Does Fampridine SR Improve Cognitive Fatigue in Multiple Sclerosis Patients? A Cross Over Study

Fampridine-SR (4-aminopyridine) is a slow release oral medication that acts as a selective neuronal potassium-channel blocker. It has been investigated in several multiple sclerosis (MS) studies and has been shown to improve ambulation, fatigue, and endurance. The hypothesis for the mode of action of fampridine in MS patients is based on the fact that demyelinated axons do not effectively conduct action potentials partly due to abnormal potassium currents that contribute to conduction failure by decreasing action potential duration and amplitude. Thus, potassium channel blockers such as 4-aminopyridine or 3,4 diaminopyridine improve nerve impulse propagation by enhancing action potential formation, improving conduction and preventing conduction block. In a randomized, multicenter, double-blind, placebo controlled phase III trial, 301 patients were treated with either fampridine (10 mg BID n=229) or placebo (n=72). Consistent improvement on the timed 25 foot walk (T25FW) was the primary outcome measure. The proportion who improved on the T25FW was higher in the fampridine than placebo group (35% vs. 8%; p<0.0001). This data shows that fampridine improves walking speed in MS. Additionally, the study suggested there is a "responder effect" meaning MS subjects who respond to the medication respond very well (timed walk responder), while others do not show any beneficial response (timed walk non-responder). A responder was defined as an increase in walking speed, compared to placebo run-in, for at least 3 of 4 assessments while on treatment during the trial. However, this study demonstrated that responders could be identified as early as the first and second week after the initiation of treatment, as there was a significant difference between responders and non-responders at this time point. After discontinuation of fampridine, T25FW scores returned to baseline within one week

MS and Cognitive Fatigue It is estimated that 43-60% of patients with MS have cognitive dysfunction and studies using objective neuropsychological (NP) tests have consistently shown impairment in speed of information processing and sustained attention. Further, MS patients complain of "cognitive fatigue", a symptom that may or may not be associated with generalized/central fatigue. Cognitive fatigue has been defined as a decline in cognitive performance during a task requiring sustained cognitive activity. Although generalized or motor/muscle fatigue has been shown to affect the subjective assessment of cognitive performance, it does not affect performance on objective cognitive measures. In contrast, cognitive fatigue has been demonstrated in MS patients on objective neuropsychological tests. Kujala et al (1995) examined MS patients with and without mild cognitive impairment on a task of sustained attention. Both groups declined over time while healthy controls did not. Krupp et al (2000) administered a verbal learning/memory task twice separated by a continuous cognitively effortful task involving processing speed and attention. Normal controls demonstrated an increase in number of words recalled (+2.6) on the 2nd test administration, as expected due to a practice effect. In contrast, the MS subjects showed a decrease in test scores (-1.8) on the 2nd test administration. This difference was found despite both groups subjectively reporting an increase in mental fatigue over the testing period. Finally, Schwid et al (2003) examined the decline in performance on the Paced Auditory Serial Addition Test (PASAT), a measure of processing speed and sustained attention. There was a 5.3-5.8% decline in correct responses when comparing the MS subjects' performance at the beginning vs. the end of the test. Normal controls did not show a significant decrease in performance.

Treating MS Associated Cognitive Impairment and Cognitive Fatigue Currently approved MS specific medications have been shown to affect physical disability, relapse rate and MRI progression in MS subjects but cognition, fatigue and cognitive fatigue have not been the main focus of any of these studies. Further, symptomatic treatments for generalized fatigue have not focused on cognitive fatigue. Studies of l-amphetamine found a positive response on measures of processing speed in a small sample of MS subjects, but a larger, multi-centered placebo controlled trial by Morrow et al did not find any significant benefit. Cognitive fatigue was not specifically addressed in this study.

Aminopyridines and Cognition in the MS Population Only two previous studies have addressed the effect of aminopyridines on cognition in MS subjects. In one study, no benefit was found. It is important to note that the primary aim of the study was to examine changes in generalized fatigue and the cognitive outcomes were tertiary outcomes only. Further, the measure of attention used has not been validated in the MS population. In the other study, performance on Rao's Brief Repeatable Neuropsychological Battery (BRN-B) before and after treatment with 4-aminopyridine was compared. A trend was found for improvement on measures of verbal learning and on the PASAT 2.0 second version, but the findings were not statistically significant. However the trial was underpowered, with only 20 subjects.

Summary Cognitive impairment and cognitive fatigue are common in MS yet there are no currently effective treatments for these debilitating symptoms. Based on the proposed mechanism of action of fampridine, it is probable that it will improve cognitive fatigue in MS by improving nerve conduction. Using a placebo controlled cross-over study with a two week washout period in between, changes on tests of attention and processing speed under the two conditions can be compared. Since cognitive impairment is the leading cause of work disability, as well as having an negative impact on social activities and relationships, improving cognitive fatigue will contribute positively to the quality of life of MS patients.