386 Neurology India September 2004 Vol 52 Issue 3

386 CMYK

Vinod Puri16, Type 5, MAMC Campus, New Delhi - 110002, India. E-mail: vpuri@bol.net.in

Total external ophthalmoplegia induced by phenytoin: A casereport and review of literature

Vinod Puri, Neera ChaudhryDepartment of Neurology, G. B. Pant Hospital, New Delhi - 110002, India.

A 28-year-old male developed total external ophthalmople-gia following oral administration of phenytoin. The case isreported and its significance is discussed.

Key Words: External ophtalmoplegia, Phenytoin inducedophtalmoplegia, phenytoin toxicity.

Introduction

There have been innumerable reports concerning phenytoin

toxicity, but few have mentioned its effects on eye movements

other than nystagmus.1 Ophthalmoplegia has been reported

with administration of large doses of Phenytoin,2,3 Phenobar-

surgical excision because of their surface location and distinct

firmness with clear demarcation from the surrounding nor-

mal brain. No adjuvant therapy is recommended after total

excision, despite the fact that the lesion has a low malignant

potential. Long-term prognosis after total surgical excision

has been excellent in all the reported series.

Histologically, these tumors have intense desmoplasia, with

neoplastic astrocytes with occasional neuronal elements.

Desmoplastic cerebral astrocytoma of infancy and DIG are

difficult to differentiate under light microscopy. Immunohis-

tochemistry plays a very important role in the diagnosis of

DIG. In DIG, the tumor shows intense positivity for Glial

Fibrillary Acidic Protein (GFAP) which is a glial marker, with

areas positive for synaptophysin or neurofilament

immunostain, which are neuronal markers. In desmoplastic1,4,7

cerebral astrocytoma, there is positivity for GFAP only.

References

1. Vanden Berg SR, May EE, Rubeinstein LJ, et al. Desmoplastic supratentorial

neuroepithelial tumors of infancy with divergent differentiation potential

(“desmoplastic infantile gangliogliomas”). J Neurosurg 1987;66:58-71.

2. Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain

tumors. Brain Pathol 1993;3:255-68.

3. Duffner PK, Burger PC, Cohen ME, et al. Desmoplastic infantile

gangliogliomas: An approach to therapy. Neurosurg 1994;34:583-9.

4. Sperner J, Gottschalk J, Neumann K, et al. Clinical, radiological and histo-

logical findings in desmoplastic infantile ganglioglioma. Childs Nerv Syst

1994;10:458-63.

5. Martin DS, Levy B, Awwad EE, et al. Desmoplastic infantile ganglioglioma:

CT and MR features. Am J Neuroradiol. 1991;12:1195-7.

6. Tenreiro-Picon OR, Kamath SV, Knorr JR, et al. Desmoplastic infantile

ganglioglioma: CT and MRI features. Pediatr Radiol 1995;25:540-3.

7. VandenBerg SR. Desmoplastic infantile ganglioglioma and desmoplastic cer-

ebral astrocytoma of infancy. Brain Pathol 1993;3:275-81.

Accepted on 11.11.2003.

tive reaction for Synaptophysin and Chromogranin. The picture was

consistent with desmoplastic infantile ganglioglioma.

Discussion

Desmoplastic supratentorial neuroepithelial tumors of in-

fancy form a rare but distinctive group of tumors occurring in

children less than 2 years of age. Vanden Berg et al1 (1987),

named these tumors as desmoplastic cerebral astrocytoma of

infancy and desmoplastic infantile ganglioglioma (DIG), on

the basis of immunohistochemistry and electron microscopy.

Both these groups of tumors occur in children less than 2

years of age. They have identical clinical and radiological fea-

tures and both have favorable outcome following successful

excision. Subsequently, these groups of tumors have been in-

cluded as a distinctive group, in the revised World Health

Organization (WHO) classification of brain tumors (Kleihues

et al21993).

Less than 50 cases of desmoplastic infantile ganglioglioma

(DIG) have been reported in the literature. Several authors

have reported single case reports and small series of cases of

DIG.3,4 The youngest patient has been 4 months of age. All

these children presented with macrocephaly, seizures, psycho-

motor delay, either in isolation or in combination. All these

patients have similar Computerized Tomographic scan (CT)

and Magnetic Resonance Imaging (MRI) characteristics (Mar-

tin et al 1991, Tenreiro-Picon et al5,6 1995). The tumors com-

monly occur in frontal or parietal lobes, with a solid compo-

nent closely attached to the dura, which intensely enhances

with contrast, surrounded by a parenchymal cystic compo-

nent and mass effect. Most of these tumors are amenable to

Short Reports

387Neurology India September 2004 Vol 52 Issue 3

CMYK 387

bitone, Primodone, Carbamazepine and Amitriptyline. Spector

et al2 reported that phenytoin could induce total external oph-

thalmoplegia irrespective of oral or intravenous administra-

tion. Incomplete4 as well as complete ophthalmoplegia5 has

been reported with phenytoin even within therapeutic range.

We present a patient with phenytoin intoxication who devel-

oped disturbances in the ocular movements.

Case Report

A 28-year-old mentally retarded male, with IQ-55, had general-

ized tonic-clonic epilepsy for two years. He was placed on

carbamazepine (Tegretol) 800mg per day. However, due to financial

reasons, he was irregular with his treatment. Subsequently, he was

placed on Diphenyl hydantoin (300mg per day). After about two

weeks of the change in the drug treatment he reported inability to

move his eyes. He denied excessive ingestion of the drug. The pupils

were 5mm in diameter, round, equal and reacting well to light. The

gaze was fixed directly forward. The patient did not move his eyes on

command and could not follow the light. The eyes could not be moved

by head turning or neck bending or by irrigation of the ears with ice

water. Fundi were normal. The rest of the neurological examination

was normal. The cerebrospinal fluid examination was normal. The

CT of the head was normal. The phenytoin drug level was 22 microgm

per ml. The phenytoin was withdrawn and he was given loading dose

of phenobarbitone, followed by its maintenance dose. On the fifth

day, he could move his eyes about 100 in horizontal direction (later-

ally and medially) but was unable to move them in the vertical direc-

tion. On the seventh day, the horizontal movements had improved

and he could move the eyes slightly downward but not upward. Irri-

gation of the left ear with ice cold water produced no movements of

the eyes but irrigation of right ear produced occasional nystagmus

with fast component to the left. On the eleventh day his eye move-

ments were normal. He was seizure-free on 120 mgm of phenobarbi-

tone per day.

Discussion

Phenytoin is a vestibular depressant.6 Spector et al2 observed

that the return of vestibulo-ocular response in their patients

with phenytoin intoxication lagged behind the return of con-

sciousness and other reflex activities and attributed it to its

depressant effect on the vestibulo-oculomotor system which

may be out of proportion to its actions on other levels of the

neuraxis. The oculomotor unresponsiveness to cold caloric ir-

Calvarial malignant fibrous histiocytoma

R. Chhabra, S. K. Gupta, K. S. Manjunath Prasad, D. Gupta*, R. K. Vasishta*, R. K. Sharma**,V. K. KhoslaDepartments of Neurosurgery, *Pathology and **Plastic Surgery , PGIMER, Chandigarh, India.

S. K. GuptaAdditional Professor, Department of Neurosurgery, PGIMER, Chandigarh - 160012, India. E-mail: sktulika@yahoo.com

rigation may occur even when the blood phenytoin level is

within the accepted therapeutic range.

GABA mediates the inhibition of oculomotor neurons pro-

duced by the vestibular system. Phenytoin increases the post-

synaptic potentials produced by GABA in the cerebral cortex7

and the spinal cord. Spector et al2 attributed the unrespon-

sive cold caloric irrigation with phenytoin to an increased ef-

fectiveness of GABA-induced inhibition at the synapses of the

vestibulo-oculomotor system. The lag in the recovery of the

oculovestibular response in the present case could be explained

with the above said hypothesis.

The cerebellum has an inhibitory role over the vestibular–

ocular reflex through Purkinje cells. Phenytoin increases the

rate of Purkinje cell discharge.8 Whether this phenytoin-aug-

mented Purkinje cell firing would act in a manner analogous

to electric stimulation of the cerebellar cortex and result in

the depression of transmission through the vestibular nucleus

and affect the normal function of the vestibulo-ocular appa-

ratus is unclear. The majority of the reported cases of pheny-

toin-induced ophthalmoplegia recovered completely over a

variable period with normalization of the phenytoin level.

The present case is unique; in spite of the drug toxicity the

patient was alert and had bilateral external ophthalmoplegia

with loss of oculocephalic and oculovestibular reflexes. The

recognition of this entity is important to avoid unnecessary

investigations in a patient on phenytoin.

References

1. Remler BF, Leigh RJ, Osorio I, Tomsak RL. The characteristics and mecha-

nisms of visual disturbance associated with anticonvulsant therapy. Neurology

1990;40:791-6.

2. Spector RH, Davidoff RA, Schwartzman RJ. Phenytoin-induced ophthalmo-

plegia. Neurology 1976;26:1031-4.

3. Fredericks CA, Giannotta SL, Sadun AA. Dilantin-induced long-term bilateral

total external ophthalmoplegia. Clin Neuro ophthalmol 1986;6:22-6.

4. Manlapaz JS: Abducens nerve palsy in Dilatin intoxication. J Pediatr

1959;55:73-4.

5. Sandyk R. Total external ophthalmoplegia induced by phenytoin. A case re-

port. S Afr Med J 1984;28;65:141-2.

6. Posner JB, Plum F: Diagnostic significance of vestibulo-ocular responses. Neurol

Neurosurg Psychiatry 1975;38:727-8.

7. Davidoff RA: Dipenylhydantoin increases spinal presynaptic inhibition. Trans

Am Neurol Assoc 1972;97:193-5.

8. Halpern LM, Julien RM: Augmentation of cerebellar Purkinje cell discharge

rate after diphenylhydantoin. Epilepsia 1972,13:377-85.

Accepted on 12.06.2003.

Short Reports