Fampridine-induced changes in walking kinetics are associated with clinical improvements in patients with multiple sclerosis.

Gait dysfunction is common in patients with multiple sclerosis (PwMS). Treatment with prolonged-release fampridine (PR-fampridine) improves walking ability in some PwMS. Associated fampridine-induced changes in the walking pattern are still poorly understood but may provide a better understanding of the mechanisms underlying the beneficial drug effects. 61 PwMS were treated with PR-fampridine in a randomized, monocentric, double-blind and placebo-controlled clinical trial with crossover design (FAMPKIN). Drug-induced improvements in walking speed (Timed-25-Foot Walk; T25FW) and endurance (6-Minute Walk Test; 6MWT) were quantified. In this sub-study of the FAMPKIN trial, fampridine-induced changes in kinetic gait patterns were analyzed by pressure-based foot print analysis during treadmill walking. Vertical ground reaction forces were analyzed during different gait phases. Kinetic data of 44 PwMS was eligible for analysis. During double-blind treatment with PR-fampridine, patients performed significantly better in the T25FW and 6MWT than during placebo treatment (p < 0.0001 for both). At the group level (n = 44), there were no significant changes of gait kinetics under PR-fampridine vs. placebo. However, we found relevant changes of walking kinetics regarding forces during loading, single limb and pre-swing phase in a patient sub-group (n = 8). Interestingly, this sub-group demonstrated superior responsiveness to PR-fampridine in the clinical walking tests compared to those patients without any fampridine-induced changes in kinetics (n = 36). Our results demonstrate fampridine-induced changes in gait kinetics in a sub-group of PwMS. These gait pattern changes were accompanied by improved clinical walking performance under PR-fampridine. These results shed some light on the biomechanical changes in walking patterns underlying enhanced fampridine-induced gait performance.

Predicting responsiveness to fampridine in gait-impaired patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Fampridine leads to significant improvements in walking in many people with multiple sclerosis (PwMS). However, a relevant proportion of PwMS does not respond to fampridine and predictors of initial drug responsiveness are unknown. METHODS: Drug response to prolonged-release (PR)-fampridine was assessed in 55 PwMS using the timed 25-foot walk (T25FW), 6-min walk test (6MWT) and 12-item multiple sclerosis walking scale as outcome parameters. Patients were treated with PR-fampridine and placebo for 6 weeks each in a randomized, double-blind, placebo-controlled trial with crossover design (NCT01576354). Possible predictors of drug responsiveness were investigated by multiple correlation analysis and binary logistic regression models. An additional longitudinal analysis followed the drug responses of 32 patients treated with PR-fampridine over 3 years to identify potential predictors of long-term drug responsiveness. RESULTS: Severity of walking disability was positively correlated with enhanced responses to PR-fampridine. The strongest single predictor of drug responsiveness was poor 6MWT performance at baseline, which was positively correlated with enhanced drug response in the 6MWT (R = -0.541; P < 0.001). A multivariable logistic regression model including 6MWT and T25FW baseline performances predicted PR-fampridine responder status with an accuracy of 85.5% (specificity, 90.0%; sensitivity, 73.3%), with a threshold of 211 m in the 6MWT best separating responders from non-responders. Enhanced drug responsiveness after 3 years correlated with decline in walking endurance during this period (R = -0.634; P = 0.001). CONCLUSIONS: Initial walking impairment is a good predictor of therapeutic responsiveness to PR-fampridine. Valid predictors of patients' responsiveness to PR-fampridine are essential for patient stratification and optimization of multiple slcerosis treatment.

Modulation of spinal reflex by assisted locomotion in humans with chronic complete spinal cord injury.

OBJECTIVE: In healthy subjects, spinal reflexes (SR) evoked by non-noxious tibial nerve stimulation consist of an early (60-120ms latency) and an occasional late-appearing (120-450ms latency) component in the ipsilateral tibialis anterior. In chronic (>1year) complete spinal cord injured (cSCI) subjects early components are small or lacking while late components are dominant. Here we report on the modulation of SR by assisted locomotion in healthy and chronic motor cSCI subjects. METHODS: SR was evoked by tibial nerve stimulation at the terminal stance phase during assisted locomotion and was compared to SR recorded during upright stance. RESULTS: In chronic cSCI subjects only a late SR component was consistently present during upright stance. However during assisted locomotion, an early SR component appeared, while amplitude of the late SR component became small. In contrast, in healthy subjects the early SR component dominated in all conditions, but a small late component appeared during assisted locomotion. CONCLUSION: A more balanced activity of early and late SR components occurred in both subject groups if an appropriate proprioceptive input was provided. SIGNIFICANCE: Early and late SR components are assumed to reflect the activity of separate neuronal circuits, which are associated with the locomotor circuitry possibly by shaping the pattern.

Outcome after incomplete spinal cord injury: central cord versus Brown-Sequard syndrome.

STUDY DESIGN: A retrospective analysis of prospectively collected data. OBJECTIVE: A hemisection of the spinal cord is a frequently used animal model for spinal cord injury (SCI), the corresponding human condition, that is, the Brown-Sequard syndrome (BS), is relatively rare as compared with the central cord syndrome (CC). The time course of neurological deficit, functional recovery, impulse conductivity and rehabilitation length of stay in BS and CC subjects were compared. SETTING: Nine European Spinal Cord Injury Rehabilitation Centers. METHODS: Motor score, walking function, daily life activities, somatosensory evoked potentials and length of stay were evaluated 1 and 6 months after SCI, and were compared between age-matched groups of tetraparetic BS and CC subjects. RESULTS: For all analyzed measures no difference in the time course of improvement was found in 15 matched pairs. CONCLUSION: In contrast to the assumption of a better outcome of subjects with BS, no difference was found between the two incomplete SCI groups. This is of interest with respect to the different potential mechanisms leading to a recovery of functions in these two SCI subgroups.

Memory retrieval after contextual fear conditioning induces c-Fos and JunB expression in CA1 hippocampus.

Using specific polyclonal antisera against c-Fos, JunB, c-Jun and JunD, we tried to identify the candidate transcription factors of the immediate early gene family which may contribute to the molecular processes during contextual memory reconsolidation. For that purpose we analyzed the expression of these proteins in the hippocampus after contextual memory retrieval in a mouse model of fear conditioning. A single exposure to a foot shock of 0.8 mA was sufficient to induce robust contextual fear conditioning in C57BI/6N mice. In these mice context dependent memory retrieval evoked a marked induction of c-Fos and JunB, but not of c-Jun and JunD, in pyramidal CA1 neurons of the dorsal hippocampus. In contrast, mice exposed and re-exposed only to the context, without foot shock, did not show behavioral signs of contextual fear conditioning and exhibited significantly less expression of c-Fos and JunB in CA1 neurons. Mice which received a foot shock but were not re-exposed to the context revealed no immediate early gene induction. These results demonstrate that contextual memory retrieval is associated with de novo synthesis of specific members of the Fos/Jun transcription factor family. Therefore we suggest that these genes may contribute to plasticity and reconsolidation accompanying the retrieval process. The specific activation of CA1 neurons during the retrieval of contextual fear associations supports the postulated concept of a mnemonic role of this hippocampal subsector during the retrieval of contextual informations.