Brain Injury, June 2011; 25(6): 634–637

CASE STUDY

Adverse cognitive effects of phenytoin in severe brain injury: A

case report

COLIN PINDER1,2 & CAROLYN YOUNG1

1
The Walton Centre NHS Foundation Trust, Fazakerley, Liverpool, UK and 2Wirral Neuro-Rehabilitation Unit,
Clatterbridge Hospital, Wirral, Merseyside, UK

(Received 5 August 2010; revised 3 March 2011; accepted 14 March 2011)

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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.

no consistent indication of choice of anticonvulsants to use in this situation.

Conclusion: As a result of the dramatic improvement in this case, one should now routinely withdraw or change phenytoin
treatment in all brain injury patients with significant cognitive impairment.

Keywords: Anticonvulsants

Introduction prophylactic anticonvulsants do reduce the risk of

There is debate about the use of prophylactic
anticonvulsants following severe brain injury.
Historically many clinicians (60% of board-certified
neurosurgeons) would use prophylactic anti-epilep-
tics in head-injured patients [1]. More recently
in 1995 the task force of the Brain Trauma
Foundation still suggested the use of anti-epileptic
prophylaxis in head-injured patients [2].
Anticonvulsants given prophyllactically have been
shown to reduce the rate of seizures in the first week
after injury, but not to have significant benefit in
terms of reducing the rate of late post-traumatic
seizures. Recently some have still recommended that
phenytoin be commenced in loading doses (intrave-
nously) as soon as possible after injury [3], but
Latronico et al. [4] stated that this recommendation
was based on weak evidence and should not be
implemented. Schierhout and Roberts [5], despite
acknowledging that there is evidence that
early seizures, recommended that there was insuffi-
cient evidence to establish the net benefit of the use of
prophylactic anticonvulsants at any time after injury.
Reflecting the conflicting advice from the litera-
ture, some patients are still treated with anticonvul-
sants prophyllactically. Anticonvulsants may also be
used for other patients as treatment for early
symptomatic seizures. Prevention of early seizure
activity may help to reduce secondary injury caused
by such seizure activity. There is also some evidence
that some anticonvulsants may have a neuroprotec-
tive effect, e.g. phenytoin [6], and hence improve
neurological outcome. Phenytoin is often used as it
can be given intravenously and has a rapid onset of
action. Anticonvulsants are, however, sometimes
continued longer term if the decision to treat is not
reviewed. Phenytoin in particular can have signifi-
cant side-effects. Temkin et al. [7] and McQueen
et al. [8] showed increased rates of skin rashes;

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

relative risks of 1.39 and 4.76, respectively; in
patients treated with phenytoin. Temkin et al. also
documented neurobehavioural effects with cognitive
impairments in patients receiving anti-epileptics.
In view of the non-linear relationship (and the
variability of this relationship) between dose and
serum levels of phenytoin, it can be very difficult to
ensure appropriate blood levels. Personal experience
shows that these cognitive effects can sometimes be
very severe. This study reports a case of a patient
with severe cognitive impairment following a brain
injury and late epilepsy who rapidly improved
following the withdrawal of Phenytoin.
Case history
A 43-year old lady with a history of rheumatoid
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arthritis was admitted to hospital having collapsed
at home. Computed tomography of her head showed
subarachnoid haemorrhage, with an inter-hemi-
spheric fissure clot and hydrocephalus. She had an
external ventricular drain (EVD) inserted.
Angiogram showed a pericallosal aneurysm which
was treated by endovascular coiling 4 days later.
For personal use only.
Despite an episode of meningitis in the intervening
period, 3 weeks post-haemorrhage it is recorded that
she was ‘lucid, orientated and not confused’. One
week later she had a further episode of infection, CT
scan showed a right frontal abscess formation. Over
the following 4 months she continued to have
problems with persistent infection including ventri-
culitis and hydrocephalus requiring prolonged intra-
venous and intrathecal antibiotics and several
revisions of her EVD. Approximately 3 months
following her haemorrhage she had a generalized
tonic clonic convulsion. Immediately afterwards she
had a further four convulsions and was started on
phenytoin (initially intravenously), after which her
seizures settled.
Her infection settled over the following month. At
this point she was able to walk with a frame but was
severely disorientated, had severe memory impair-
ment and required constant prompting to initiate
and carry out all activities of daily living. Although
there was some slight improvement over the subse-
quent weeks she remained severely disorientated.
Other problems including dysphasia, perseveration
and perceptual difficulties became apparent. There
was very little further change prior to her transfer
back to her district general hospital, 6 months after
her haemorrhage.
She was then transferred to the rehabilitation unit
for further assessment, nearly 8 months following
her haemorrhage. She was found to have poor
attention (focused for 3 minutes in therapy;
required supervision whilst eating, despite normal
Adverse cognitive effects of phenytoin 635
swallowing); she was totally disoriented to time and
place; she had very poor semantic, episodic and
anterograde memory; she perseverated such that she
had difficulty finishing simple tasks; she wandered
aimlessly around the unit; she had no initiation of
activities, even toileting, resulting in incontinence
unless routinely toileted regularly. In view of her
poor prognosis for further recovery (based on lack of
improvement and length of time since injury) and
intensity of the future nursing input she would
require, 9 months following her injury the authors
met with her family and recommended considering
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
(recommended range 10–20 mg l 1). Her phenytoin
dose was therefore reduced from 350 mg to 300 mg
per day.
Following this she became brighter, more alert
and needed less assistance for cueing of activities.
Her memory improved such that she could remem-
ber therapists’ names and could find her way around
the unit unprompted. Although her orientation
improved, she remained disorientated in time and
place. Her mood became more positive and her
initiation improved. Her ability to learn tasks (pro-
cedurally) improved.
Her phenytoin level was rechecked and found to
be low at 7.2 mg l 1. In view of the severity of her
seizures at onset, her phenytoin dose was increased
back to an intermediate dose of 325 mg day 1.
Following this, her cognitive function deteriorated
again, she became disorientated, she lacked initia-
tion, her abilities in personal activities of daily living
became worse. Her phenytoin level had increased
but was still in the sub-therapeutic range at 8.6.
In view of the deterioration in her condition with
the higher dose of phenytoin, a decision was made to
change her anti-epileptic medication to carbameze-
pine and her phenytoin was gradually withdrawn.
Following this she gradually became more orien-
tated. Her initiation improved. Her executive func-
tion improved such that within 3 weeks of reducing
her phenytoin she was able to make hot drinks safely
and could recall information over a period of 10
minutes.
Over the next few weeks she improved further so
that she would respond to prompts from a Datalink
wrist watch to the extent that she became continent.
She became orientated to time and place. This was
11 months following her brain injury, but only 5
weeks after the initial reduction in her phenytoin.
She continued to improve such that it was possible
to discharge her home to the care of her father 2
months following commencing the reduction in
Phenytoin.
 636 C. Pinder & C. Young
She was reviewed 2 months following discharge.
At this point she was starting to use memory
strategies effectively and did not have a problem
with forgetting things.
Four months following discharge (13 months
post-injury) she underwent neuropsychological
assessment. This showed preserved accuracy of
work, verbal recognition, visual learning, visual
discrimination, space perception and social skills;
mild impairment in immediate memory, working
memory, verbal reasoning, visuo-constructional
skills; moderate impairment in working memory;
severe impairment in language, attention and imme-
diate and delayed verbal and visual recall; and very
severe impairment of delayed memory, visual scan-
ning speed, number and letter sequencing and
attentional switching.
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When reviewed 8 months following discharge she
had improved further. She was having less problems
with memory and attention and had now started
doing voluntary work in a charity shop.
Twenty-five months post-injury she underwent
further neuropsychological testing. There had been
further improvements in working memory (now
mildly impaired) and verbal recall and retention
For personal use only.
(now moderately impaired).
When last reviewed 31 months post-injury, she felt
that she had improved further. She was having fewer
problems with her memory, though recognized that
it was not back to normal. She was still doing
voluntary work, but was working with the local
disability employment advisor towards returning to
paid work. She had returned to driving. She had had
no further fits since discharge from the neurosurgical
unit.
Discussion
Previous studies regarding the cognitive side-effects
of anticonvulsants have shown contradictory results.
Some studies have shown that there are increased
cognitive side-effects of anticonvulsants in patients
with epilepsy [9, 10]. Thompson and Trimble [9]
showed deficits in psychological test performance
at high serum concentrations in epilepsy patients on
anticonvulsants (mainly phenytoin or carbameze-
pine). Trimble and Thompson [10] showed that
healthy volunteers experienced significant deficits
of cognitive function and behaviour. The most
widespread changes experienced were in those on
phenytoin. Patients with high anticonvulsant levels
performed worse and improved when the dosage was
reduced; and if carbamezepine was substituted for
another drug then performance improved [10].
Dikmen et al. [11] showed that patients with
severe brain injury who were taking prophylactic
Phenytoin performed worse at 1 month post injury,
than those taking placebo, on a neuropsychological
test battery including tests of attention, speed and
memory; and two psychosocial measures. Also
patients who stopped taking phenytoin improved
more than the patients who continued on it.
However, those with moderate injury did not show
a difference. Neither group showed a difference at
1 year [12]. Ellenberg et al. [13] found that use of
phenytoin was associated with a longer duration of
post-traumatic amnesia and was also predictive of
6 month outcome, although this did not control for
injury severity. This case demonstrates the extent
which patients can improve following the discontin-
uation of Phenytoin.
Smith et al. [14] compared the adverse cognitive
effects of phenytoin with carbamezepine. They
concluded that both phenytoin and carbamezepine
seem to have negative effects on performance. The
differences between the two drugs were small. This
was only significant for speed of finger tapping
(worse for phenytoin) and delayed recall (worse for
carbamezepine). Meador et al. [15] did not find any
differences on neuropsychological evaluation
between phenytoin and carbamezepine in patients
with complex partial epilepsy. In the above patient
there was a significant improvement in cognitive
function, despite her remaining on carbamezepine,
suggesting that, particularly in this case, carbameze-
pine may have less of an effect on cognition.
Conclusion
This case demonstrates the possible severity and
significance of the cognitive side-effects that phenyt-
oin can cause, even with non-toxic blood levels and
the possible benefit that can be obtained by with-
drawing it. Several studies have shown that cognitive
side-effects do occur with phenytoin, particularly
among those with severe brain injury. However,
evidence for the differential effect compared to other
anticonvulsants is lacking.
This case has led the authors to change their
practice so that patients with severe brain injury who
are on phenytoin have this withdrawn or changed to
an alternative anticonvulsant. This approach has led
to observing of other similar (albeit less dramatic)
improvements in cognitive function when phenytoin
is withdrawn.
Declaration of Interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.

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