King Edward Memorial Hospital - Departments: Clinical Pharmacology- ADR April 2005

Clinical Pharmacology

"Adverse Drug Event of the month"

Month :	April
Year :	2005
Department of Clinical Pharmacology* and Dermatology**	M N Patekar, R Sonawane, N J Gogtay, S S Mehta*, N A Kshirsagar

Other Cases

Phenytoin induced agitation

Case report:

A 35-year-old female was admitted to general medical ward of our institution with complaints of agitated behavior. She gave history of consumption of an unknown quantity of phenytoin tablets. The patient was very restless at presentation. She was not able to recognize relatives and was confused in time and place. She also complained of urinary incontinence. She did not have any history of fever, convulsions or trauma. There was no other significant past history. There was no history of similar complaints in the past. There was no family history of any psychiatric illness.

The patient was a known case of seizure disorder and was under treatment with tablet phenytoin 300 mg daily (morning-100mg, night-200mg) since the age of seven years. On examination her vital signs were stable. On central nervous system examination she was very restless and agitated. She was disoriented in time, place and person. However she was able to follow simple oral commands. Cerebellar examination showed a positive finger-nose-finger test. She was not able to stand or walk without support. There was no nystagmus. All other central nervous system examination was normal.

Laboratory findings on admission (Day 1) were as follows

SGOT	232 IU/L
SGOT	115 IU/L
Random Blood Sugar	169 IU/dL

Her CSF examination was normal; it did not show any pus cells.
Plasma phenytoin levels were 77.7 µg/ml (Normal 10-20 µg/ml).

In view of the history of over ingestion of phenytoin tablets and toxic serum phenytoin levels the agitation was attributed to phenytoin. A causality analysis was done using Naranjo's algorithm and a score of 4 (possible adverse drug reaction) was obtained.

Phenytoin was stopped immediately on admission. The patient was managed in the ward symptomatically. She was started on valproic acid for her seizure disorder. She was referred to psychiatry department for evaluation and was diagnosed to have behavioral disturbances with depressed mood with deliberate self-harm (DSH) attempt. She was prescribed tablet imipramine 25 mg twice daily and chlordiazepoxide 10 mg daily. Over next seven days the patient improved gradually and was ambulatory. Imipramine and chlordiazepoxide were tapered and stopped.

Discussion:
Phenytoin is a widely used antiepileptic drug that has been extensively studied with respect to both its efficacy as well as adverse effects. Phenytoin toxicity can lead to increased levels of hepatic enzymes possibly by induction of their synthesis. At times phenytoin at toxic concentrations can exacerbate seizures or even precipitate generalized status in some epileptic patients, a paradoxical effect. In such cases decrease in serum phenytoin levels produced an improvement (1, 2). However phenytoin induced agitation in adults is not reported in literature.

Clinical features of acute overdosage with phenytoin include nystagmus, blurred vision, diplopia and ataxia, nausea, vomiting, drowsiness, stupor, and finally coma with hypotension (3).

Overdosage in humans has been reported to cause computerized tomographic appearance of cerebellar atrophy (4).

Till date only one report of agitation with restlessness and choreoathetosis has been published where 3 children developed choreoathetosis and marked agitation during phenytoin therapy and discontinuation of phenytoin resulted in prompt cessation of symptoms (5).

Agitation includes inappropriate verbal, vocal, or motor behaviors that, in the opinion of an observer, do not result directly from the needs or confusion of the agitated individual. At present the exact mechanism that might have led to agitation following phenytoin toxicity in this patient is not clear.

This report underlines the need to continuously monitor drug for its adverse events even if the drug is in use for long since such rare adverse events can be picked up only on widespread use of the drug. This needs alertness and an open approach on part of the treating physician to such reactions, which might be ignored if one is not vigilant.

Note: Please report adverse events to us (any adverse event associated with drugs newly marketed within last four years or unusual, uncommon adverse events with the older drugs). The Adverse Drug Event Reporting Form can be downloaded from http://cdsco.nic.in/adr3.pdf ). Please fax or post the report to us. You will get an acknowledgement from us within 72 hours and will be put on our mailing list. Please contribute to increasing the Indian database of Adverse Drug Reactions.

Please report to us at the following address - ·

Dept. of Clinical Pharmacology,
1st Floor, MS Building,
Seth GS Medical College and KEM Hospital,
Parel, Mumbai. 400012.
Ph. 91-22-24174420, 91-22-24133767
Fax 91-22-24143435
dcpkem@vsnl.com

References:

1.Chua HC, Venketasubramanian N, Tan CB, Tjia H. Paradoxical seizures in phenytoin toxicity. Singapore Med J 1999;40:276-7.
2. Osorio I, Burnstine TH, Remler B, Manon-Espaillat R, Reed RC. Phenytoin-induced seizures: a paradoxical effect at toxic concentrations in epileptic patients. Epilepsia 1989;30:230-4.
3. Dollery C, editor. Therapeutic drugs. 2nd ed. Edinburgh, UK: Churchill Livingstone; 1999. p. P110-4.
4. Masur H, Elger CE, Ludolph AC, Galanski M. Cerebellar atrophy following acute intoxication with phenytoin. Neurology 1989;39:432-3.
5. Krishnamoorthy KS, Zalneraitis EL, Young RS, Bernad PG. Phenytoin-induced choreoathetosis in infancy: case reports and a review. Pediatrics 1983;72:831-4.