CASE STUDY
Abstract
Background: The use of prophylactic anticonvulsants following brain injury is controversial. When used for this reason or
for treatment of early seizures, anticonvulsants, particularly phenytoin, can cause severe cognitive side-effects.
Case report: This study presents a case of a woman with a severe brain injury with severe cognitive impairment who improved
dramatically following withdrawal of phenytoin. The literature regarding such cognitive side-effects is contradictory with
For personal use only.
Keywords: Anticonvulsants
Correspondence: Dr Colin Pinder, Consultant in Neurological Rehabilitation, The Walton Centre NHS Foundation Trust, Lower Lane, Fazakerley,
Liverpool L9 7LJ, UK. Tel: 01515292947. Fax: 01515298594. E-mail: colin.pinder@nhs.net
ISSN 0269–9052 print/ISSN 1362–301X online ß 2011 Informa UK Ltd.
DOI: 10.3109/02699052.2011.572946
Adverse cognitive effects of phenytoin 635
relative risks of 1.39 and 4.76, respectively; in swallowing); she was totally disoriented to time and
patients treated with phenytoin. Temkin et al. also place; she had very poor semantic, episodic and
documented neurobehavioural effects with cognitive anterograde memory; she perseverated such that she
impairments in patients receiving anti-epileptics. had difficulty finishing simple tasks; she wandered
In view of the non-linear relationship (and the aimlessly around the unit; she had no initiation of
variability of this relationship) between dose and activities, even toileting, resulting in incontinence
serum levels of phenytoin, it can be very difficult to unless routinely toileted regularly. In view of her
ensure appropriate blood levels. Personal experience poor prognosis for further recovery (based on lack of
shows that these cognitive effects can sometimes be improvement and length of time since injury) and
very severe. This study reports a case of a patient intensity of the future nursing input she would
with severe cognitive impairment following a brain require, 9 months following her injury the authors
injury and late epilepsy who rapidly improved met with her family and recommended considering
following the withdrawal of Phenytoin. a nursing home placement.
A few days later she became very drowsy. Her
phenytoin level was found to be raised at 28.9 mg l 1
Case history (recommended range 10–20 mg l 1). Her phenytoin
dose was therefore reduced from 350 mg to 300 mg
A 43-year old lady with a history of rheumatoid
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per day.
arthritis was admitted to hospital having collapsed
Following this she became brighter, more alert
at home. Computed tomography of her head showed
and needed less assistance for cueing of activities.
subarachnoid haemorrhage, with an inter-hemi-
Her memory improved such that she could remem-
spheric fissure clot and hydrocephalus. She had an
ber therapists’ names and could find her way around
external ventricular drain (EVD) inserted.
the unit unprompted. Although her orientation
Angiogram showed a pericallosal aneurysm which
was treated by endovascular coiling 4 days later. improved, she remained disorientated in time and
For personal use only.
Despite an episode of meningitis in the intervening place. Her mood became more positive and her
period, 3 weeks post-haemorrhage it is recorded that initiation improved. Her ability to learn tasks (pro-
she was ‘lucid, orientated and not confused’. One cedurally) improved.
week later she had a further episode of infection, CT Her phenytoin level was rechecked and found to
scan showed a right frontal abscess formation. Over be low at 7.2 mg l 1. In view of the severity of her
the following 4 months she continued to have seizures at onset, her phenytoin dose was increased
problems with persistent infection including ventri- back to an intermediate dose of 325 mg day 1.
culitis and hydrocephalus requiring prolonged intra- Following this, her cognitive function deteriorated
venous and intrathecal antibiotics and several again, she became disorientated, she lacked initia-
revisions of her EVD. Approximately 3 months tion, her abilities in personal activities of daily living
following her haemorrhage she had a generalized became worse. Her phenytoin level had increased
tonic clonic convulsion. Immediately afterwards she but was still in the sub-therapeutic range at 8.6.
had a further four convulsions and was started on In view of the deterioration in her condition with
phenytoin (initially intravenously), after which her the higher dose of phenytoin, a decision was made to
seizures settled. change her anti-epileptic medication to carbameze-
Her infection settled over the following month. At pine and her phenytoin was gradually withdrawn.
this point she was able to walk with a frame but was Following this she gradually became more orien-
severely disorientated, had severe memory impair- tated. Her initiation improved. Her executive func-
ment and required constant prompting to initiate tion improved such that within 3 weeks of reducing
and carry out all activities of daily living. Although her phenytoin she was able to make hot drinks safely
there was some slight improvement over the subse- and could recall information over a period of 10
quent weeks she remained severely disorientated. minutes.
Other problems including dysphasia, perseveration Over the next few weeks she improved further so
and perceptual difficulties became apparent. There that she would respond to prompts from a Datalink
was very little further change prior to her transfer wrist watch to the extent that she became continent.
back to her district general hospital, 6 months after She became orientated to time and place. This was
her haemorrhage. 11 months following her brain injury, but only 5
She was then transferred to the rehabilitation unit weeks after the initial reduction in her phenytoin.
for further assessment, nearly 8 months following She continued to improve such that it was possible
her haemorrhage. She was found to have poor to discharge her home to the care of her father 2
attention (focused for 3 minutes in therapy; months following commencing the reduction in
required supervision whilst eating, despite normal Phenytoin.
636 C. Pinder & C. Young
She was reviewed 2 months following discharge. Phenytoin performed worse at 1 month post injury,
At this point she was starting to use memory than those taking placebo, on a neuropsychological
strategies effectively and did not have a problem test battery including tests of attention, speed and
with forgetting things. memory; and two psychosocial measures. Also
Four months following discharge (13 months patients who stopped taking phenytoin improved
post-injury) she underwent neuropsychological more than the patients who continued on it.
assessment. This showed preserved accuracy of However, those with moderate injury did not show
work, verbal recognition, visual learning, visual a difference. Neither group showed a difference at
discrimination, space perception and social skills; 1 year [12]. Ellenberg et al. [13] found that use of
mild impairment in immediate memory, working phenytoin was associated with a longer duration of
memory, verbal reasoning, visuo-constructional post-traumatic amnesia and was also predictive of
skills; moderate impairment in working memory; 6 month outcome, although this did not control for
severe impairment in language, attention and imme- injury severity. This case demonstrates the extent
diate and delayed verbal and visual recall; and very which patients can improve following the discontin-
severe impairment of delayed memory, visual scan- uation of Phenytoin.
ning speed, number and letter sequencing and Smith et al. [14] compared the adverse cognitive
attentional switching. effects of phenytoin with carbamezepine. They
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When reviewed 8 months following discharge she concluded that both phenytoin and carbamezepine
had improved further. She was having less problems seem to have negative effects on performance. The
with memory and attention and had now started differences between the two drugs were small. This
doing voluntary work in a charity shop. was only significant for speed of finger tapping
Twenty-five months post-injury she underwent (worse for phenytoin) and delayed recall (worse for
further neuropsychological testing. There had been carbamezepine). Meador et al. [15] did not find any
further improvements in working memory (now differences on neuropsychological evaluation
mildly impaired) and verbal recall and retention
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6. Tasker RC, Coyle JT, Vornov JJ. The regional vulnerability of Neurology 1996;53:782–791.
to hypoglycaemia-induced neurotoxicity in organotypic 14. Smith K, Goulding P, Wilderman D, Goldfader P,
hippocampal culture; Protection by early tetrodotoxin or Holterman-Hommes P, Wei F. Neurobehavioural effects of
delayed MK-80 1. Journal of Neuroscience 1992;12: phenytoin and carbamezepine in patients recovering from
4298–4308. brain truama: A comparative Study. Archives of Neurology
7. Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, 1994;51:653–660.
Winn HR. A randomized, double-blind study of phenytoin 15. Meador K, Loring D, Huh K, Gallagher B, King D.
for the prevention of post-traumatic seizures. New England Comparative cognitive effects of anticonvulsants. Neurology
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