Methylphenidate for the Treatment of Epilepsy-related Cognitive Deficits
Methylphenidate for the Treatment of Epilepsy-related Cognitive Deficits
Methylphenidate (MPH) is a stimulant, FDA-approved for the treatment of attention deficit
 hyperactivity disorder (ADHD). It is unknown, however, if stimulants would be of benefit for
 memory and thinking problems due to epilepsy. In this study, participants will be assigned
 randomly (i.e., by flip of a coin), to a group that takes MPH and a group that takes a
 placebo (sugar pill). Participants will not know the group to which they have been assigned.
 Tests of attention and memory will be completed before taking the study pills, at Week 4, and
 at Week 8. All participants will then have the option of taking MPH for the next two months,
 and attention and memory will be tested again at Week 16. The study will determine whether
 methylphenidate is helpful for the treatment of attention and memory problems in adults with
 epilepsy, and whether the medication is safe and beneficial when taken over an extended time
 period.
The proposed study is a randomized, double-blind, crossover trial of MPH vs. placebo in
 subjects with epilepsy and impaired attention. In the blinded phase, subjects will receive
 placebo and MPH (20mg twice daily) for 4 weeks each, in randomized order. Subjects will then
 receive open-label MPH for 8 weeks (20mg twice daily). Cognitive tests will be performed at
 baseline, Week 4, Week 8, and at the end of the open-label period.

 The primary aim is to evaluate the efficacy of MPH for the treatment of attentional
 dysfunction in subjects with epilepsy. It is expected that subjects will have improved
 attention when taking MPH compared to placebo, measured by the Conner's Continuous
 Performance Test (CPT). The effects of MPH on other cognitive functions that rely in part on
 attention, including memory (MCG Paragraph Test) and psychomotor speed (Symbol Digit
 Modalities Test), as well as the impact on an overall measure of divided attention,
 psychomotor speed, and response inhibition (Stroop Color Word Interference Test), will be
 ascertained. Improved performance when taking MPH compared to placebo is expected. Finally,
 the study will establish the effect of MPH on overall quality of life. It is hypothesized
 that there will be improvement in self-reported quality of life with MPH, but no change while
 taking placebo, as assessed by the Quality of Life in Epilepsy Patient Inventory.

 Secondary analyses will determine the safety of MPH, including effects on seizure frequency,
 the impact on mood and subjective cognitive function, and continued efficacy over an
 open-label period. Epilepsy type, concurrent use of antiepileptic drugs that impair
 cognition, and history of head trauma will be assessed as covariates.
1. SUBJECTS WITH EPILEPSY Participants will include subjects with epilepsy, based on
 clinical history, imaging studies and ictal and/or interictal EEG interpreted by a
 clinical epileptologist. Seizures may be either symptomatic or idiopathic, primary
 generalized or focal-onset, and traumatic or non-traumatic in etiology. Subjects must
 have self-reported cognitive dysfunction.

 Subjects must meet the following eligibility criteria:

 -  Age > or = 18 years old;

 -  IQ > or = 70, estimated by the Wechsler Test of Adult Reading (WTAR);

 -  Capacity to provide informed consent;

 -  Ability to live independently and complete activities of daily living;

 -  Stable seizure frequency at the time of enrollment, such that the subject's
 treating physician does not believe a change in anticonvulsant regimen to be
 warranted during the trial (the anticonvulsant drugs should remain unchanged
 during the 16 weeks of participation unless absolutely required clinically due an
 unanticipated change in seizure frequency or severity);

 -  Fluency in English.

 Exclusion criteria

 -  Psychogenic, non-epileptic spells;

 -  Diagnosis of dementia (i.e., Alzheimer's disease);

 -  Other progressive neurologic illness (i.e., malignant brain tumor). A benign,
 stable neoplasm with no plans for resection will not be cause for exclusion;

 -  Alcohol or illicit drug abuse within the past year, as this may affect cognition
 by other mechanisms. This information may be obtained by self-report, from the
 referring physician or by medical record. Subjects will also undergo urine drug
 testing at the baseline visit. Chronic, stable use of marijuana will not be cause
 for exclusion. In cases of intermittent, recreational use, it will be required
 that subjects refrain from marijuana for 2 weeks prior to testing. Cannabidiol
 use will be permitted.

 -  Generalized tonic-clonic or other generalized motor seizure(s) within 48 hours or
 focal-onset seizures with impaired awareness within 24 hours of
 neuropsychological testing. This restriction will avoid testing during a
 post-ictal state. This timing is conservative, based on practice as well as prior
 studies of post-ictal cognitive function demonstrating return to baseline within
 one day (Dodrill and Ojemann, 2007; Helmstaedter, Elger, & Lendt, 1994).

 -  Prior status epilepticus in the past year;

 -  Neurosurgery within the past 6 months, as there may be recovery in cognition
 post-operatively;

 -  Current pregnancy or pregnancy planned during the trial;

 -  Breastfeeding;

 -  Concurrent treatment with a monoamine oxidase inhibitor (MAOI; e.g., selegiline,
 tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue), or use of
 an MAOI within 14 days of beginning the trial (due to the risk of hypertensive
 crisis);

 -  Structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or
 coronary artery disease, as complications due to small MPH-related increases in
 heart rate and blood pressure may be of concern in these populations;

 -  History of a suicide attempt in the past year;

 -  Psychotic or bipolar disorders, due to the risk of psychotic or manic symptom
 exacerbation;

 -  Concurrent use of medications for erectile dysfunction (e.g., tadalafil,
 sildenafil), due to an increased risk of priapism;

 -  Use of medications that may lower seizure threshold (e.g., tramadol, immediate
 release bupropion);

 -  Known allergy to methylphenidate;

 -  Use of narcotic or other sedating medications within 6 hours of testing (i.e.,
 diphenhydramine), which may interfere with cognition;

 -  Uncontrolled hypertension;

 -  Concurrent severe major medical illness (e.g., cancer requiring chemotherapy or
 resection).

 2. CONTROLS *DO NOT UNDERGO ANY DRUG OR PLACEBO INTERVENTION Two additional subject
 groups will be included, to control for effects of repeated testing in the open-label
 extension phase: healthy subjects and epilepsy patients without cognitive complaints,
 who will not receive the study drug at any point during the study.

 Epilepsy patients without cognitive complaints must otherwise meet all of the above
 inclusion criteria, and will be excluded for the following:

 -  Psychogenic, non-epileptic spells;

 -  Diagnosis of dementia (i.e., Alzheimer's disease);

 -  Other progressive neurologic illness (i.e., malignant brain tumor). A benign, stable
 neoplasm with no plans for resection will not be cause for exclusion;

 -  Alcohol or illicit drug abuse within the past year. This information may be obtained
 by self-report, from the referring physician or by medical record. Subjects will also
 undergo urine drug testing at the baseline visit. Chronic, stable use of marijuana
 will not be cause for exclusion. In cases of intermittent, recreational use, it will
 be required that subjects refrain from marijuana for 2 weeks prior to testing.
 Cannabidiol use will be permitted.

 -  Generalized tonic-clonic or other generalized motor seizure(s) within 48 hours or
 focal-onset seizures with impaired awareness within 24 hours of neuropsychological
 testing.

 -  Prior status epilepticus in the past year;

 -  Neurosurgery within the past 6 months;

 -  History of a suicide attempt in the past year;

 -  Psychotic disorders;

 -  Use of narcotic or other sedating medications within 6 hours of testing, which may
 interfere with cognition;

 -  Concurrent severe major medical illness (e.g., cancer requiring chemotherapy or
 resection).

 Healthy controls must meet the following inclusion criteria:

 -  Age > or = 18 years old;

 -  IQ > or = 70, estimated by the Wechsler Test of Adult Reading (WTAR);

 -  Capacity to provide informed consent;

 -  Ability to live independently and complete activities of daily living;

 -  Fluency in English.

 Healthy controls will be excluded based on the following criteria:

 -  History of seizures, epilepsy, or psychogenic, non-epileptic spells;

 -  Diagnosis of dementia (i.e., Alzheimer's disease);

 -  Other progressive neurologic illness (i.e., malignant brain tumor);

 -  Moderate or severe traumatic brain injury, or mild trauma within the past 6 months;

 -  Alcohol or illicit drug abuse within the past year. This information may be obtained
 by self-report. Subjects will also undergo urine drug testing at the baseline visit.
 Chronic, stable use of marijuana will not be cause for exclusion. In cases of
 intermittent, recreational use, it will be required that subjects refrain from
 marijuana for 2 weeks prior to testing.

 -  History of a suicide attempt in the past year;

 -  Psychotic disorders;

 -  Use of narcotic or other sedating medications within 6 hours of testing, which may
 interfere with cognition;

 -  Ongoing major neurological or medical illness (e.g., cancer requiring chemotherapy or
 resection).