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Short-term impact of fampridine on motor and cognitive functions, mood and quality of life among multiple sclerosis patients
Clinical Neurology and Neurosurgery, Volume 139, December 2015, Pages 35 - 40
- Fampridine is licensed to improve walking in all types of multiple sclerosis.
- We examined fampridine's impact on various functions besides walking.
- Fampridine seems to improve arm/hand function, fatigue, mood and quality of life.
- We did not demonstrate improvement of cognitive function after fampridine treatment.
Previous studies have predominantly investigated the effect of fampridine on lower extremities motor functions while data on its impact on other symptoms of multiple sclerosis (MS) are scarce. The aim of our study was to assess the impact of fampridine on walking, arm/hand function, fatigue, cognitive function, mood and quality of life among responders.
Our prospective non-randomized study included 30 patients with different types of MS, aged 35–70, EDSS value 3.5–6.5. They were treated with 10 mg of fampridine twice daily. The examinations were performed before the treatment, after 14 days, when responders were defined by T25FW (Timed 25-Foot Walk) and 2-min walk test (2MWT) was performed, and after 28 days of treatment, when only the responders were examined. Standardized protocols and questionnaires were used to evaluate the impact of fampridine on walking speed (T25FW, 2MWT), arm/hand function (9-HPT – Nine-Hole Peg Test), cognitive function (PASAT – Paced Auditory Serial Addition Test), total MSFC score (Multiple Sclerosis Functional Composite), fatigue (MFIS – Modified Fatigue Impact Scale), mood (BDI – Beck Depression Inventory) and quality of life (EQ-5D index, EQ-VAS – Euro Quality of Life – 5 Dimension questionnaire and visual analogue scale) in responders.
Response rate was 56.7%. Average improvement of T25FW and 2MWT after 14 days of treatment in responders was 3.6 s (34.5%) and 37.4 m (42.3%), respectively. This improvement persisted after 28 days of treatment. In non-responders there was no significant improvement of T25FW after 14 days (p = 0.689), but there was improvement of 2MWT for 13.4 m (14.3%) (p = 0.000). After 28 days of treatment significant improvement among responders occurred in total MSFC score (p = 0.001), 9-HPT (p = 0.002), BDI (p = 0.005), MFIS total score (p = 0.003), physical (p = 0.001), cognitive (p = 0.008) MFIS subscales, and EQ-5D index (p = 0.012). There were implied trends towards improvement in EQ-VAS and psychosocial MFIS subscale, yet not significant (p = 0.057 and p = 0.127, respectively). There was no statistically significant improvement of PASAT (p = 0.432).
The results of our study highlight the potential of fampridine for improving not only walking speed but also arm/hand function, physical and cognitive fatigue, mood and quality of life. There was no objective improvement of cognitive function. Further placebo-controlled studies will be needed for precise definition of fampridine's action beyond its impact on walking.
Keywords: Fampridine, 4-Aminopyridine, Multiple sclerosis, Cognitive function, Mood, Depression, Quality of life, Arm/hand function.
Fampridine is the first drug licensed to improve walking ability in adult patients with all types of multiple sclerosis (MS)  and . Fampridine, which is a prolonged-release form of 4-aminopyridine, is a fat soluble molecule that has the ability to cross the blood-brain barrier and acts as an inhibitor of voltage-gated potassium (Kv) channels
Fampridine leads to clinical improvement only in certain patients with MS. According to different studies the percentage of so-called responsive patients (responders) ranges from 30% to 74% , , , and . Responsiveness to fampridine is determined after 14 days of treatment based on 20%
The aim of our study was to assess the impact of fampridine on arm/hand function, fatigue, cognitive function, depression and quality of life among responders in addition to study its impact on walking ability.
2. Materials and methods
A prospective non-randomized study was conducted from 2013 to 2014 in the Centre for Multiple Sclerosis at the Department of Neurology, University Clinical Centre Ljubljana, Slovenia as a named patient programme. The patients with clinically definite MS, who fulfilled the entry criteria (EDSS of 3.5–6.5 and clinically significant impairment of ambulation) were invited to participate in the study. All the patients signed a written informed consent to participate in the study which was approved by Republic of Slovenia National Medical Ethics Committee and was performed in accordance with the Declaration of Helsinki. Thirty-two patients entered the study. Two people withdrew from the study prematurely due to acute illness and they were not included in the data analysis. The final research group therefore included thirty patients (15 women) with an average age of 48.3 ± 10.3 years and median EDSS value of 6 (5.0–6.5). Eleven patients (36.7%) had primary progressive (PPMS), eighteen (60.0%) secondary progressive (SPMS) and one (3.3%) relapsing-remitting (RRMS) type of MS.
Examinations were performed prior to treatment, after 14 and 28 days of treatment with fampridine (10 mg every 12 h). At the initial clinical visit the patients were acquainted with the drug administration and its possible side effects. They then filled in three questionnaires: The EQ-5D health-related quality of life questionnaire (Euro Quality of Life – 5 Dimension), Beck Depression Inventory (BDI) and Modified Fatigue Impact Scale (MFIS). Patients’ arm/hand function was then tested with 9-HPT (Nine-Hole Peg Test), cognitive function was assessed by PASAT (Paced Auditory Serial Addition Test) and walking speed was tested by T25FW (Timed 25-Foot Walk) and 2-min walk-test (2MWT). 9-HPT, PASAT and T25FW are a part of MSFC protocol (Multiple Sclerosis Functional Composite). At the second visit, after 14 days of treatment, responders were defined based on 25% or greater improvement of T25FW. In addition, 2MWT was performed in all the patients. Fampiridine was introduced as a regular therapy to responders and they were invited to attend the third visit. Fampridine treatment was discontinued in the group of non-responders and their participation in the study was completed. During the third visit, after 28 days of treatment, responders underwent the same tests as performed at the initial visit. All tests in each patient were performed in the same order at the same time of day using the same walking aids. During the study the subjects could receive all regular MS therapy, including immunomodulatory and symptomatic therapy, whereas introduction of new drugs was not allowed.
All tests of the MSFC protocol were performed according to the recommendations of the National Multiple Sclerosis Association Society from 2001
We also calculated the total MSFC score as described in the MSFC protocol, using the following formula
2.2. 2-Min Walk Test (2MWT)
The 2MWT was performed as described elsewhere
The standard 21-item version of the MFIS scale, divided into three subscales: cognitive (MFIScog), physical (MFISphy) and psychosocial (MFISps), was carried out as described by National Multiple Sclerosis Society in 1997
A modified Slovenian version of the latest BDI, which meets the criteria of depression according to fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) was used. In this version, the question about libido/sex life was omitted resulting in a total sum of 60 instead of 63 points. The questionnaire was used to ascertain whether short-term fampridine treatment has any impact on mood disorders in patients with MS. We did not use BDI to determine the gravity of depression.
2.5. The EQ-5D health-related quality of life questionnaire
The Slovenian translation of the EQ-5 D questionnaire, which consists of a questionnaire and a visual analogue scale (EQ-VAS), was used
2.6. Statistical analysis
Data were analyzed by SPSS program for Windows®, version 20.0. The normality of distribution was checked using q–q plots, histograms and Shapiro–Wilk test. In the cases of normal distribution, t-test for dependent samples was used, otherwise Wilcoxon-signed rank test was performed (only for the comparison of 9-HPT test and EQ-5D index). All the data is presented as mean ± standard deviation. Significance was assumed for p < 0.05 in all tests.
Seventeen out of thirty patients (56.7%) were classified as responders. The response rate was the biggest among patients with PPMS (72.7%). In the group of SPMS patients the response rate was 44.4% and the patient with RRMS was classified as responder.
After 14 days of fampridine treatment the average improvement of T25FW walking time and 2MWT in responders was 3.6 s (34.5%) and 37.4 m (42.3%), respectively. This improvement persisted after 28 days of treatment; results of T25FW and 2MWT after 14 and 28 days of treatment did not demonstrate a statistically significant difference (p = 0.462 and p = 0.346, respectively) (
Fampridine-induced improvement of Timed 25-Foot Walk (T25FW) and 2-min Walk Test (T25FW) after 14 days of treatment persists also after 28 days of treatment in responders. The bar graph depicts the mean T25FW and 2MWT of responders before the introduction of fampridine, after 14 and 28 days of treatment. The average values of walking time and standard deviations are given above the columns. Between the columns, marked with x, there is no statistically significant difference.
Results of timed-25-Foot Walk (T25FW) and 2-min Walk Test (2MWT) in responders and non-responders before the introduction of fampridine and after 14 days of treatment.
The total MSFC score in responders improved significantly for 0.21 points (31.8%) (p = 0.001). Arm/hand function as assessed by 9-HPT significantly improved in responders after 28 days of treatment for 12.3 s (23.3%) (p = 0.002). Two of the patients were not able to complete the test trial with one hand at baseline and were therefore attributed 300 s for incomplete trials. After 28 days of therapy, both of these patients completed the test with both hands within the time limit. There was also significant improvement of mood in responders based on BDI results which improved for 6 points (37.0%) (p = 0.005). Fatigue based on the total MFIS score improved significantly among responders for 11.9 points (23.2%) (p = 0.003), MFIS physical subscale for 5.6 points (20.1%) (p = 0.001) and MFIS cognitive subscale for 5.4 points (30.2%) (p = 0.008). In the psychosocial MFIS subscale the result improved by an average of 0.9 points (16.4%), but not statistically significant (p = 0.127). Fampridine had no impact on cognitive function as assessed by PASAT (p = 0.432). Quality of life in responders, measured by EQ-5D index, significantly improved for 0.06 points (11.1%) (p = 0.012). The results of EQ-VAS showed a trend of improvement by 8.4 points (17.1%), but did not reach statistical significance (p = 0.057) (
Comparison of test results before the introduction of fampridine and after 28 days of treatment in responders. Data are presented as mean ± standard deviation. p-Value is derived from paired t-test or from Wilcoxon-signed rank test (the latter noted by *).
MSFC: Multiple Sclerosis Functional Composite, 9-HPT: 9-Hole Peg Test, PASAT: Paced Auditory Serial Addition Test, MFIS: Modified Fatigue Impact Scale, MFISt: total MFIS score, MFISphy: physical MFIS subscale, MFIScog: cognitive MFIS subscale, MFISps: psychosocial MFIS subscale, BDI: Beck Depression Inventory, EQ-5D index: health utility index based on the Euro Quality of Life: 5 Dimension health-related quality of life questionnaire, EQ-VAS: visual analogue scale on quality of life (part of EQ-5D).
Besides improvement of walking in responders, we found that after 28 days of fampridine treatment significant improvement among responders also occurred in the following areas: total MSFC score, arm/hand function, cognitive and physical fatigue, mood and quality of life as assessed by EQ-5D index. There were implied trends towards improvement of EQ-VAS and psychosocial fatigue, however non-significant. We demonstrated no impact of fampridine on cognitive function.
4.1. T25FW and 2MWT
As expected and in accordance with the literature we found improvement of the T25FW after 14 days in responders that persisted during 28 days of fampridine treatment , , and . There was no significant improvement of T25FW after 14 days of treatment among non-responders. However, some of the non-responders showed trend of improvement on T25FW and also reported subjective improvement of fatigue, balance and other functions. The analysis of a longer walking test, 2MWT, showed significant improvement in both responders (37.4 m) and non-responders (13.4 m). Baert et al. demonstrated that clinically meaningful changes for 2MWT after physical rehabilitation were 9.6 m from patient and 6.8 m from therapist perspective
Jensen et al. found that Six Spot Step Test (SSST) is more responsive to fampridine treatment than T25FW. Their proposed reason for this is that the SSST encompasses not only walking speed but also coordination and balance
The T25FW provides good objective evaluation of walking ability and has a high practical value in the clinical setting, requiring a minimum of time and space. However, a limitation of the T25FW is floor effect, making it less sensitive for detecting differences among patients with very mild disability. This raises a question, whether this test falsely indicates less responders among patients who walk faster on T25FW
Regarding these facts and the fact that fampridine exhibits a broader effect than on mere walking speed, it would be meaningful to investigate if tests, other that T25FW, could prove more appropriate in defining responders.
4.2. MSFC total score
Previous studies assessing the impact of fampridine on total MSFC score are scarce. Goodman et al. found no improvement of MSFC score in two placebo-controlled studies  and ; however these studies did not define responders to the drug. In a study by Ruck et al., the MSFC overall score showed a tendency to improve over the observational period but did not reach statistical significance
4.3. Arm/hand function
Two previous studies without a control group  and  and a placebo-controlled study by Goodman et al.
4.4. Depression and mood
In accordance with our study, two previous studies have also demonstrated positive effect of fampridine on mood. The study by Sobek et al. showed significant improvement of mood after 14 days of treatment among responders in comparison to non-responders
Similarly to our results most previous studies demonstrated both short and long-term reduction in motor and cognitive fatigue after fampridine treatment , , , , and . However, most of these studies lacked a control group. Only the study by Rossini et al. was placebo-controlled and it demonstrated significant improvement of fatigue only in patients showing an adequate blood concentration of fampridine
Improvement of both motor end cognitive fatigue may be explained by fampridine's ability to improve conduction in demyelinated axons and to cross the blood-brain barrier  and . On the other hand, this improvement might also be due to treatment or improvement of secondary factors that cause fatigue in MS patients
Intriguingly, despite of implied trend of improvement, we did not demonstrate significant impact of fampridine on psychosocial fatigue. One would expect that due to the improvement of physical function, mood and subjective cognitive and motor fatigue, psychosocial aspect of patients’ functioning would also improve. The reason for no statistically significant difference in MFISps can be sought, perhaps, in a lesser sensitivity of MFIS to detect the changes in psychosocial functioning as only two questions of MFIS cover this topic. This claim is supported by a study of Romano et al., in which FIS scale, a longer version of MFIS, was used and results demonstrated significant improvement of psychosocial fatigue after fampridine treatment
4.6. Cognitive function
In line with most previous studies that failed to demonstrate either short or long-term impact of fampridine on cognitive function , , , and , no significant improvement of PASAT was shown in our study. Ruck et al. found improvement of PASAT only after 12 months of fampridine treatment in responders, whereas Jensen et al. showed significant improvement of cognitive function after 28 days of therapy as assessed by Symbol Digit Modalities Test
Despite the fact that we did not find improvement of cognitive function by an objective method, we demonstrated significant improvement of subjective cognitive fatigue. Such divergence of results could be attributed to the impact of mood and fatigue improvement on subjective cognitive fatigue. In fact, it was proven that subjective cognitive complaints in MS patients usually do not coincide with objective neuropsychological assessment and more likely correlate with depression and fatigue
4.7. Quality of life
In accordance with our study, which showed improvement of EQ-5D index, two previous studies demonstrated both short as well as long-term improvements of quality of life after fampridine treatment  and . A nine-month interim analysis of the ENABLE study (without a control group) demonstrated benefits in health related quality of life measured by several measures, including EQ-5D, after 12 weeks and 9 months of treatment
Improvement of quality of life is an expected result since fampridine improves walking, ambulatory function and independence, which all greatly influence the patients’ quality of life  and . Moreover, quality of life improvement can be attributed to the changes of mood and fatigue, which improved in both our and the two previous studies
4.8. Limitations and significances of the study
An important limitation of our study is small size of the investigated group and the absence of placebo-treated control group. In addition, the patients were monitored only for 28 days and thereby we obtained only the data on the short-term effects of fampridine. As the question on libido/sex life was omitted in BDI, results of our study are somewhat less comparable with results of other studies that used BDI as a research tool. A smaller comparability with other studies could also be due to the fact that when we assessed response to the drug, we took 25% improvement of T25FW walking time as response criteria whereas some other studies used improvement of walking speed.
Our study enclosed a relatively high proportion of PPMS patients (35.7%) and is as such not representative of a typical MS collective. This could be due to inclusion criteria, which were EDSS 3.5–6.5 and clinically significant impairment of ambulation. Furthermore, the majority of our patients had EDSS values between 5 and 6.5. As PPMS patients are more likely to have significant impairment of ambulation and higher EDSS values compared to RRMS, a high proportion of these patients was selected for the study. However, as treatment options for PPMS are limited, it is important to investigate the possible treatments for this MS type, and our study shows that fampridine represents an important treatment modality for PPMS patients.
The significance of our study lies in the fact that we extended our research of fampridine beyond its known impact on walking in MS patients. Our results highlight the potential of fampridine to improve various functions besides lower extremity function and therefore the need for new, more extensive and long-term studies, which would precisely define the impact of fampridine on these variables and would possibly, serve as a basis to expand the range of indications for fampridine treatment. Furthermore, we demonstrated that longer walking tests (2MWT) could be more responsive to fampridine treatment than T25FW, raising the question if tests, other that T25FW, could prove more appropriate in defining responders.
The drug was supplied by Biogen under a named patient programme.
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