Iranian specialists' approach to treatment escalation in multiple sclerosis patients with cognitive impairment.

Background: People with multiple sclerosis (MS) and their physicians recognize cognitive retention as an important desired outcome of disease-modifying therapies (DMTs). In this study, we attempted to gather the opinions of Iranian MS experts regarding the treatment approach toward clinical cases with different physical and cognitive conditions. Methods: Opinions of 20 MS specialists regarding the best approach to 6 case scenarios (with different clinical, cognitive, and imaging characteristics) were gathered via a form. Results: The estimated kappa of 0.16 [95% confidence interval (CI): 0.159-0.163; P < 0.001] suggested a poor degree of agreement on the treatment choice among the professionals. Conclusion: Although most specialists agreed with treatment escalation in cases with cognitive impairment, there was no general agreement. Furthermore, there was not enough clinical evidence in the literature to develop consensus guidelines on the matter.

Alternate dosing of fingolimod in relapsing-remitting multiple sclerosis: A systematic review.

Background: Fingolimod is approved in relapsing-remitting multiple sclerosis (RRMS) with the recommended dose of 0.5 mg daily. To tackle possible adverse events, some clinicians may reduce the dose of fingolimod, mainly in the alternate-day form. We systematically reviewed the literature for efficacy measures of this method. Methods: PubMed (Medline®), Web of Science, Embase, Scopus, and the Cochrane Library databases were searched until April 9, 2021. Clinical studies (other than case reports and case series), in English, were included. Then, publications concerning alternate dose fingolimod (including every other day, every two or three days) were selected. Those studies concerning reduced daily dose (any daily dose less than 0.5 mg/day) were excluded to focus on alternate dosing. Results: Four observational studies were included. Data on Ohtani et al. study were limited. Three other studies were of good quality based on the Newcastle-Ottawa Scale. A total of 296 patients on the standard dose were compared to 276 patients on the alternate dosage. The most common reason for switching to the alternate dose was lymphopenia, followed by elevated liver enzymes. Two studies concluded that the alternate dosing could be a safe, yet effective strategy in patients with intolerable adverse effects of daily dose. However, Zecca et al. warned about the high possibility of disease reactivation. Due to the differences in outcome measures of the studies, meta-analysis was not applicable. Conclusion: This systematic review highlights the ambiguity of evidence on safety and efficacy of alternate dosing of fingolimod, encouraging further research on the subject.

Iranian specialists' approach to surgery in patients with multiple sclerosis.

Background: Data on perioperative risk stratification in patients with multiple sclerosis (MS) are limited. In this regard, the present study was conducted to investigate Iranian specialists' approach to surgical counseling for patients with MS (PwMS). Methods: 21 MS specialists were asked about 11 case scenarios with different MS disease statuses, disease-modifying therapies (DMTs), and urgency of the operation. The reasons for refusing surgery or factors that have to be considered before surgery were studied. Results: Overall, Fleiss Kappa was estimated to be 0.091 [95% confidence interval (CI): 0.090-0.093, P < 0.001] indicating a very poor level of agreement among responders. Conclusion: PwMS face surgery for various reasons. Risk assessment of surgery, the effect of various drugs such as anesthetics and DMT on patients, as well as many other aspects of MS are issues challenging the practitioners. Clarifying the various dimensions of these issues requires further research.

The effects of different types of smoking on recovery from attack in hospitalized multiple sclerosis patients.

BACKGROUND: Several studies demonstrated the association between tobacco smoking and higher risk and increased progression of multiple sclerosis (MS). Data about the effect of smoking during the recovery from MS attacks is limited. Furthermore, different types of tobacco exposures such as water pipe and passive smoking are not well assessed separately. So this study evaluated the effect of different types of smokes, cigarette and water pipe as well as passive smoking on the function recovery of relapsing-remitting MS (RRMS) attacks METHODS: This cohort study evaluated the adult patients with RRMS and Expanded Disability Status Scale (EDSS) < 5 in the attack phase. Patients were divided into two groups: smokers and non-smokers. The smokers included those who use cigarette, water pipe as well as passive smokers as subgroups for more analyses later. EDSS was monitored after relapse and two months after relapse. Change of EDSS considered as the criteria for functional recovery. The correlation between the amount of consumption and disability level was assessed among smokers by Pearson's correlation test. While, the difference of EDSS between smoker and non-smoker were assessed by Independent samples T-test. RESULTS: 142 patients were evaluated. 79 (55.6%) were smokers (43% male) while 63 (44.4%) were non-smokers (36.5% male). There was a statistically significant difference in change of EDSS between smoker and non-smoker groups, which change of EDSS was higher in non-smoker (-2.62 ± 0.90 non-smoker vs. -1.75 ± 0.76 smoker, P < 0.001). Also, only there was a significantly lesser decline in EDSS after two months in the cigarette smokers in subgroups analyses (P < 0.001). A correlation analysis revealed a significant positive correlation between the number per day of cigarette smoking and EDSS after relapse (r = 0.3, P = 0.03) and a significant positive correlation between minutes per month of smoking of water pipe and EDSS two months after relapse (r =  0.6 , P > 0.001). CONCLUSION: Tobacco smoking especially cigarette smoking is associated with a negative effect on recovery from the attack in patients with RRMS.

Late-onset multiple sclerosis in Iran: A report on demographic and disease characteristics.

BACKGROUND: Today, it is estimated that around 5% of multiple sclerosis (MS) patients are in the late-onset category (age at disease onset ≥ 50). Diagnosis and treatment in this group could be challenging. Here, we report the latest update on the characteristics of Iranian patients with late-onset MS (LOMS). METHODS: This cross-sectional study used the information provided by the nationwide MS registry of Iran (NMSRI). The registrars from 14 provinces entered data of patients with a confirmed diagnosis of MS by neurologists. Patients with disease onset at or later than 50 years of age were considered LOMS. RESULTS: Of 20,036 records, the late-onset category included 321 patients (1.6%). The age-standardized LOMS prevalence was around 75 per 100,000 people. 215 patients (67%) were female. Median Expanded Disability Status Scale (EDSS) was 3 (interquartile range: 1.5-5). The majority of the cases (56%) suffered from relapsing-remitting (RR) course while 20% were diagnosed with primary progressive (PP) MS. Significantly higher proportion of male sex, PPMS, and higher EDSS were seen in the late-onset group compared with early-onset and adult-onset cases (p-value < 0.05). Seventy-five (23%) patients did not receive any disease-modifying treatment. DISCUSSION: The more prominent degenerative pathology of LOMS may be the underlying mechanism of the observed differences in comparison to non-LOMS. CONCLUSION: There are substantial differences and knowledge gaps regarding LOMS which could be the subject of further research.

Safety and Effectiveness of Cinnomer® on Disease Characteristics, Depression, and Quality of Life of Patients with Multiple Sclerosis: A Phase IV, Post-marketing, Prospective, Multicenter Study.

BACKGROUND: Every patient diagnosed with definite multiple sclerosis (MS) should begin disease modifying therapies. Cinnomer® contains 40 mg glatiramer acetate (GA) and is available in prefilled syringes and autoinjector devices. METHODS: A phase IV multicenter study was conducted to explore the safety and effectiveness of Cinnomer® in the treatment of MS. Study-related data were collected for 14 months. RESULTS: Totally, 368 Iranian relapsing-remitting MS patients in nine cities were enrolled. The patients were either treatment naïve (n=191) or switchers (n=177). Cinnomer® treatment was associated with a significant reduction in annual relapse rate (ARR) (RR: 0.65, 95% CI: 0.43, 0.98). Final mean Expanded Disability Status Scale (EDSS) scores showed improvement from baseline (difference: -0.21, 95% confidence interval (CI): -0.34, -0.08). There was a significant decrease in gad-enhancing lesions during treatment (difference: -0.38, 95% CI: -0.64, -0.12). The mean score for the depression measure (21-item BDI-II questionnaire) significantly improved (difference: -2.39, 95% CI: -3.74, -1.03). There was a significant change in the "psychological well-being" dimension (P=0.02) (in line with BDI-II scores) and "rejection" MusiQoL dimensions (P=0.04). The adverse events documented throughout the study were not unexpected for GA and were principally not serious. CONCLUSION: Safety measures were in line with the known profiles of GA. The results suggest that Cinnomer® is effective with respect to clinical outcomes and from the patient's perspective and in reducing MRI-measured MS activity.

Economic and Social Standing of Individuals in Iran Diagnosed with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) may be affected by socioeconomic status (SES). This study aims to explore the determinants of SES among Iranian patients with MS and examine how these factors relate to disability and disease progression. METHODS: All patients with MS listed in the nationwide MS registry of Iran (NMSRI) until January 8, 2022, were included in this population-based study. RESULTS: Among the 5153 patients, most were female (74.5%), married (70.8%), and did not hold an academic degree (53.8%). Unemployment (OR: 3.75) and being unmarried (OR: 2.60) were significantly associated with Expanded Disability Status Scale (EDSS)≥6, and the time to progression was shorter in the unemployed group (P value: 0.03). There was also a significant negative correlation between the time to progression and the age at disease onset. CONCLUSION: The study suggests that providing financial and social support to MS patients and their families through investment could reduce both individual and societal burdens.

Gut microbiome in multiple sclerosis-related cognitive impairment.

Cognition is one of the most evaluated neurologic subjects with which the gut microbiome is supposed to be associated. Cognitive impairment is a prevalent finding in patients with multiple sclerosis (MS). Here, we are about to study the current evidence on the effect of gut microbiota on cognition and MS. Although no direct evidence is in hand, putting all indirect research together, one could think of the hypothetical benefit of brain-gut axis interventions (possibly diet changes, probiotic administration, microbiota transplant) to solve the drastic problem of cognitive impairment in MS. Hence, researchers are encouraged to scan this horizon in order to fill the knowledge gaps in the field.

Evaluation of liver injury in multiple sclerosis patients receiving pulsed steroid therapy.

OBJECTIVES: There is a paucity of literature about the methylprednisolone induced liver injury in multiple sclerosis (MS) patients. In this study, we intended to investigate the incidence, severity, and risk factors for liver injury in MS patients treated with pulsed methylprednisolone therapy. METHODS: This is a prospective observational study on MS patients treated with methylprednisolone pulses. All MS subjects with relapses who were referred to Sina Hospital between May 2020 to May 2021 were included in the study. They were evaluated for the demographic, clinical characteristics, and liver function tests. Liver injury was diagnosed if there was an elevation of serum aminotransferase levels above the upper normal limit (45 IU/L). RESULTS: A total of 314 individuals participated in the study. The prevalence of liver injury after treatment with pulsed methylprednisolone therapy was 2.86%. None of the cases with liver injury were severe. Univariate regression analysis demonstrated that the patients with liver injury had a significantly higher frequency of hyperlipidemia (p: 0.002), alcohol abuse (p: 0.021), and non-alcoholic fatty liver disease (NAFLD) (p: 0.005) compared to those without liver injury. Multivariate regression analysis showed that hyperlipidemia (p: 0.04, odds ratio (OR): 6.31), and history of alcohol abuse (p: 0.007, OR: 36.71) were significantly associated with liver injury. CONCLUSIONS: Our study highlights the importance of a close follow-up of the liver function tests in MS patients following pulsed methylprednisolone therapy, particularly in patients with NAFLD, hyperlipidemia, and history of alcohol-abusing.

Prescription trends of disease-modifying treatments for multiple sclerosis in Iran over the past 30 years.

BACKGROUND: Iran, as a middle income country, is one of the places with high and rising prevalence of multiple sclerosis (MS). Regarding the substantial economic burden, reviewing the trend in prescribed disease modifying treatments (DMTs) could be of help. Here we studied the DMT information of nearly 14000 MS cases and its trends change for 30 years to improve health services to patients. METHODS: The population base of this descriptive-analytical (cross-sectional) study consisted of all MS patients in the nationwide MS registry of Iran (NMSRI), up to August 1, 2021. Registrars from 15 provinces, 24 cities, 13 hospitals,8 MS associations, 16 private offices, and 7 clinics had entered the data. RESULTS: Overall, 14316 cases were enrolled. The majority (76.1%) were female. The youngest and eldest patients were 5 and 78 years old, respectively. Diagnosis delay was under one year in most cases (median: 0, IQR: 0 - 1). Most (61.4%) had RRMS. Generally, platform injectables (IFN beta, glatiramer acetate) were the most used DMTs until 2010. It seems that introduction of newer agents (antiCD20s and oral DMTs) resulted in a decrease in the use of former drugs since around 2015. Some unusual practices are prominent such as using not approved DMTs for PPMS over the years, or administering high efficacy drugs like natalizumab for CIS. The results indicate the remaining popularity of first line injectable DMTs in female and pediatric patients. DISCUSSION: Mean age (SD) at onset in our study (29 ± 8.8) is near the statistics in Asia and Oceania (28 ± 0.7). Concerns about COVID-19 had a noticeable impact on administering high efficacy drugs like rituximab and fingolimod. However, in male patients this approach has not been the case. It may be related to more aggressive disease course in this group. The other possible explanation could be planning for pregnancy in female cases. The popularity of platform injectable drugs in pediatric MS may be related to its favorable safety profile over the years. Another point in this group, is the superiority of rituximab over other highly efficient medications.

COVID-19 vaccine hesitancy in Iranian patients with multiple sclerosis.

BACKGROUND: World Health Organization (WHO) mentioned COVID-19 vaccination as the safest way to eradicate this pandemic. In the meantime, vaccine hesitancy (a delay in accepting or rejecting the vaccine despite the availability of vaccination services) is a barrier. Hence, we studied this obstacle in the Iranian multiple sclerosis (MS) population. OBJECTIVE: MS patients eligible for vaccination were asked to complete a google form survey. Demographic information, MS disease-related factors, flu vaccination history, COVID-19 vaccination history, cause of vaccination refusal, past history of COVID-19 infection, and their compliance with public health guidelines after vaccination were recorded. RESULTS: 1479 patients participated in this study. 6.9% of participants have not received the vaccination. Sinopharm was the most commonly used vaccine (92.9%). Vaccine hesitancy was associated with young age, lower education, unemployment, negative flu vaccination history, no previous episode of COVID-19 infection, less concern about COVID-19, and the expectation of not getting infected with the virus after vaccination. Participants mentioned concerns about the side effects of the vaccines as the most prevalent cause of avoiding vaccination (58.0%). Patients' concern of SARS-CoV-2 significantly decreased after vaccination (p-value < 0.001). CONCLUSION: Our findings in this study elucidate that a minor group of patients with MS has vaccine hesitancy, which may expose them to more severe COVID 19. The treating physicians should ask the history of vaccination and try to persuade such patients with scientific knowledge transformation. The long-term consequences of not being vaccinated should be clarified to such patients especially those who are receiving immunosuppressive agents.

The study of COVID-19 infection following vaccination in patients with multiple sclerosis.

BACKGROUND: At this time vaccination against SARS-CoV2 is a global priority. Cases with multiple sclerosis (MS) were among the first vaccinated populations in Iran. We evaluated the change in the frequency of COVID-19 after vaccination and the associated factors with severe COVID-19 infection before and after full vaccination. METHODS: A questionnaire was validated to investigate the basic characteristics (age, gender, education, body mass index, smoking status, and comorbidities), MS disease and treatment status (MS type, MS duration, The Expanded Disability Status Scale (EDSS), disease modifying treatments) and the information about COVID-19 infection and severity. RESULTS: 692 (91.9%) of participants have received both doses of vaccines, of which Sinopharm appeared to be the most common type. Significant difference of COVID-19 infection prevalence was seen before vaccination and after full vaccination (difference: 0.16, 95% CI: 0.12-0.20) (p value < 0.001). The difference was not significant for severe cases (those who were admitted in the ward or ICU) relative to the COVID-19 cases or the whole participants. Of all the basic and disease factors, only EDSS showed a significant association with severe COVID-19 before vaccination. Severe COVID-19 in fully vaccinated cases did not show any significant relation to any of basic or disease characteristics except with prior history of severe allergic reactions (OR: 17.1, p value: 0.001). DISCUSSION: The decreased frequency of infection with SARS-CoV2 was predictable but the insignificant difference in cases with the severe forms of the disease raise concern. The only significant predictor was found to be severe allergic reactions. As there are debates on antiCD20 s association with severe COVID-19 and vaccine efficacy, we could not find such significant relation. The other noticeable point about the found relation of EDSS and critical COVID-19 before vaccination is the absence of such relation after full vaccination.

Telemedicine as a strategic intervention for cognitive rehabilitation in MS patients during COVID-19.

The recent COVID-19 pandemic has taken the lives of nearly 5.2 million up to now. With no definite treatment and considering close contact as the primary mode of transmission, telemedicine has emerged as an essential medical care platform. Virtual medical communications have offered clinicians the opportunity to visit and follow up on patients more efficiently during the lockdown. Not only has telemedicine improved multiple sclerosis (MS) patients' health and quality of life during the pandemic, but it could also be used as a cost-effective platform for physical and cognitive MS rehabilitation programs. Cognitive impairment is a common problem among MS patients even at the initial phases of the disease. Rehabilitation training programs such as RehaCom, BrainHQ, Speed of Processing Training (PST), and COGNI-TRAcK have made great strides in improving a wide range of cognitive functions that MS patients are challenged with. Regarding the impact of COVID-19 on the cognitive aspects of MS patients, efforts to implement rehabilitation training applications have been increased. Web-based mobile applications, virtual visits, and telephone follow-ups are examples of such efforts. Having said that, limitations such as privacy, socioeconomic disparities, e-health literacy, study settings, and challenges of neurologic examinationss have been raised. Since most MS patients are young, all the beneficiaries are encouraged to embrace the research in the field to pave the road for more feasible and efficient ways of cognitive enhancement in MS patients.