Overview

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 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.

Eligibility

Inclusion Criteria:

1. SUBJECTS WITH EPILEPSY

   Participants will include adult subjects with focal-onset epilepsy, based on clinical history, imaging studies and ictal and/or interictal EEG interpreted by a clinical epileptologist. Seizures may be symptomatic, idiopathic, traumatic, or non- traumatic in etiology. Subjects must have self-reported cognitive dysfunction. Subjects must also meet the following eligibility criteria:

   • Age 18 years of age or older;
   • 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 ASM regimen to be warranted during the trial (ASMs should remain unchanged during the 16 weeks of participation unless absolutely required clinically due an unanticipated change in seizure frequency or severity);
   • Fluency in written and spoken English.
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 deficits must otherwise meet all of the above criteria.

Healthy controls must meet the following inclusion criteria:

• Age 18 years or older;
• Capacity to provide informed consent;
• Ability to live independently and complete activities of daily living;
• Fluency in written and spoken English.

Exclusion Criteria:

SUBJECTS WITH EPILEPSY

        Subjects with epilepsy with or without cognitive complaints will be excluded from
        participation for:
          -  Psychogenic, non-epileptic spells
          -  Delirium in the past year
          -  Other progressive neurologic illness (i.e., malignant brain tumor). A benign, stable
             neoplasm with no plans for resection will not be cause for exclusion.
          -  A history of alcohol or illicit drug abuse;
          -  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;
          -  Status epilepticus in the past year;
          -  Neurosurgery within the past 6 months;
          -  Suicide attempt in the past year and/or high-risk suicide flag in the medical record;
          -  Psychotic disorders
          -  Severe anxiety (>26 on the Beck Anxiety Inventory [BAI]) and impulse control
             disorders;
          -  Untreated sleep disorders;
          -  Use of narcotic or other sedating medications within 6 hours of testing (i.e.,
             diphenhydramine);
          -  Concurrent severe major medical illness (i.e., cancer requiring chemotherapy or
             resection)
          -  Prior transient ischemic attack (TIA) or stroke
        Subjects with epilepsy will also be excluded for a diagnosis of dementia (i.e., Alzheimer's
        disease). Subjects with epilepsy and cognitive complaints must have a MoCA score 22.
        Subjects with epilepsy and no cognitive complaints must have a MoCA score 26.
        Subjects with epilepsy and cognitive complaints must meet additional exclusion criteria, to
        minimize risks of MPH:
          -  Current pregnancy or pregnancy planned during the trial
          -  Breastfeeding
          -  Concurrent treatment with a monoamine oxidase inhibitor (MAOI) or MAOI use within 14
             days of beginning the trial;
          -  Structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or coronary
             artery disease (including a history of myocardial infarction, cardiac stent placement,
             coronary artery bypass graft surgery, or angina);
          -  Bipolar disorders;
          -  Concurrent use of medications for erectile dysfunction (e.g., tadalafil, sildenafil);
          -  Use of medications that may lower seizure threshold (e.g., tramadol, bupropion) or
             induce psychosis (i.e., varenicline);
          -  Known allergy or intolerance to MPH;
          -  Uncontrolled hypertension;
        HEALTHY CONTROLS
        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), MoCA score of <26;
          -  Delirium in the past year;
          -  Other progressive neurologic illness (i.e., malignant brain tumor);
          -  Prior moderate or severe traumatic brain injury (TBI);
          -  Mild TBI within the past 6 months;
          -  A history of alcohol or illicit drug abuse;
          -  Suicide attempt in the past year and/or high-risk suicide flag in the medical record;
          -  Psychotic, severe anxiety (BAI >26), or impulse control disorders;
          -  Untreated sleep disorders;
          -  Use of narcotic or other sedating medications within 6 hours of testing;
          -  Ongoing major neurological or medical illness (i.e., cancer requiring chemotherapy or
             resection);
          -  Prior TIA or stroke;