Henrik Boye Jensen

4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review.

This systematic review summarizes the existing evidence on the effect of 4-aminopyridine (4-AP) as a symptomatic treatment of decreased walking capacity in patients with multiple sclerosis (MS) when administered as an immediate release compound and a slow release compound. It summarizes existing evidence on the basic mechanisms of 4-AP from experimental studies and evidence on the clinical use of the compound. A systematic literature search was conducted of the following databases: PubMed and EMBASE. Thirty-five studies were included in the review divided into 16 experimental studies, two clinical studies with paraclinical endpoints and 17 clinical studies with clinical endpoints. Animal studies show that 4-AP can improve impulse conduction through demyelinated lesions. In patients with MS this translates into improved walking speed and muscle strength of the lower extremities in a subset of patients at a level that is often of clinical relevance. Phase III trials demonstrate approximately 25% increase in walking speed in roughly 40% and improved muscle strength in the lower extremities. Furthermore, 4-AP might have an effect on other domains such as cognition, upper extremity function and bowel and bladder, but this warrants further investigation. Side effects are mainly mild to moderate, consisting primarily of paraesthesia, dizziness, nausea/vomiting, falls/balance disorders, insomnia, urinary tract infections and asthenia. Side effects are worse when administered intravenously and when administered as an immediate release compound. Serious adverse events are rarely seen in the marketed clinical dosages. In conclusion, 4-AP is easy and safe to use. Slow release 4-AP shows more robust clinical effects and a more beneficial side-effect profile than immediate release 4-AP.

Changes in cognition, arm function and lower body function after Slow-Release Fampridine treatment

Objective: We aimed to evaluate the effect of slow-release (SR) Fampridine on multiple outcome measures reflecting different domains, and to compare the responsiveness of the Six Spot Step Test (SSST) and the Timed 25 Foot Walk (T25FW). Methods: For this study 108 participants were included. On day 0 they were tested with the T25FW, the SSST, the 9-Hole Peg Test (9-HPT), the 5 Times Sit-To-Stand test (5-STS) and the Symbol Digit Modalities Test (SDMT). Four weeks of treatment with SR Fampridine 10 mg BID was commenced. Participants were tested again after 26–28 days of treatment. Results: Mean changes observed were: SSST −3.4±6.4s (p<0.001), T25FW −1.2±3.7s (p<0.001), 9-HPT −1.2±6.0s (p<0.001), 5- STS −3.4±7.2s (p<0.001) and SDMT 1.4±4.8 a.u. (p=0.003). Change on the SSST differed significantly from T25FW (SSST 17.0±19.6% vs. T25FW 11.2±17.1%, p=0.0013). Some 48.6% were found to have a meaningful change on the SSST compared with 25.7% on the T25FW. The response to treatment with SR Fampridine did not correlate with age, sex, Expanded Disability Status Scale and disease duration. Conclusion: SR Fampridine treatment has significant effects on different domains including upper and lower body and cognition. Furthermore, the SSST is more responsive to the effect of SR Fampridine than is the T25FW. ClinicalTrials.gov identifier: NCT01656148

Distribution-based estimates of minimum clinically important difference in cognition, arm function and lower body function after slow release-fampridine treatment of patients with multiple sclerosis

OBJECTIVE To provide distribution-based estimates of the minimal clinical important difference (MCID) after slow release fampridine treatment on cognition and functional capacity in people with MS (PwMS). METHOD MCID values were determined after SR-Fampridine treatment in 105 PwMS. Testing included the Timed 25 Foot Walk (T25FW), the Symbol Digit Modalities Test (SDMT), the Six Spot Step Test (SSST), the 9-Hole-Peg-Test (9-HPT), and the 5-Time-Sit-To-Stand test (5-STS). RESULTS MCID values: T25FW 17.8% (9.1-17.8), SDMT 17.1% (9.2-17.1), SSST 16.7% (8.5-16.7), 9-HPT 15.3% (0-15.3), and 5-STS 34.6% (16.9-34.6). CONCLUSION This study presents distribution-based estimates of MCID values for the SSST, the 9-HPT, and the 5-STS and confirms MCID estimates for the T25FW and the SDMT.

Effect of slow release-Fampridine on muscle strength, rate of force development, functional capacity and cognitive function in an enriched population of MS patients. A randomized, double blind, placebo controlled study

DESIGN This study was conducted as a randomized, double blind, placebo-controlled parallel group trial preceded by open label enrichment phase. OBJECTIVES The objectives of this study were 1) to examine the effect of SR-Fampridine treatment on muscle strength in terms of maximal voluntary contraction (MVC) and rate of force development (RFD) of the lower extremities and 2) to replicate previously published data on the effect of slow release-Fampridine (SR-Fampridine) on the functional capacity of the lower limbs, the upper limb and cognitive function, in persons with multiple sclerosis (pwMS). METHODS Previously identified responders to SR-Fampridine were randomized to SR- Fampridine or placebo treatment for four weeks. On days 0 and 26-28 participants underwent testing by isokinetic dynamometry, Nine Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Six Spot Step Test (SSST), Timed 25 Foot Walk Test (T25FW) and 5-Times Sit-to-Stand (5-STS). RESULTS A statistical significant effect of SR-Fampridine on MVC was demonstrated during knee extension, knee flexion and hip flexion of the weakest leg, as well as on RFD during knee extension and knee flexion of the weakest leg. Furthermore, a significant effect of SR-Fampridine on T25FW, SSST and 5-STS was demonstrated. CONCLUSION Gold standard dynamometry assessment of muscle strength showed improved MVC and RFD in persons with MS treated with SR-Fampridine compared to placebo. Furthermore, previous findings on the effects of SR-Fampridine on functional capacity of the lower limbs were replicated. ClinicalTrials.gov identifier: NCT01656148.

Association of myasthenia gravis with polymorphisms in the gene of histamine N-methyltransferase

INTRODUCTION Histamine N-methyltransferase (HNMT) is the main metabolizing enzyme of histamine. Histamine modulates immune responses and plays a role in the pathogenesis of autoimmune disorders. METHODS The non-synonymous HNMT C314T polymorphism and the A939G single-nucleotide polymorphism (SNP) influencing HNMT mRNA stability were genotyped in 213 patients with myasthenia gravis (MG) and 342 healthy controls. RESULTS The carrier frequency of the A allele of the A939G SNP was over-represented among patients with anti-AchR and anti-Titin antibodies (P = 0.05 and P = 0.004, respectively); the presence of the minor G allele was protective against anti-AchR and anti-Titin positive MG (OR = 0.67 and OR = 0.54, respectively). The combination of the G allele carrier status with wild-type C314C homozygosity was also protective against MG (OR = 0.55, P = 0.008) and against the development of anti-AchR antibodies (OR = 0.37, P = 0.01). DISCUSSION The A939G HNMT polymorphism is associated with autoimmune MG, while no association with C314T SNP was found.

FAME - Fampridine outcome Measure study - an ongoing study

S Multiple Sclerosis Journal 2012; 18: S25–S28

Aerobic Capacity Is Not Associated with Most Cognitive Domains in Patients with Multiple Sclerosis—A Cross-Sectional Investigation

(1) Background: Cognitive impairment is highly prevalent in multiple sclerosis (MS). Staying physically fit may be associated with preservation of cognitive performance in persons with MS (pwMS); (2) Objective: To investigate the association between aerobic capacity and the cognitive domains of information processing, learning and memory, and verbal fluency as well as single and composite z-scores of the Brief Repeatable Battery of Neuropsychological tests (BRBNT) in pwMS; (3) Methods: All subjects first performed the BRBNT and then a maximal oxygen consumption (VO2-max) test on a bicycle ergometer as a measure of aerobic capacity. Simple and multiple (adjusting for age, sex, and education level) regression analyses were performed to evaluate the relationship between aerobic capacity and cognitive performance in different domains. Published international norms were used to compute z-scores for each individual and composite BRBNT score. Furthermore, cognitive impairment was defined as one or more z-scores ≤−1.5 standard deviation (SD) of healthy controls; (4) Results: Eighty-four subjects were included (44.9 ± 9 years, 16.3 ± 2 education years, Expanded Disability Status Scale (EDSS): 2.6 ± 1.4, MS-type (relapsing-remitting, primary progressive, or secondary progressive): 73/6/5, disease duration: 9.9 ± 7 years, VO2-max: 28.4 ± 7.0 mL O2/min/kg). No significant associations between aerobic capacity and cognitive performance in the individual BRBNT tests were found, except that a weak relationship was found between aerobic capacity and the composite processing speed z-score (R2 = 0.06, p = 0.02). The average global BRBNT z-score (−0.2 ± 0.66) was not associated with aerobic capacity. Comparison of the cognitively impaired group (34.5%) with the nonimpaired group (65.5%) showed lower aerobic capacity in the impaired group (25.9 ± 1 vs. 29.7 ± 1 mLO2/min/kg, p = 0.02); (5) Conclusions: Limited support was found for an association between performance in most cognitive domains and aerobic capacity in the present MS group with a third of patients showing signs of cognitive impairments.

The six spot step test: a new method for monitoring walking ability in patients with chronic inflammatory polyneuropathy

The aim of this study was to evaluate whether the six‐spot‐step test (SSST) is more suitable for monitoring walking ability in patients with chronic inflammatory polyneuropathy than the timed 25‐foot‐walking test (T25FW). In the SSST, participants have to walk as quickly as possible across a field measuring 1 × 5 m, while kicking blocks out of five circles on the floor. Sixty‐two patients and 61 controls performed the SSST and T25FW. Patients also performed the overall disability sumscore, INCAT sensory sumscore, Medical Research Council sumscore, and 9‐hole‐peg‐test. Twenty‐one patients treated with intravenous immunoglobulin (IVIG) every 4–6 weeks were tested prior to and 2–3 weeks after treatment and judged change in their own clinical condition using the patient global impression of change (PGIC) scale. In patients, SSST ranged from 5.7 to 26.8 s and T25FW ranged from 3.6 to 12.9 s. Intra‐class correlation between repeated tests was 0.97 for SSST and 0.95 for T25FW. Correlation with the additional tests was stronger for SSST than T25FW. In IVIG‐treated patients, the mean change in walking time was −2.3 s for SSST and −0.6 s for T25FW. The SSST showed larger responsiveness in terms of effect size, standardized response means, and relative efficiency. Both ambulation tests correlated moderately to PGIC. The SSST may be superior to the T25FW in terms of dynamic range, floor effect, and responsiveness which makes the SSST a possible alternative for monitoring walking ability in patients with chronic inflammatory polyneuropathy.

Can aerobic exercise alleviate flu-like symptoms following interferon beta-1a injections in patients with multiple sclerosis?

BACKGROUND Flu-like symptoms (FLS) are common side effects of interferon beta (IFNß) treatment, and may affect the willingness to initiate therapy, the long-term acceptability, and the adherence to the treatment. Case reports suggest that aerobic exercise is able to markedly reduce FLS following IFNß-1a injections in persons with multiple sclerosis (PwMS). OBJECTIVE To test the hypothesis that aerobic exercise can alleviate FLS following IFNß-1a injections in PwMS, and secondarily to examine whether or not fluctuations in circulating cytokines provide a mechanism that can explain a potential positive effect. METHODS Seventeen PwMS who frequently experience FLS following IFNß-1a injections completed four days of testing. On two of the testing days they completed 35min of aerobic exercise on a bicycle-ergometer following IFNß-1a injection. On the two other testing days, no intervention took place following the injection. FLS were assessed pre-injection and 3h, 5h, 12h and 24h post-injection. Blood samples were taken pre-injection and 1h and 3h post-injection to determine levels of circulating interleukin 6 and 17 and IFNγ. The primary study endpoint was the comparison of the change in FLS severity from pre-injection to 5h post-injection between days with injection alone and days with injection followed by aerobic exercise. RESULTS FLS severity change was significantly lower on days with exercise compared to days with rest. IL6 was significantly increased 3h following IFNß-1a injection and exercise compared to 1h post and pre and when compared to the resting condition. Participants reported no adverse events in addition to FLS during the study period. CONCLUSION Data from this study suggest that moderate intensity aerobic exercise following IFNß-1a injections is safe and can alleviate the FLS severity in PwMS. Based on these results, 35min of aerobic exercise should be encouraged for PwMS who often experience FLS following IFNß-1a injections.