Phenytoin and Driving Safety

Patients with epilepsy are at elevated risk for automobile crashes, causing great personal
suffering and financial costs to society. Most collisions involving epileptic drivers are not
seizure related but may instead result from cognitive effects upon driving performance of
epilepsy and antiepileptic drugs (AEDs). Several million American drivers take AEDs for
treatment of medical conditions besides epilepsy and may also be at risk for cognitive
impairments that can reduce driving performance. Empirical evidence of the effects of AEDs on
driving performance would enable development of driving guidelines that could lower the risk
of injurious motor vehicle collisions; however, this evidence is currently lacking.

The broad goal of the current project is to determine the specific effects of AEDs on
cognitive function and driving performance. To address this goal we will assess driving
performance and cognitive abilities in neurologically normal volunteers taking phenytoin
(Dilantin), the most commonly prescribed AED. Effects of phenytoin on driving performance and
cognition will be addressed in a randomized, double-blind, placebo-controlled, crossover
study. Driver cognition will be assessed using a battery of neuropsychological tests. Driving
performance will be objectively assessed in all participants on standardized tasks enacted in
a state-of-the-art driving simulator. Our 3 Specific Aims are:

Aim 1: To assess the effects of phenytoin on cognitive abilities that are crucial to the
driving task, including perception, attention, memory, and executive function.

Hypothesis 1: A driver's cognitive abilities will decline during steady-state phenytoin
administration compared to placebo. Drivers with higher blood levels of phenytoin will show
greater decline.

Aim 2: To assess effects of phenytoin on driving performance and safety errors in a
state-of-the-art driving simulator.

Hypothesis 2: Driving performance will decline and driver safety errors will increase during
phenytoin administration compared to placebo. Drivers with higher blood levels of phenytoin
will show greater impairments of driving.

Aim 3: To assess the effects of phenytoin-related cognitive impairments upon driving
performance in a state-of-the-art driving simulator.

Hypothesis 3. Impairments of cognitive function affecting perception, attention, memory,
executive function, and arousal will increase the likelihood of driver errors that may lead
to a crash.

Our hypotheses would be supported if the drivers taking phenytoin, as opposed to placebo,
demonstrate worse cognitive performance on neuropsychological tests, and more safety errors
and crashes in the simulator. The hypotheses would also be supported if drivers with higher
phenytoin levels show greater impairments of cognition and driving. Once the effects of
phenytoin on driving performance are demonstrated in this project, we will have evidence to
support more comprehensive research addressing specific dosing and serum levels and acute
versus chronic administration.

There is currently no evidence concerning the effects of phenytoin on driving performance.
Accurate driving performance data on patients receiving phenytoin would allow determination
of fair and accurate criteria for making recommendations to drive or not to drive affecting
millions of patients taking AEDS for epilepsy and other conditions. These data could also
help reduce the risk of car crashes due to medication side effects.

Inclusion Criteria:

- Anticipating a 10-15% drop-out rate, we will induct 30 neurologically normal subjects
(age 18 (21) -60) to obtain 25 evaluable subjects who are legally licensed to drive in
their state of residence and have been actively driving under appropriate legal
guidelines for at least 5 years (to minimize performance variations of novice
drivers).

- Because this study is intended to determine the potential effects of phenytoin on
driving performance, a relatively healthy cohort of patients must be chosen. Chronic
medical or psychiatric conditions could cause significant alterations in driving
performance independent of those caused by phenytoin, which would complicate
interpretation of performance impairments.

Exclusion Criteria:

- Subjects who are younger than 18 or older than 60

- Have history of prior seizures, family history of epilepsy, or prior history of head
injury

- Have a known history of prior drug or alcohol abuse or unwillingness to abstain from
drug or alcohol use during the study period

- Have a past or current active neurological or psychiatric disorder that could impair
cognitive or driving performance (i.e. baseline IQ < 90, dementia, mental retardation,
stroke, severe head injury, schizophrenia, active clinical depression, progressive
brain tumor).

- Subjects who have a chronic medical condition (i.e. diabetes mellitus, renal
insufficiency, congestive heart failure, hepatic dysfunction, hematologic condition,
HIV)

- Taking medications known to affect the central nervous system (i.e. baseline pre-study
treatment with antiepileptic drug, anxiolytics, sedatives, hypnotics, antidepressants,
antipsychotics, narcotics and tranquilizers)

- Regularly use over-the-counter cough suppressants, antihistamines, or sleep aids; or
who ingest over 7 cups of daily coffee or currently smoke cigarettes.

- Subjects will be excluded if they cannot complete SIREN testing or neuropsychological
instruments because of visual or hearing impairment (history or screening discovery of
corrected visual acuity of less than 20/50) or other physical disability, or if they
have a history of severe motion sickness as an adult—a marker for patients who develop
simulator sickness and therefore cannot participate in SIREN testing.