Methylphenidate Treatment of Attention Deficits in Epilepsy

Prospective participants with seizures will be identified primarily through the Stanford
Neurology and Neuropsychiatry clinics and Stanford Medical Center, with the assistance of
clinic staff and providers. Participants may also be identified and referred by their
physicians in the community as well. Informational fliers will be distributed to these
clinics and throughout Stanford Medical Center and Stanford campus in order to identify
participants with epilepsy as well as healthy volunteers. Prospective participants may also
contact study staff directly via contact information listed on the flier or provided to them
by their providers. Those identified will be contacted, either in person or by telephone, by
study staff.

A telephone or in-person pre-screening will occur, expected to last approximately 20-30
minutes, in order to determine eligibility for the study, interest in participating, and any
questions related to the study. A brief summary of study procedures and goals will be
reviewed during this pre-screening. Participants who meet inclusion/exclusion criteria may
take part in an initial in-person visit at Stanford Medical Center, where informed consent
will be obtained and signed (see attached informed consent form). Any additional history
needed in order to confirm a participant's eligibility will be reviewed at this visit. If
the individual chooses to proceed, the participant's blood pressure and heartrate will be
measured, and if necessary (because a recent physical exam including cardiac auscultation is
not available), a brief physical exam will be performed by a licensed physician. If vital
signs and exam (if necessary) are normal, participants will be asked to complete
neuropsychiatric questionnaires, self-report questionnaires, a quality-of-life
questionnaire, and a seizure diary. The full 40-minute neurocognitive battery will be
performed, and baseline scores obtained.

Participants will be asked to complete the seizure diary once per week, either in-person at
their visits or at home. Thereafter, the participant will be asked to attend at least three
additional 2-hour sessions at Stanford Medical Center. The participant will be asked to
avoid taking any non-routine sedating medications within 24 hours of his/her scheduled
visit, and to refrain from eating, drinking caffeine, or smoking for 2 hours prior to
his/her visit. When the participant arrives, they will be given either a placebo, 20mg of
methylphenidate, or 40mg of methylphenidate (randomized and blinded by the research
pharmacy), and asked to remain within the hospital for 1 hour prior to testing to allow the
medication to enter their system. Both study staff and the participant will be blinded to
whether they are receiving active medication or placebo. During this time, the participant
will complete self-report questionnaires reporting any medication changes, medical events,
or significant adverse events, and their seizure diary will be reviewed and kept by study
staff. After this, the full neurocognitive battery will be completed. Following the
completion of neurocognitive testing, the participant's next visit will be scheduled for
approximately the same time of day in approximately one week, and payment will be provided.
This procedure will be repeated for the next two visits. Participants will not receive any
additional study drug during this period other than the single dose they receive in-person.

At the participant's fourth visit, they will be asked to repeat the neuropsychiatric
questionnaires from visit #1, as well as the usual self-report forms and seizure diary.
Heartrate and blood pressure will be obtained again prior to the administration of the
neurocognitive battery. At the end of the fourth visit, participants will be asked if they
wish to take part in the four-week open-label phase of this study, designed to evaluate the
ongoing efficacy and safety of methylphenidate for use in patients with epilepsy. Regardless
of their answer, payment will be provided for their fourth visit.

Those participants who are interested in participating in the open-label trial will be
provided with a prescription for two weeks of methylphenidate 10mg PO BID, followed by two
weeks of methylphenidate 20mg PO BID. Participants will be provided with copies of the
seizure diary and asked to complete it weekly. Participants will be able to contact the
protocol director by phone to report any significant side effects or adverse events during
this trial. At the protocol director's discretion, in keeping with standard of care for this
medication, the dosage of the medication may be lowered (minimum dose 5mg PO BID) in
response to any side effects experienced by participants during this period.

Participants in the open-label trial will be asked to return after four more weeks for a
fifth and final visit. Participants will again be asked to refrain from eating, caffeine,
and nicotine for 2 hours prior to their visit, and will take their prescribed
methylphenidate upon arriving at Stanford Medical Center. Participants will wait 1 hour for
the medication to enter their system, during which time they will complete neuropsychiatric
and self-report questionnaires as before, their seizure diaries will be reviewed, and their
heart rate and blood pressure will again be measured. The cognitive battery will be
administered again. Afterwards, any participant questions will be answered and final
financial compensation will be provided, and the participant's involvement has ended. Data
will remain blinded until the completion of the study. Participants wishing to receive the
active medication following the termination of the open-label phase of the study may do so
at the discretion of their physicians.

Inclusion Criteria:

1. For participants with seizures:

- H/o seizures of any cause

- Subjective cognitive complaints

- Stable antiepileptic drug doses which are not expected to change during the
study

- Recent normal cardiac auscultation (may be done prior to enrollment by personal
physician or study staff)

2. For healthy volunteers

- No history of seizures or other neurological disorders

- No history of cognitive complaints for any reason (including ADHD)

- Not on any medications which would interfere w/ cognitive testing

Exclusion Criteria:

1. IQ

2. History of an adverse reaction to methylphenidate

3. Seizure frequency > than 1 complex partial seizures (CPS) or absence seizure per
month or > than 3 generalized tonic-clonic seizures (GTCS) per year

4. Age >60 or <18

5. Family history of sudden cardiac death at age <40

6. Personal medical history of

- Arrhythmias,

- Structural cardiac disease,

- Other cardiac abnormality

- Uncontrolled hypertension (BP >140/90 during study)

- Uncontrolled tachycardia (HR >100 during study)

- Progressive neurological disorders (e.g., dementia) which may interfere w/
cognition for reasons other than seizures

- Glaucoma

- Other major medical illnesses which may interfere with cognition or medication
(e.g., severe liver or renal disease, active infections, etc)

- Intellectual disability/mental retardation

7. Substance use history

- Met criteria for substance use disorder within the past year

- Any active illicit substance use

- Alcohol use meeting criteria for substance abuse

- Unwillingness to abstain from alcohol w/in 24 hours of testing

8. Personal psychiatric history

- Any history of psychosis or mania

- History of suicide attempts within the last year

- Active suicidality

9. Severe cognitive impairments (e.g. aphasia) which render a participant unable to
consent

10. Currently receiving medications which would be expected to interfere with the study
tasks, if they cannot be held for study visits

11. Pregnancy or active breastfeeding

12. Women of childbearing potential who are sexually active and not willing or able to
use a contraceptive strategy during the course of the study

13. Any other factor which may interfere w/ a participant's ability to consent or to
complete the required cognitive tasks, or may significantly interfere with their
performance on the required tests