Nystagmus-induced phenytoin toxicity is directly related to the blood levels of the drug. Fine nystagmus may occur even at therapeutic dosages, but coarse nystagmus is indicative of toxic states. Downbeat and unidirectional gaze paretic nystagmus have also been reported. Instances of nystagmus persisting for 20 months or longer after discontinued use of phenytoin have been reported. Paralysis of extraocular muscles is uncommon, reversible and primarily found in toxic states. Remler et al (1990) have reported an idiosyncratic response in patients on carbamazepine and phenytoin with an increase in incidences of vertical and horizontal diplopia with or without oscillopsia. This appears to be a central effect on the vergence centers and/ or the vestibulo-ocular reflex. A prodrome of ocular or systemic ‘discomfort’ frequently occurred prior to the onset of the above. Color vision changes are complex with various manifestations, including frosting or white tinges on objects, decreased brightness or specific color loss. Benign intracranial hypertension in a patient with a seizure disorder has been confirmed with phenytoin rechallenge. Bar et al (1983) and Mathers et al (1987) reported cases of presenile cataracts in patients on prolonged hydantoin therapy at toxic levels of phenytoin or with ­concomitant phenobarbital ingestion.

Phenytoin alone or in combination has a two to three times greater risk for delivering a child with congenital defects. Ocular abnormalities are not unusual in these deformities.

References and Further Reading

Bar S, Feller N, Savir N. Presenile cataracts in phenytoin-treated epileptic patients. Arch Ophthalmol 101: 422, 1983.

Bartoshesky LE, et al. Severe cardiac and ophthalmologic malformations in an infant exposed to diphenylhydantoin in utero. Pediatrics 69: 202, 1982.

Bayer A, Zrenner E, Thiel HJ, et al. Retinal disorders induced by anticonvulsant drugs. Third Congress, International Society of Ocular Toxicology, November 15–19, Sedona, Arizona, pp 11, 1992.

Bayer A, Thiel HJ, Zrenner E, et al. Sensitive physiologic perceptual tests for ocular side effects of drugs exempliflied by various anticonvulsants. Pediatrics 92(2): 182–190, 1995.

Boles DM. Phenytoin ophthalmoplegia. S Afr Med J 65: 546, 1984. Glover SJ, Quinn AG, Barter P, et al. Ophthalmic findings in fetal anticon-

vulsant syndrome. Ophthalmology 109: 942–947, 2002.

Herishanu Y, Osimani A, Louzoun Z. Unidirectional gaze paretic nystagmus induced by phenytoin intoxication. Am J Ophthalmol 94: 122, 1982.

Kalanie H, et al. Phenytoin-induced intracranial hypertension. Neurology 36: 443, 1986.

Lachapelle P, Blain L, et al. The effect of diphenylhydantoin on the ­electroretinogram. Doc Ophthalmol 73: 359–368, 1990.

Mathers W, et al. Development of presenile cataracts in association with high serum levels of phenytoin. Ann Ophthalmol 19: 291, 1987.

Puri V, Chaudhry N. Total external ophthalmoplegia induced by phenytoin: a case report and review of literature. Neurol India 52: 386–387, 2004.

Remler BF, Leigh J, Osorio I, Tomsak RL. The characteristics and mechanisms of visual disturbance associated with anticonvulsant therapy. Neurology 40: 791–796, 1990.

Rizzo M, Corbett J. Bilateral internuclear ophthalmoplegia reversed by naloxone. Arch Neurol 40: 242, 1983.

Shores MM, Sloan KL. Phenytoin-induced visual disturbances misdiagnosed as alcohol withdrawal. Psychosomatics 43: 336–355, 2002.

Spaeth GL, Nelson LB, Beaudoin AR. Ocular teratology. In: Ocular Anatomy, Embryology and Teratology, Jakobiec FA (ed), J.B. Lippincott, Philadelphia, pp 955–981, 1982.

Wittbrodt ET. Drugs and myasthenia gravis: an update. Arch Intern Med 157: 399–408, 1997.

Generic names: 1. Sodium valproate; 2. valproate semisodium; 3. valproic acid.

Proprietary names: 1. Depacon; 2. Depakote; 3. Depakene, myproic acid.

Primary use

Valproic acid is a carboxylic acid derivative, and sodium valproate is the sodium salt of valproic acid. Valproate semisodium is a compound comprised of sodium valproate and valproic acid. These antiepileptic agents are used in the prophylactic management of petit mal seizures.

Ocular side effects

Systemic administration

Certain

1. Blurred vision

2. Diplopia

3. Nystagmus

4. Oscillopsia

5. Visual hallucinations

Possible

1.Non-specific ocular irritation

a.Ocular pain

b.Photophobia

2. Eyelids or conjunctiva

a.Stevens-Johnson syndrome

b.Toxic epidermal necrolysis

c.Conjunctivitis

3. Subconjunctival or retinal hemorrhages secondary to drug-induced hemopoietic abnormalities

Conditional/Unclassified

1. Intracranial hypertension

Ocular teratogenic effects – fetal anticonvulsant syndrome­

Certain

1. Myopia

Probable

1. Hypoplastic front – orbital edges

2. Proptosis

3. Depigmentation of eyelashes and eyebrows

4. Epicanthus

5. Shallow orbitals

6. Septo-optic dysplasia

Clinical significance

All three agents appear to have identical adverse ocular side effects. Compared to placebo, in clinical trials by the manufacturers all three drugs caused diplopia, blurred vision and nystagmus. There may be an idiosyncratic susceptibility in some patients characterized by various forms of diplopia, oscillopsia, impaired vergence mechanisms, vertical nystagmus or abnormalities of the vestibular-ocular reflex due to these drugs. Other side effects include ocular motor abnormalities involving pursuit and gaze holding patterns. Based on animal work, this group of drugs may have some effect on the retinal pigment epithelium. A 14-year- old showed retinal pigment epithelial changes while on valproic acid, but there are no other clinical data to support this. Bayer et al (1997) feel that based on psychophysical testing, valproic

CNS the affecting Agents • 2 Section