Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with unknown etiology. MS causes demyelination of CNS neurons and signaling impairments which generate a variety of signs and symptoms. Patients with MS suffer from psychological and physical disabilities including walking disability, depression, fatigue, and cognitive impairment which impair their quality of life ( 1 - 6 ). CI is prevalent in patients with MS which interferes with daily activities, occupation, social activities, and quality of life ( 7 ). It is reported that between 40-65% of affected cases suffer from CI which is present from the early stages of the disease ( 8 ). All aspects of cognition especially information processing speed and memory ( 9 ). To improve cognition in subjects with MS different medications such as memantine, rivastigmine and donepezil are administered while their safety and efficacy are not satisfactory ( 10 - 12 ). Fampridine which is also called 4-aminopyridine is a fat-soluble medication that crosses the blood-brain barrier easily ( 13 ).
Fampridine enhances action-potential conduction in demyelinated nerve fibers and facilitates synaptic transmission ( 13 ). It improves muscle strength and walking speed in patients with MS and routinely is used for walking difficulties in MS ( 6 ). Based on its effects on demyelinated axonal fibers in different sites of the CNS, it is suggested to positively improve psychological well-being like depression and fatigue in MS ( 6 , 14 ). Up to now, different studies showed the effects of fampridine on cognition based on various tests. Some of them show significant improvement after treatment and others did not confirm the efficacy profile. Therefore, we aimed to conduct a systematic review and meta-analysis to investigate the effect of fampridine on cognition in patients with MS.
Methods
We performed a comprehensive search in PubMed, EMBASE, Scopus, Web of Science, google scholar, and also gray including references of the references and conference abstracts on January 1 th 2020. After deleting duplicate articles, two independent researchers screened the titles and abstracts of the potentially eligible studies. In the case of discrepancy, they asked the third one. Afterward, they screened the full texts of the remained studies and extracted the data.
The extracted data were entered by each researcher in a separate datasheet. Another expert researcher checked the two data sheets to solve the discrepancies. Data extraction was performed based on a predefined table including: number of participants, first author, publication year, country of origin, age, disease duration, Expanded Disability Status Scale (EDSS), duration of low up, type of cognition test, and scores before and after the treatment.
The MeSH terms were: ((Multiple Sclerosis) OR (Sclerosis AND multiple) OR (sclerosis AND disseminated) OR (disseminated sclerosis) OR ((multiple sclerosis) AND (acute fulminating)) AND ((4 Aminopyridine) OR Dalfampridine OR Pymadine OR VMI-103 OR (VMI 103) OR VMI103 OR (4-Aminopyridine Sustained Release) OR (4 Aminopyridine Sustained Release) OR ((Sustained Release) AND 4-Aminopyridine) OR Fampridine-SR OR (Fampridine SR) OR Fampridine)
Inclusion criteria were defined as follows: Before-after studies trials reporting scores of the tests before and after treatment, articles published in English.
Exclusion criteria were defined as follows : 1) Case-control, Letters to the editor, Cross-sectional, and Case report studies 2) Studies that had no clear data regarding the scores of the cognition tests.
Risk of bias assessment: Two independent researchers performed risk of bias assessment using the Cochrane Collaboration's tool for assessing the risk of bias and Newcastle - Ottawa Quality Assessment Scale (adapted version for cohort studies) ( 15 , 16 ).
Statistical analysis: For this study, we performed all statistical analyses using STATA 14.0 (Stata Corp LP, College Station, TX, USA). Standardized mean difference (SMD) was calculated and presented as the effect size for all outcomes. To determine heterogeneity, Inconsistency (I 2 ) of included studies was calculated. We used random-effects model for meta-analysis as the heterogeneity between study results (I 2 ) was more than 50%.
Results
We identified 4972 studies in the preliminary search. After deduplication, 2607 articles remained. Two researchers screened the title and the abstracts, removing 2592 studies. Finally, 15 studies remained for meta-analysis ( figure 1 ). The included studies were published between 2013 and 2021 and were conducted in 10 countries including Denmark, Germany, Greece, Italy, Mexico, Switzerland, USA, Canada, Spain, and Slovenia. Totally, 723 patients were included in meta-analysis with the mean age in range of 39 and 53 years. Also, in the included studies patients had the mean EDSS ranged between 4 and 5.8 ( table 1 ). The SMD of SDMT (after-before treatment) was 0.45(95%CI: 0.06-0.84) (I 2 =75.3%, p<0.001) ( figure 2 ). The SMD of PASAT (after-before treatment) was 0.25(95%CI: 0.13-0.37) (I2=84.3%, p<0.001) ( figure 3 ). The risk of bias assessment of included studies is summarized in table 2 .
Table 1
Data extracted from included studies.
PASAT=Paced Auditory Serial Addition Test, SDMT=Symbol Digit Modalities Test, ER-FAM=extended release of Fampridine, PR-FAM=prolonged release of Fampridine, SR-FAM=slow release of Fampridine, NR=not reported, NA=not applicable, ABS*=abstract, QA=quality assessment, D= day, M=month, W= week, SD=standard deviation, SE=standard error, CI= confidence interval.
| Author | Year | Country | Number Female Male | Age | Disease duration Mean (SD) year | EDSS Mean (SD) | Follow up | Drug type | Cognition test | Pretreatment in Fampridine group | Post treatment in Fampridine group | Quality assessment |
| Sepehr Mamoei (17) | 2021 | Denmark | 39 | NR | NR | NR | 12 W | Fampridine | SDMT | 40.2 (10.6) | 38.7 (9.8) | |
| Dimos D. Mitsikostas(6) | 2021 | Greece | 94 | NR | NR | NR | 24 W | PR-FAM | PASAT | 30.64 (21.358) | 31.72 (21.874) | 6 /9 |
| Francisco Alejandro Rodriguez-Leal (18) | 2019 | Germany | 189 | 53.55 (10.83) | 12.92 (10.83) | 5.22 (1.29) | 2 W | Fampridine | PASAT | 45.15 (12.17) | 46.62 (11.91) | 7 /9 |
| Laura De Giglio (19) | 2019 | Italy | 80 50 30 | 49.3 (78) | 14.7 (9) | Median (range) 4(1-6) | 4 W | ER-FAM | PASAT | 28.5 (12.6) | Mean (SD) in 70 patients 35.9 (11.70) | |
| Laura De Giglio (19) | 2019 | Italy | 80 50 30 | 49.3 (78) | 14.7 (9) | Median (range) 4 (1-6) | 4 W | ER-FAM | SDMT | 30.1 (7.2) | Mean (SD) in 70 patients 39.8 (9.196) | |
| C. Arreola-Mora (20) | 2018 | Mexico | 11 7 4 | 39.5 (8) | 8.55 (5.9) | 4.7 (1.4) | 21-22 W | Fampridine | SDMT | 37.9 (11.1) | 41.3 (13.9) | |
| C. Arreola-Mora (20) | 2018 | Mexico | 11 7 4 | 39.5 (8) | 8.55 (5.9) | 4.7 (1.4) | 21-22 W | Fampridine | PASAT | 33.7 (11.4) | 35 (14.3) | |
| C. Bakirtzis (21) | 2018 | Greece | 35 17 18 | Mean (median) 52.4 (52) | Mean (median) 14.4 (14) | Mean 5.3 | 24 W | PR-FAM | SDMT | 32 (13.6) | 35.6 (14.6) | 5 /9 |
| Sarah D. Broicher (14) | 2018 | Switzerland | 20 | NR | NR | NR | 22 M | Fampridine | SDMT | 47 (3.1) | 50.5 (4.7) | |
| Elizabeth W. Triche (22) | 2016 | USA | 31 24 7 | 53.7 (10.3) | 13.1 (8.8) | 5.1 (1.7) | 14 W | ER-FAM | SDMT | median (25th, 75th): 40.0 (29.0, 45.0) | 41.0 (35.0, 48.0) | 5 /9 |
| H.B Jensen (23) | 2016 | Denmark | 16 7 9 | 50.8 (6.5) | 9.5 (5.4) | 5.8 (0.8) | 26-28 D | SR-FAM | SDMT | 39 (10) | 41.3 (13.1) | |
| Sarah A. Morrow (24) | 2016 | Canada | 24 | NR | NR | NR | 4 W | SR-FAM | PASAT | 44.9 (11) | 46.7 (10.3) | |
| Melanie Korsen (25) | 2015 | Germany | 22 15 7 | 48.0 (10.4) | NR | 4.0 (4.0–5.0) | 12-14 D | ER-FAM | PASAT | 42.9 (13.5) | 46.1 (13.3) | 4 /9 |
| I. González-Suárez (26) | 2015 | Spain | 10 7 3 | 53.78 (8.012) | NR | 5.72 (0.67) | 6 M | Fampridine | SDMT | 34.71 (7.41) | 40.57 (9.81) | NA |
| Katja Pavsic (27) | 2015 | Slovenia | 17 | NR | NR | NR | 28 D | Fampridine | PASAT | 42.1 (10.1) | 43.4 (10.8) | 4 / 9 |
| HB Jensen (28) | 2014 | Denmark | 105 | 48.6 (7.1) | 10.8 (7.2) | 5.6 (0.9) | 4 W | SR-FAM | SDMT | 37. 4(13.2) | 38.7 (13.6) | |
| T. Ruck (29) | 2013 | Germany | 30 | NR | NR | NR | 9-12 M | ER-FAM | PASAT | 39.45 (2.84) | 46.35 (2.84) | 5/9 |
Table 2
Risk of bias asessment of included interventional studies
| Random sequence generation (selection bias) | Allocation concealment (selection bias) | Blinding of participants and researchers (performance bias) | Blinding of outcome assessment (detection bias) | Incomplete outcome data (attrition bias) | Selective reporting (reporting bias) | |
| Sepehr Mamoei 2021 Denmark | High risk | High risk | High risk | High risk | Low risk | Unclear |
| Laura De Giglio 2019 Italy | High risk | Low risk | High risk | Low risk | High risk | Low risk |
| Nikhil Satchidanand 2018 USA | Low risk | Low risk | High risk | Low risk | High risk | Low risk |
| C. Arreola-Mora 2018 Mexico | Low risk | Low risk | High risk | Low risk | Low risk | Low risk |
| Sarah D. Broicher 2018 Switzerland | Low risk | Unclear | High risk | High risk | High risk | High risk |
| Sarah A. Morrow 2016 Canada | Low risk | Low risk | High risk | Low risk | High risk | Unclear |
| HB Jensen 2014 Denmark | High risk | High risk | High risk | High risk | High risk | High risk |
Discussion
To our knowledge, this is the first systematic review and meta-analysis which focused only on the effects of fampridine on cognition status in patients with MS. Our results demonstrated that fampridine treatment significantly improved scores of both SDMT and PASAT, indicating positive effects of treatment on cognition in patients with MS. In a previous systematic review and meta-analysis which aimed to assess the effects of fampridine on walking, cognition, and quality of life, Valet et al. included only four studies for the cognition part and reported no significant improvement after treatment, although its effects on walking were significant ( 30 ).
In a multi-centric study, Mitsikostas et al. enrolled 92 patients with MS and assessed the efficacy of prolonged-release fampridine on cognition (PASAT), fatigue (MFIS), depression (BDI-II), and quality of life (MusiQoL) after 6 months. They found that scores of all items improved 3 and six months after treatment. They found that information processing speed which is a core test in PASAT was improved significantly after 6 months of treatment ( 6 ). Significant improvement of information processing speed was reported by Ruck et al. after 9-12 months of treatment with fampridine which was evaluated by PASAT ( 29 ). In an open-label study, Bakirtzis et al. evaluated the effects of prolonged-release (PR) fampridine during 6 months of treatment. They investigated significant improvement in walking, cognition (SDMT), and MSIS-29 scores while after 12 months quality of life scores improved significantly, too ( 21 ). Jensen et al. reported improvement of SDMT score after one month of treatment with fampridine ( 28 ).
In contrast, some other studies which used SDMT or PASAT for cognition assessment did not show a significant improvement after completion of the study period ( 24 , 27 , 31 ). Based on demyelinating axons, high-speed signals are not transmitted properly which leads to impaired information processing speed ( 32 ). Information processing speed is the key deficit of cognition in MS which is not always associated with a deficit of other domains ( 33 ). On the other hand, learning and memory deficit is not always associated with information processing speed ( 34 , 35 ). By blocking potassium channels, fampridine improves nerve conduction and faster processing speed as a result ( 6 ). Literature shows that fampridine positively affects fatigue and depression in MS ( 6 , 19 ). Depression and fatigue negatively affect cognition and it should be considered that fampridine improves cognition by improving psychological well-being in MS ( 22 , 36 , 37 ).
Disease duration, physical disability, gray matter atrophy, and disease progression negatively affect cognition in MS ( 38 , 39 ). To improve cognition, medications such as fampridine, cognitive behavior therapy, psychological well-being (treating depression and fatigue), and sleep quality improvement should be considered ( 40 ). This study had some limitations. First, different types of fampridine such as extended-release, slow-release, and prolonged-release were administered. Second, all studies did not have the same follow-up time. Clinical trials with the same follow-up duration, and medication type is recommended. Based on this systematic review, Fampridine has a significant role in decreasing cognitive impairments is MS patients.
Acknowledgments
None.
Ethics approval:
Not applicable.
Funding:
None.
Conflict of interests:
All authors have no conflict of interest to disclosure.
Authors’ contribution:
Abdorreza Naser Moghadasi, study conception, data gathering, article writing. Narges Ebrahimi, data gathering, article writing. Sara Bagherieh, data gathering, article writing. Aida Mohammadi, data gathering, article writing. Mohammad Ali Sahraian, data gathering, article writing. Mahsa Ghajarzadeh, study design, data analysis, article writing and editing.
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