Effects of Dalfampridine on Cognition in Multiple Sclerosis

Treatment tested

• Dalfampridine

  Voltage-gated potassium channel blocker

Placebo or sham

• placebo

Inclusion Criteria: Patients will be eligible for the study if they fulfill all the inclusion criteria specified below: 1. Males/Females who are ≥ 18 years old and \< 65 years old and are capable of understanding and complying with the protocol, including speaking and writing fluent English and having at least a 9th grade education. 2. Have a diagnosis of MS, as per revised McDonald's Criteria. 3. Have not received steroids in last thirty (30) days or a relapse in the last ninety (90) days, and whose MS is considered stable. 4. Impression of cognitive impairment as indicated by one of the following: (a) positive NP testing following diagnosis of MS as determined by board certified neuropsychologist or with z scores \<-1.5 below expectation in at least one cognitive domain, or (b) informant MSNQ >28. 5. An Expanded Disability Status Scale (EDSS) of ≤ 6.5. 6. Have given written informed consent prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his/her future medical care. 7. Are capable of performing the requirements of a NP test battery including at least 20/70 near visual acuity by near vision chart, with correction allowed. 8. If female, must neither be pregnant nor breast-feeding and must either (a) be > 12 months post-menopausal or surgically sterilized, or (b) agree to use an acceptable method of birth control for the duration of the study. Abstinence will not be considered an acceptable method of birth control. Exclusion Criteria: 1. Have cognitive deficits caused by concomitant medication usage or other significant neurological/psychological disease e.g. Alzheimer's disease, Parkinson's disease, stroke, transient ischemic attack, Vascular Dementia, Huntington's disease, traumatic brain injury or chronic CNS infection 2. Have evidence of other medical cause(s) of cognitive impairment 3. Evidence of major mental illness predating the onset of MS 4. Have evidence of major depression as determined by a positive BDIFS and clinician interview 5. Have report of uncontrolled or labile hypertension, tachycardia, cardiovascular or cerebrovascular disease 6. History of seizure disorder. 7. Optic neuritis within 6 months of enrollment. 8. Trigeminal neuralgia. 9. Prior exposure to aminopyridines within the last six months.

Cognitive impairment is common in multiple sclerosis (MS) and has devastating impact on functional activities. There is great demand for medications that will enhance cognitive capacity in MS patients. To date, there is no evidence for improvement in cognition following treatment with aminopyridines, but the few studies on the topic included neuropsychological (NP) tests as secondary or tertiary outcomes, and were methodologically flawed. Dalfampridine may enhance cognition by direct pharmacological mechanisms, and should have effects on motor outcomes as in prior studies. By combining cognition and motor outcomes in the proposed study, the investigators will evaluate if the same patients with positive effects show beneficial responses on motor outcomes including physical activity and if such motor outcomes mediate and/or moderate cognitive improvements with dalfampridine