Consensus recommendations for diagnosis and treatment of Multiple Sclerosis: 2023 revision of the MENACTRIMS guidelines.

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for Multiple Sclerosis (MS), most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and time and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of MS therapies is critical to maximize patient benefit. The current guidelines review the current diagnostic criteria for MS and the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, progressive MS, pediatric cases and pregnant women. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.

Comparing infusion-related reactions of the first full dose (600 mg) biosimilar ocrelizumab administration with the standard divided protocol in multiple sclerosis patients: a randomized controlled trial study.

BACKGROUND: Ocrelizumab is a humanized antiCD20, thought to be a highly effective disease-modifying therapy (DMT). Its most frequent adverse effects are infusion-related reactions (IRRs). To reduce these reactions, the first dose of ocrelizumab is administered as two 300 mg infusions separated by two weeks. However, in the phase II trial of ocrelizumab, severe IRRs were not significantly different between two doses of 600 mg dose (two separate 300 mg doses) and 2000 mg dose (two separate 1000 mg doses). We compared the IRRs in undivided full (one 600 mg) and divided (two 300 mg) doses of ocrelizumab which is the standard protocol. METHODS: MS patients (relapsing or primary progressive MS) who are selected to receive ocrelizumab by neurologist or MS fellowship were enrolled in an open-label randomized controlled trial. Iranian biosimilar of the drug (Xacrel® by Cinnagen, approved by the Iranian Food and Drug Administration in 2021) was used. The participants received the first dose of ocrelizumab as either one 600 mg dose in one session or two 300 mg doses in two weeks apart. IRRs during or in the first 24 h after infusion were recorded. RESULTS: Of 332 participants, 150 received two 300 mg doses, and 182 received one 600 mg dose (by random selection). Life-threatening adverse effects were not observed in both groups. Overnight admission or permanent drug discontinuation was not needed. Temporary drug discontinuation was significantly higher in the one 600 mg dose group (p-value < 0.001). During the infusions, malaise (p-value: 0.003), skin reactions (p-value: 0.04), throat swelling (p-value: 0.03), and dyspnea (p-value: 0.01) were significantly increased in the intervention group. However, in the first 24 h, there was no significant difference between two different treatment protocols (one 600 mg dose or two 300 mg doses) in the onset of IRRS (p-value: 0.12). CONCLUSION: These findings suggest one 600 mg dose of ocrelizumab administration for the first dose is relatively safe. With some protocol modifications, it could lead to fewer patient referrals, saving time and cost and improvement the access for patients.

Late-onset neuromyelitis optica spectrum disorder: A case series from Iran.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a disabling autoimmune disease of the central nervous system that can start at ages of 50 or more, when it is called late-onset NMOSD (LO-NMOSD). Data on this disorder are sparse. In this cross-sectional study, patient characteristics of the disease were studied. LO-NMOSD patients of a tertiary center in Tehran were studied from 2016 to 2020. CASE REPORTS: Eight patients were identified, half of whom were men. The diagnostic delay was from no time-lapse to three years (mean: 0.62, SD: 1.06), which was significantly shorter than in early-onset patients. Seven patients (87.5%) tested positive for AQP4-IgG which was significantly higher compared to early-onset patients (p-value=0.01). Four patients (50%) had both transverse myelitis and optic neuritis as presenting symptoms, while three (38%) had just myelitis and only one (12%) had optic neuritis. CONCLUSION: There is discrepancy regarding different aspects of LO-NMOSD. Further studies are needed to clarify the subject in order to enhance diagnosis and treatment.

Burden of musculoskeletal disorders in Iran during 1990-2017: estimates from the Global Burden of Disease Study 2017.

Musculoskeletal diseases (MSDs) are the leading cause of disability and facing them demands updated reports on their burden for efficient policymaking. We showed Iran had the highest female-to-male ratio and highest increase in the burden of musculoskeletal diseases, in the past three decades, worldwide. We further confirmed the role of population aging as the main cause. PURPOSE: MSDs comprise most of the top causes of years lived with disability (YLDs) worldwide and are rapidly increasing in lower- and middle-income countries. Here, we present disability and mortality due to MSDs in Iran at the national level from 1990 to 2017. METHODS: We used Global Burden of Disease (GBD) 2017 Study data and standard methodology and presented the burden of MSDs in rates of years of life lost (YLLs), YLDs, and disability-adjusted life years (DALYs) during 1990-2017, for population aged ≥ 5 years old. We further explored attributable risk factors and decomposed the changing trend in DALYs to assess underlying causes. RESULTS: In Iran, MSDs were responsible for 1.82 million (95%uncertainty interval [UI] 1.3-2.4) DALYs, in 2017. During the past 28 years, with 1.75% annualized percentage change (APC), Iran had the highest percentage increase in the all-ages MSD DALYs rate worldwide, while the age-standardized DALYs APC was negligible. Low back pain was the greatest contributor to DALYs and caused 4.5% of total DALYs. The female population is experiencing considerably higher burden of MSDs, with 115% and 48% higher all-ages YLLs and YLDs rates per 100,000, respectively (YLLs 28.7; YLDs 2629.1), than males (YLLs 13.2; YLDs 1766.1). However, due to wide UIs, difference was not significant. Only 17.6% of MSD YLDs are attributable to assessed risk factors. CONCLUSION: Despite that MSDs are rising as an important cause of disability in Iran, these conditions are not sufficiently addressed in health policies. There is urgent need for cross-sectoral engagement, especially addressing the MSDs in females.

Consensus recommendations for the diagnosis and treatment of multiple sclerosis: 2019 revisions to the MENACTRIMS guidelines.

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for MS, most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and in time, and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of multiple sclerosis (MS) therapies is critical to maximize patient benefit. The current guidelines review the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, and progressive MS. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.

Burden of neurodegenerative diseases in the Eastern Mediterranean Region, 1990-2016: findings from the Global Burden of Disease Study 2016.

BACKGROUND AND PURPOSE: The Eastern Mediterranean Region (EMR) is experiencing a demographic shift towards rapid aging at a time of political unrest. We aimed to estimate the burden of neurodegenerative disorders and its relationship with sociodemographic index in the EMR countries from 1990 to 2016. METHODS: Using data from the Global Burden of Disease Study 2016, we calculated country-specific trends for prevalence, mortality, disability-adjusted life-years (DALY), years of life lost and years lived with disability (YLD) for Alzheimer's disease/other dementias and Parkinson's disease in the EMR during 1990-2016. RESULTS: In the EMR, the age-standardized prevalence rate of Alzheimer's disease/other dementias and Parkinson's disease was estimated at 759.8/100 000 (95% uncertainty intervals, 642.9-899.9) and 87.1/100 000 (95% uncertainty intervals, 69.8-108.2) people in 2016, demonstrating 0.01% and 42.3% change from 1990, respectively. Neurodegenerative disorders contributed to 5.4% of total DALY and 4.6% of total YLD among the older EMR population (70 years of age or older in 2016). Age-standardized DALY due to Parkinson's disease were strongly correlated with the sociodemographic index level (r = 0.823, P < 0.001). The YLD:DALY ratio of neurodegenerative diseases declined during this period in the low-income but not the high-income EMR countries. CONCLUSIONS: Our findings demonstrated an increasing trend in the burden of dementias and Parkinson's disease in most EMR countries between 1990 and 2016. With aging of the EMR populations, countries should target the modifiable risk factors of neurodegenerative diseases to control their increasing burden.

B cells in multiple sclerosis therapy-A comprehensive review.

For decades, B cells were ignored in multiple sclerosis (MS) pathogenesis, and the disease was always regarded as a T cell-mediated disorder. Recent evidence shows that there is an antigen-driven B-cell response in the central nervous system of patients with MS, and memory B cells/plasma cells are detectable in MS lesions. The striking efficacy of B cell-depleting therapies in reducing the inflammatory activity of the disease highlights that B cells may play more pathogenetic roles than expected. B cells express several unique characteristic markers on their surface, for example, CD19, CD20 molecules, that provide selective targets for monoclonal antibodies. In this respect, several B cell-targeted therapies emerged, including anti-CD20 antibodies (rituximab, ocrelizumab, and ofatumumab), anti-CD19 antibody (inebilizumab), and agents targeting the BAFF/APRIL signaling pathway (atacicept, belimumab, and LY2127399). In this review, we discuss, in detail, the immunobiology of B cells and their protective and destructive roles in MS pathogenesis. In the second part, we list the completed and ongoing clinical trials investigating the safety and efficacy of B cell-related monoclonal antibodies in MS.

Smoking and worsening disability in multiple sclerosis: A meta-analysis.

OBJECTIVES: Multiple sclerosis (MS) is a chronic demyelinating disorder affecting young adults. Environmental factors and lifestyle behaviors are pivotal in MS pathophysiology. Smoking has been considered as an important risk factor in MS. Various recent studies have been conducted to measure the role of smoking on worsening disability in patients with MS, thus we intended to systematically assess effect of smoking on evolution of disability in this study. MATERIALS & METHODS: We queried MEDLINE, EMBASE and Cochrane Library with following keywords "Multiple Sclerosis, Smoking, Tobacco Use, Disability" on December 1st 2016. Original articles were included when smoking history was mentioned, disability was measured via expanded disability status scale (EDSS) or multiple sclerosis severity score (MSSS). Studies with insufficient outcome data, non-human, or in other languages than English were excluded. RESULTS: Through literature review after duplicate removals, 268 articles were retrieved. A total of 56 articles were screened and 15 articles were assessed for eligibility, finally, eleven articles were included in this systematic review and meta-analysis. Ever smoking was significantly associated with increased EDSS (standardized mean difference (SMD) = 0.15, 95% CI = 0.01-0.28), but had no significant association with risk of reaching EDSS 4 (HR = 1.24, 95% CI = 0.89-1.72) or EDSS 6 (HR = 1.17, 95% CI = 0.88-1.57). Smoking had no effect on MSSS (SMD = 0.14, 95% CI = -0.04-0.32) or T2 lesion volume (SMD = 0.07, 95% CI = -0.08-0.22). CONCLUSIONS: This meta-analysis showed smoking increased EDSS, insignificant findings were possibly due to the small number of studies, significant differences in methodologies, and variations in reporting of disability outcomes.

A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients.

Identification of autoimmune processes and introduction of new autoantigens involved in the pathogenesis of multiple sclerosis (MS) can be helpful in the design of new drugs to prevent unresponsiveness and side effects in patients. To find significant changes, we evaluated the autoantibody repertoires in newly diagnosed relapsing-remitting MS patients (NDP) and those receiving disease-modifying therapy (RP). Through a random peptide phage library, a panel of NDP- and RP-specific peptides was identified, producing two protein data sets visualized using Gephi, based on protein--protein interactions in the STRING database. The top modules of NDP and RP networks were assessed using Enrichr. Based on the findings, a set of proteins, including ATP binding cassette subfamily C member 1 (ABCC1), neurogenic locus notch homologue protein 1 (NOTCH1), hepatocyte growth factor receptor (MET), RAF proto-oncogene serine/threonine-protein kinase (RAF1) and proto-oncogene vav (VAV1) was found in NDP and was involved in over-represented terms correlated with cell-mediated immunity and cancer. In contrast, transcription factor RelB (RELB), histone acetyltransferase p300 (EP300), acetyl-CoA carboxylase 2 (ACACB), adiponectin (ADIPOQ) and phosphoenolpyruvate carboxykinase 2 mitochondrial (PCK2) had major contributions to viral infections and lipid metabolism as significant events in RP. According to these findings, further research is required to demonstrate the pathogenic roles of such proteins and autoantibodies targeting them in MS and to develop therapeutic agents which can ameliorate disease severity.

Consensus recommendations for the diagnosis and treatment of multiple sclerosis: the Middle East North Africa Committee for Treatment and Research In Multiple Sclerosis (MENACTRIMS).

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for MS, most current diagnostic and treatment algorithms need re-evaluation and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and in time, and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate multiple sclerosis (MS) therapy selection is critical to maximize patient benefit. The current guidelines review the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, secondary progressive MS, and primary progressive MS. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.

Dominant and Protective Role of the CYTH4 Primate-Specific GTTT-Repeat Longer Alleles Against Neurodegeneration.

Primate-specific genes and regulatory mechanisms could provide insight into human brain functioning and disease. In a genome-scale analysis of the entire protein-coding genes listed in the GeneCards database, we have recently reported human genes that contain "exceptionally long" short tandem repeats (STRs) in their core promoter, which may be of adaptive/selective evolutionary advantage in this species. The longest tetra-nucleotide repeat identified in a human gene core promoter belongs to the CYTH4 gene. This GTTT-repeat is specific to Hominidae and Old World monkeys, and the shortest allele of this repeat, (GTTT)6, is linked with neural dysfunction and type I bipolar disorder in human. In the present study, we sought a possibly broader role for the CYTH4 gene core promoter GTTT-repeat in neural functioning and investigated its allelic distribution in a total of 949 human subjects, consisting of two neurodegenerative disorders, multiple sclerosis (MS) (n = 272) and Alzheimer's disease (AD) (n = 257), and controls (n = 420). The range of the alleles of this GTTT-repeat in the human sample studied was between 6- and 9-repeats. The shortest allele, (GTTT)6, was significantly in excess in the MS and AD patients in comparison with the controls (p < 0.004). The 6/6, 6/7, and 7/7 genotypes were in excess in the MS and AD patients, whereas the overall frequency of all other genotypes (consisting of at least one longer allele, i.e., 8- or 9-repeat) was higher in the controls (p < 0.005), indicating a dominant and protective effect for the longer alleles against neurodegeneration. This is the first indication of the involvement of a primate-specific STR in neurodegeneration in humans. We propose an adaptive evolutionary role for the expansion of the CYTH4 gene core promoter GTTT-repeat in the human brain, which is supported by a link between the shortest allele of this repeat with neuropsychiatric disorders.

A polymorphism in the resistin gene promoter and the risk of multiple sclerosis.

AIM: Multiple sclerosis (MS) is an inflammatory neurodegenerative disorder that inflammatory cytokines have been implicated in its immunopathogenesis. Resistin, a member of cysteine-rich secretory proteins family, identified with inflammatory properties in humans. To elucidate whether different genotypes of resistin are involved in MS pathogenesis, we compared serum levels of TNF-α, IL-1ß, hs-CRP, and resistin levels in different genotypes of MS patients with relapsing remitting type and healthy subjects. METHODS: IN a case-control study, 86 MS patients and 86 age- and sex-matched healthy subjects were enrolled. The age, gender distribution, and BMI of MS patientsand control group were similar. The serum levels of TNF-α, IL-1ß, and Resistin were measured by ELISA. hs-CRP was measured by imunoturbidimetric method. After DNA extraction, the analysis of -420C/G SNP (rs1862513) was performed via PCR-RFLP method. RESULTS: The resistin, TNF-α, IL1ß, and hs-CRP levels were significantly higher in MS patients compared with control group. The distribution of "rs1862513" genotypes were not significant between MS and control groups. Although resistin and TNFα levels were higher in GG genotype carriers of both groups, but the difference was significant only in MS patient. CONCLUSION: Resistin gene polymorphisms may modify the being susceptible to MS disease, which may cause through various levels of cytokines between genotypes.

Mitochondrial and nuclear genes as the cause of complex I deficiency.

Multiple sclerosis (MS) is an immunological inflammatory disease of the central nervous system. The pathogenesis of MS is incompletely understood, but various studies have suggested that mitochondrial dysfunction is associated with the disease. Mitochondria are among the main cellular sources of reactive oxygen and nitrogen species, and they play a pivotal role in many neuro-pathological conditions. The mitochondrial nuclear subunit of complex I gene in mitochondria may play a role in MS, and understanding this role may provide rationale for novel approaches to treatment of the disease and the development of novel therapies. We designed a molecular study to demonstrate biochemical defects in complex I activity and found some novel nucleotide substitutions in mitochondrial DNA that might be involved in the pathogenesis of MS. The mitochondrial complex subunit I sequence was amplified and sequenced in MS patients. Although no reported pathogenic mutations were found in these patients, other studies have clearly indicated that the mitochondrial nuclear complex subunit I gene plays a significant role in MS pathogenesis.

Avascular necrosis of the femoral head in multiple sclerosis: report of five patients.

Osteonecrosis of the femoral head is a severe complication of corticosteroids, which may lead to more disability in multiple sclerosis (MS) patients because of delayed diagnosis. The exact dose and risk period of steroids which cause the necrosis are not clearly known. The aim of the study was to enhance the attention of clinicians to leg pain in MS patients with regard to steroid therapies. We report five MS patients with femoral head necrosis who had relapsing remitting MS and received different doses of methyl prednisolone. Our young cases consist of three females and two males. The duration of disease varied between 1 and 3 years. The least interval between the last pulse of prednisolone and diagnosis of avascular necrosis was 6 months. Two of them received one pulse of 5 g of methyl prednisolone. All five patients had delayed diagnosis because the signs and symptoms were attributed to MS, which indicate the necessity of further focusing attention to early evaluations.

Serum and CSF PDGF-AA and FGF-2 in relapsing-remitting multiple sclerosis: a case-control study.

BACKGROUND AND PURPOSE: Fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor-A (PDGF-AA) are potent modulators of oligodendrocytes, the main responsible cells for myelin regeneration. We measured FGF-2 and PDGF-AA in the sera and cerebrospinal fluid (CSF) of patients with relapsing-remitting multiple sclerosis (RR-MS) and compared these values with control subjects. METHODS: Twenty-three patients with RR-MS and 23 subjects without inflammatory and demyelinating diseases were included. Serum samples of the patients were collected in both relapse and remission phases and were analyzed with ELISA method. CSF was drawn during the relapse period. Blood and CSF were drawn from control subjects for comparison. Wilcoxon and Mann-Whitney U-test and Spearman's rank correlation were used for analysis. P values of <0.05 were considered significant. RESULTS: Age and sex distribution were similar in both groups. Serum values of FGF-2 were higher in relapse phase compared with remission phase, with a trend toward significance (P=0.052). CSF PDGF-AA showed significant negative correlation with disease duration (correlation coefficient=-0.58, P=0.004). Serum levels of PDGF did not differ between two phases significantly. There was no difference in serum and CSF values of these factors between patients and controls. When we compared patients with prolonged disease with controls, a significant difference between the CSF levels of PDGF-AA was observed (mean±SEM 2.78±0.8 in controls vs. 0.55±0.29 in patients with MS≥2 years, P<0.05). CONCLUSION: Our study was the first to show that CSF PDGF-AA is related to disease duration. Supporting previous findings we showed that serum and CSF levels of these factors are weak indicators of disease severity.

Evaluation of apoptosis-related genes: Fas (CD94), FasL (CD178) and TRAIL polymorphisms in Iranian multiple sclerosis patients.

Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating disease characterized by a relapsing-remitting course leading to progressive disability. Given the critical role of apoptosis-related genes in the maintenance of homeostasis in the immune privilege sites, mutations in these genes have a profound effect on occurring autoimmune diseases such as multiple sclerosis. In the current study, polymorphisms in the apoptosis-related genes: Fas _-670 A>G, FasL _-844C>T, FasLIVS2nt _124 A>G and TRAIL_1595C>T were analyzed in 107 Iranian patients suffering from MS and 112 unrelated healthy controls using PCR-RFLP method. Our results demonstrated that among Iranian patients with MS and controls being homozygous in Fas_670A/A, G/G and FasL_-844C/C, TT in the promoter region and homozygocity in the minor allele for FasLIVS2nt_124G/G and TRAIL_1595C/C, polymorphisms were not associated with the MS risk in Iranian patients when compared with normal controls. However, the Fas _-670G/G genotype had a borderline significantly increased frequency with secondary progressive MS type (X(2)=5.8, P=0.05). In conclusion, no statistical association was found between the Fas, FasL and TRAIL polymorphisms and the risk of MS in Iranian patients.

Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis.

Progressive multifocal leukoencephalopathy (PML) is an uncommon and often fatal demyelinating disease of human central nervous system, which is caused by reactivation of the polyomavirus JC (JCV). PML generally occurs in patients with profound immunosuppression such as AIDS patients. Recently, a number of PML cases have been associated with administration of natalizumab for treatment of multiple sclerosis (MS) patients. Diagnosis and management of PML became a major concern after its occurrence in multiple sclerosis patients treated with natalizumab. Diagnosis of PML usually rests on neuroimaging in the appropriate clinical context and is further confirmed by cerebrospinal fluid polymerase chain reaction (PCR) for JCV DNA. Treatment with antiretroviral therapies in HIV-seropositive patients or discontinuing natalizumab in MS patients with PML may lead to the development of immune reconstitution inflammatory syndrome (IRIS) which presents with deterioration of the previous symptoms and may lead to death. In patients under treatment with monoclonal antibodies in routine practice, or new ones in ongoing clinical trials, differentiating PML from new MS lesions on brain MRI is critical for both the neurologists and neuroradiologists. In this review, we discuss the clinical features, neuroimaging manifestations of PML, IRIS and neuroimaging clues to differentiate new MS lesions from PML. In addition, various neuroimaging features of PML on the non-conventional MR techniques such as diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and MR spectroscopy (MRS) are discussed.

The human caveolin 1 gene upstream purine complex and neurodegeneration--a common signature.

The caveolin 1 gene (CAV1) is over-expressed in experimental animal models of multiple sclerosis (MS). Increased expression of this gene has also been reported in the Alzheimer's disease (AD) brain. Loss of this gene, on the other hand, has recently been reported to be associated with neruodegeneration. We have recently reported skew in the homozygote haplotypes of the human CAV1 gene -1.5 kb upstream purine complex in patients afflicted with MS and late-onset AD vs. controls. In order to examine reproducibility of those findings, we sequenced the region in independent groups of MS patients (n=120) and controls (n=150). We report two novel extreme homozygote haplotypes at 86-bp and 142-bp in the patients vs. controls. The above haplotypes were also detected in the previously reported cases of late-onset AD. The range of homozygote haplotypes in the controls was detected at between 106-bp to 122-bp. Following pooling of the neurodegenerative (n=486) and non-neurodegenerative (n=610) subjects studied for the human CAV1 purine complex to date, twenty haplotypes were found to be homozygous in the neurodegenerative, and not in the control pool (p<0.000001). Six overlapping haplotypes were detected in the MS and AD patients (p<0.007), strengthening the role of this region as a common etiological factor in the pathophysiology of neurodegenerative disorders, possibly through inflammatory mechanisms. Those overlapping haplotypes contained motif lengths that were non-existent in the control homozygote pool. The CAV1 purine complex GGAA and GAAA motifs are binding sites for numerous inflammatory transcription factors including the Ets, STAT, and IRF family members. Further work on the functionality of this region will shed light on the downstream events to the disease-linked haplotypes.

Dalfampridine: review of its efficacy in improving gait in patients with multiple sclerosis.

Multiple sclerosis (MS) is a progressive immune-mediated neurodegenerative disease of human central nervous system (CNS), which causes irreversible disability in young adults. The cause and cure for MS remain unknown. Pathophysiology of MS includes two arms: inflammatory demyelination and neurodegeneration. The inflammatory demyelination of MS which is mainly promoted by a massive activation of the immune system against putative CNS antigen(s) leads to loss of oligodendrocyte/myelin complex which slows down or halts impulse conduction in denuded axons. Practically, loss of myelin significantly reduces signal conduction along the demyelinated axons through alterations in the distribution of axonal ion channels. Dalfampridine (4-aminopyridine or 4-AP) is an oral potassium channel blocker, which was recently approved by FDA for symptomatic treatment of MS. Dalfampridine, which acts at the central and peripheral nervous systems, enhances conduction in demyelinated axons and improves walking ability of MS patients. A number of clinical trials have evaluated the safety and efficacy of fampridine in MS patients with the degree of gait improvement as the main outcome. The objective of this manuscript is to provide an overview of the pharmacology, pharmacokinetics, clinical trials, side effects and interactions of dalfampridine used in treatment of MS patients.