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Principal Investigator: Beth Ami Leeman-Markowski
Organization: VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Objective: The proposed study will determine the efficacy of methylphenidate (MPH) for the treatment of
epilepsy-related attentional dysfunction. Epilepsy patients often have attention and other cognitive deficits,
which can impair quality of life. The causes are typically multifactorial, including frequent seizures, interictal
discharges, brain lesions, and antiseizure medication side effects. The comorbidity of attentional dysfunction
and epilepsy may be partially explained by abnormalities in ascending reticular activating system networks.
There are no FDA-approved medical therapies for epilepsy-related cognitive deficits, and rehabilitation
strategies provide limited benefit. 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 epilepsy-related
cognitive dysfunction. Studies of MPH in children with epilepsy and ADHD suggest efficacy and safety.
Further, large database and registry studies found beneficial effects of MPH on seizure risk in children with
and without epilepsy. Small, single-dose and open label trials of MPH in adults with epilepsy and attentional
dysfunction suggest benefit and safety, but longer-duration, controlled trials with larger numbers of subjects
are needed.
The proposed study is a multi-site, randomized, double-blind, placebo-controlled trial of MPH, with an open-
label extension period, to determine the efficacy of MPH for adult epilepsy-related attentional dysfunction. The
study will also establish the effects of MPH on other attention-dependent cognitive processes ({i.e., a
combined measure of} memory, psychomotor speed, and executive function) and quality of life. The
hypothesis is that subjects will have improved cognitive function and quality of life with MPH compared to
placebo. Secondary analyses will determine the impact of MPH on mood and subjective cognitive abilities,
efficacy over an open-label period, and safety, including effects on seizure frequency.
Research Plan/Methods: Subjects will include {186} adults with epilepsy and self-reported cognitive
deficits, recruited from the Manhattan, Portland, Miami, and Boston VA hospitals. In the blinded phase,
subjects will {be randomly assigned to} receive either placebo or MPH (titrated to 20 mg twice daily) for 8
weeks. Subjects will then receive open-label MPH for 8 weeks (titrated to 20 mg twice daily). Cognitive testing
will be administered at baseline, the end of blinded treatment (Week 8), and the end of the open-label period
(Week 16). The cognitive battery will include tests of attention (Continuous Performance Test), memory (MCG
Paragraph Test), psychomotor speed (Symbol Digit Modalities Test), and a combined measure of divided
attention, psychomotor speed, and response inhibition (Stroop Color Word Interference Test). Additional
measures will include quality of life (Quality of Life in Epilepsy Patient Inventory-89), side effects (Adverse
Events Profile), mood (Beck Depression Inventory-II), and anxiety Beck Anxiety Inventory). Twenty healthy
subjects and 20 epilepsy patients without cognitive complaints, who will not receive the study drug, will be
included to control for repeated testing.
Clinical Relevance: If efficacious, MPH would be the first successful medical treatment for epilepsy-related
cognitive deficits. Results will be of particular importance to combat Veterans and others with head injuries, as
common sequelae of traumatic brain injury (TBI) are seizures and neuropsychological dysfunction. Improving
cognition in Veterans with epilepsy can lead to greater independence with activities of daily living, increased
employability, and better quality of life.
Terms: <0-11 years old><21+ years old><AD/HD><ADHD><Activities of Daily Living><Activities of everyday life><Adult><Adult Human><Adverse Experience><Adverse event><Anticonvulsant Agent><Anticonvulsant Drugs><Anticonvulsants><Anticonvulsive Agents><Anticonvulsive Drugs><Anxiety><Arousal><Attention><Attention deficit hyperactivity disorder><Attentional deficit><Beck depression inventory><Blinded><Boston><Brain><Brain Nervous System><Brain Trauma><Causality><Child><Child Youth><Children (0-21)><Clinical><Clinical Management><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Color><Concerta><Craniocerebral Injuries><Craniocerebral Trauma><Data Bases><Databases><Daytrana><Digit><Digit structure><Disturbance in cognition><Dose><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Drugs><Dysfunction><Encephalon><Epilepsy><Epileptic Seizures><Epileptics><Equipment and supply inventories><Etiology><FDA approved><Frequencies><Functional disorder><Head Injuries><Head Trauma><Health Care Systems><Healthcare Systems><History><Hospitals><Impact Seizures><Impaired cognition><Impairment><Impulsivity><Inventory><Lesion><Measures><Medical><Medication><Memory><Metadate><Methods><Methylphenidate><Modality><Moods><Neuropsychologies><Neuropsychology><Outcome Measure><Patient Self-Report><Patients><Performance><Pharmaceutical Preparations><Phase><Physiopathology><Placebo Control><Placebos><Post-Traumatic Epilepsy><Post-Traumatic Seizure Disorder><Posttraumatic Epilepsy><Posttraumatic Seizure Disorder><Predominantly Hyperactive-Impulsive Type Attention-Deficit Disorder><Predominantly Hyperactive-Impulsive Type Hyperactivity Disorder><QOL><Quality of Life Assessment><Quality of life><Randomized><Recording of previous events><Registries><Research><Risk><Ritalin><Safety><Seizure Disorder><Seizures><Self-Report><Sham Treatment><Site><Speed><Stimulant><Syndrome><System><Testing><Titrations><Traumatic Brain Injury><Traumatic Epilepsy><Treatment Period><Veterans><adulthood><attentive deficit><causation><clinical relevance><clinically relevant><co-morbid><co-morbidity><cognitive ability><cognitive assessment><cognitive benefits><cognitive defects><cognitive dysfunction><cognitive function><cognitive loss><cognitive performance><cognitive process><cognitive testing><combat veteran><comorbidity><computerized><daily functioning><daily living function><daily living functionality><data base><determine efficacy><disease causation><double-blind placebo control trial><double-blind placebo controlled trial><double-masked controlled trial><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epilepsia><epileptogenic><evaluate efficacy><examine efficacy><executive control><executive function><expectation><functional ability><functional capacity><histories><improved><kids><measurable outcome><medical college><medical schools><neuropsychologic><open label><open label study><outcome measurement><pathophysiology><performance tests><placebo controlled><primary end point><primary endpoint><primary outcome><psychiatric co-morbidity><psychiatric comorbidity><randomisation><randomization><randomly assigned><recruit><rehab strategy><rehabilitation strategy><response><school of medicine><secondary analysis><seizure drug><seizure medication><sham therapy><side effect><sustained attention><traumatic brain damage><treatment days><treatment duration><youngster>