MD 21287, U. S. A. CASE REPORT In February 1992, a 36- year- old woman saw an ophthalmologist and reported a 6- month history of oscillopsia and a feeling that her eyes were quivering. The patient had a 21- year history of sniffing airplane glue initially, then paint sniffing, and eventually sniffing pure toluene. Three years earlier, she had begun to experience seizures characterized by intermittent episodes of a dream- like state associated with unusual activity. During these episodes, she would rub her thigh, walk around in an unusual manner, and become unresponsive to people around her. She had no recall of anything that occurred during these periods. Her seizures were thought to be related to an episode of physical abuse at age 27 when FIG. 1. Photograph of appearance of patient in February, 1994, showing bilateral internuclear ophthalmoplegia. 277 278 J. HUNNEWELL AND N. R. MILLER she was hit in the head but did not experience loss of consciousness. The patient was treated with valproic acid for 3 years and was subsequently prescribed carbamaz-epine ( Tegretol; Ciba Pharmaceuticals, Broomfield, CO, U. S. A.), which she had been taking for 10 months when her visual symptoms began. The patient had undergone a complete ocular examination in June 1990, 16 months earlier, when the physician who evaluated her reported normal findings, including ocular motility. In July 1991, 7 months earlier, a neurologic examination revealed nystagmus, intention tremor, mild gait ataxia, mild dysdiadochokinesia, and generalized hyperreflexia. The patient reported that she was not abusing alcohol or drugs at that time. Magnetic resonance imaging showed mild atrophic changes of the brainstem and cerebellum. Shortly thereafter, oscillopsia developed, followed by slurred speech, and increasing difficulty walking. On examination in February 1992, the patient's visual acuity was 20/ 30 OD and 20/ 25 OS. She had conjugate, horizontal, nystagmus that was primarily pendular but had a jerk component, with the fast phase to the right. The nystagmus was initially thought to be related to the effects of carbamazepine, which was then discontinued. However, the patient continued to have oscillopsia, and another examination revealed worsening nystagmus, which was somewhat disconjugate, with a torsional component. In addition, the patient exhibited a wide- based unsteady gait and tended to lose her balance whenever she attempted to turn around while standing in place. An electroencephalogram showed diffuse slowing, and another magnetic resonance imaging scan revealed generalized cerebral and cerebellar atrophy and diffuse atrophy of the corpus callosum. A few small focal areas of nonenhancing abnormal increased signal were present in the right putamen, left internal capsule, left frontal lobe white matter, and right side of the brainstem. A more diffuse increased signal was present in the periventricular white matter surrounding the frontal and posterior horns of the lateral ventricles. It was suspected that the patient had chronic multiple sclerosis ( MS), and the physician decided to observe her at regular intervals. Approximately 15 months later, her family disclosed for the first time the patient's history of toluene abuse. In February 1994, the patient saw an ophthalmologist with a report of persistent oscillopsia. She had no numbness, paresthesia, bowel or bladder abnormality, Uhthoff s symptom, or Lhermitte's sign. Best corrected visual acuity was 20/ 100 OU. The patient identified five of 10 Hardy- Rand- Rittler pseudoisochromatic plates correctly with each eye. Visual fields were full. In primary position, the patient had disconjugate, primarily pendular nystagmus. In addition, the patient had moderate bilateral limitation of adduction associated with bilaterally slowed adducting saccades and horizontal jerk nystagmus in the abducting eye, consistent with bilateral INO ( Fig. 1). A third magnetic resonance imaging scan showed the previously noted changes. In addition, sev- « I A 1 ' » JL1*] 1 n i l ; ' ' i * 7 i> n ^ ~~ x \ ^ / FIG. 2. Magnetic resonance images of patient at time of initial examination revealing bilateral internuclear ophthalmoplegia. A, T1- weighted sagittal image shows moderate cerebral, cerebellar, and brainstem atrophy. The corpus callosum is significantly atrophic for a person of this age. B, T2- weighted axial image shows diffuse white matter changes { large arrowheads) in the left temporal and parietal regions as well as areas of hyperintensity on both sides of the pons { small arrowheads), some of which are in the region of the medial longitudinal fasciculi. ./ Nritm- Oplillwlmol, Vol. IS, No. 4, 199H BILATERAL INTERNU'CLEAR OPHTHALMOPLEGIA 279 eral hyperintense lesions were present on both sides of the pons, some of which were in the region of the medial longitudinal fasciculi ( Fig. 2). Analysis of cerebrospinal fluid obtained in a lumbar puncture showed normal concentrations of glucose and protein, no white blood cells, no oligoclonal bands, and no evidence of myelin basic protein. A diagnosis of neurotoxicity caused by chronic toluene abuse was made. When last evaluated in 1995, the patient had severe dysarthria, ataxia, and tremor. The bilateral INO and nystagmus were still present. DISCUSSION Unilateral and bilateral INO are often caused by ischemia or inflammatory disease, particularly MS; however, TABLE 1. Etiology of bilateral iiiternuclear ophthalmoplegia 1. Demyelinalion a. Multiple sclerosis b. Poslirradialion demyelinalion 2. Brainstem infarction a. Hypertension b. Diabetes mellitus c. Vasculitides ( eg, systemic lupus erythematosus, temporal arteritis) d. Complications of arteriography 3. Brainstem hemorrhage 4. Brainstem and 4th ventricular tumors 5. Mesencephalic cleft 6. Chiari malformation, and associated hydrocephalus and syringobulbia 7. Infection, including bacterial, viral, spirochetal, and other forms of menigoencephalitis 8. Hydrocephalus 9. Subdural hematoma 10. Supratentorial arteriovenous malformation 11. Nutritional disorders a. Wernickes encephalopathy b. Pernicious anemia 12. Metabolic disorders a. Hepatic encephalopathy b. Maple syrup urine disease c. Abetalipoproteinemia d. Fabry disease 13. Drug intoxications a. Phenothiazmes b. Tricyclic antidepressants c. Narcotics d. Propranolol e. Lithium f. Barbiturates g. Toluene 14. Cancer a. Direct effect ( e. g., brainstem infiltration) b. Remote ( paraneoplastic) effect 15. Injury a. Blunt head trauma b. Cervical hyperextension c. Neck manipulation ( e. g., chiropractic) 16. Degenerative conditions ( e. g., progressive supranuclear palsy) 17. Pscudointernuclear ophthalmoplegia of myasthenia gravis and myotonic dystrophy Modified from Zee DS. Supranuclear and intcrnuclcar disorders of ocular motility. In: Walsh and Hoyt's Clinical Nearo- Ophlhalmology. Vol I. 5th ed. Eds, Miller NR, Newman NJ. Baltimore, Williams & Wilkins, 1998; 1298- 1305. a variety of other causes can produce INO ( Table 1) ( 10). In particular, a variety of substances, including pheno-thiazines ( 11), tricyclic antidepressants ( 12- 14), narcotics ( 15,16), barbiturates ( 17), propranolol ( 18), and lithium ( 19) can cause neurotoxicity that includes bilateral INO. In our patient, MS was considered the most likely cause of the patient's neurologic disorder, and the patient underwent neuroimaging studies and a lumbar puncture in an attempt to confirm this diagnosis. When these studies failed to confirm a diagnosis of MS, alternative causes were considered. Our case indicates that toluene should be added to the list of causes of an INO and that chronic toluene abuse should be considered in any patient who has pendular nystagmus associated with bilateral INO, particularly when neuroimaging studies, lumbar puncture, evoked potentials, serologic studies, or a combination of these diagnostic techniques failed to document the presence of any of the more common causes of the disorder, such as MS or vasculitis. This is especially important because, although the neurotoxicity of toluene can produce a clinical picture similar to that of MS ( 5), patients who abuse toluene may experience improvement in neurologic and ocular manifestations with abstinence from the substance ( 1), whereas continued abuse can result in a progressive decline in neurologic function. REFERENCES 1. Hormes . IT, Filley CM, Rosenberg NL. Neurologic sequelae of chronic solvent vapor abuse. Neurology 1986; 36: 698- 702. 2. Lazar RB, Ho SU, Mclen O, Daghestani AN. Multifocal central nervous system damage caused by toluene abuse. Neurology 1983: 33: 1337- 40. 3. Sasa M, Igarashi S, Miyazaki T, Miyazaki K, Nakano S, Matsuoka I. Equilibrium disorders with diffuse brain atrophy in long- term toluene sniffing. Arch Otorlhnolaryngol 1978; 221: 162- 9. 4. Ron MA. Volatile substance abuse: a review of possible long term neurological, intellectual and psychiatric sequelae. Br .1 Psychiatry 1986; 148: 235^ 16. 5. 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