Repeated prefrontal tDCS for improving mental health and cognitive deficits in multiple sclerosis: a randomized, double-blind, parallel-group study.

BACKGROUND: Multiple Sclerosis (MS) is an autoimmune disease associated with physical disability, psychological impairment, and cognitive dysfunctions. Consequently, the disease burden is substantial, and treatment choices are limited. In this randomized, double-blind study, we conducted repeated prefrontal electrical stimulation in 40 patients with MS to evaluate mental health variables (quality of life, sleep difficulties, psychological distress) and cognitive dysfunctions (psychomotor speed, working memory, attention/vigilance), marking it as the third largest sample size tDCS research conducted in MS to date. METHODS: The patients were randomly assigned (block randomization method) to two groups of sham (n = 20), or 1.5-mA (n = 20) transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex (F3) and right frontopolar cortex (Fp2) with anodal and cathodal stimulation respectively (electrode size: 25 cm2). The treatment included 10 sessions of 20 min of stimulation delivered every other day. Outcome measures were MS quality of life, sleep quality, psychological distress, and performance on a neuropsychological test battery dedicated to cognitive dysfunctions in MS (psychomotor speed, working memory, and attention). All outcome measures were evaluated at the pre-intervention and post-intervention assessments. Both patients and technicians delivering the stimulation were unaware of the type of stimulation being used. RESULTS: Repeated prefrontal real tDCS significantly improved quality of life and reduced sleep difficulties and psychological distress compared to the sham group. It, furthermore, improved psychomotor speed, attention, and vigilance compared to the sham protocol. Improvement in mental health outcome variables and cognitive outperformance were interrelated and could predict each other. CONCLUSIONS: Repeated prefrontal and frontopolar tDCS ameliorates secondary clinical symptoms related to mental health and results in beneficial cognitive effects in patients with MS. These results support applying prefrontal tDCS in larger trials for improving mental health and cognitive dysfunctions in MS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06401928.

Efficacy and safety of peginterferon beta-1a compared to interferon beta-1a in relapsing remitting multiple sclerosis patients: A phase 3, randomized, non-inferiority clinical trial (PEGINTEGRITY).

BACKGROUND: Multiple sclerosis (MS) is a prevalent, disabling, inflammatory, neurodegenerative disease that typically manifests during a highly productive stage of life. Interferon beta-1a was among the first approved disease-modifying therapies for MS and remains among the first-line treatment options. Pegylation of the interferon beta-1a molecule prolongs its half-life while maintaining its efficacy and safety profile. In PEGINTEGRITY study, we aimed to compare peginterferon beta-1a with interferon beta-1a in terms of efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: This study was a randomized, active-controlled, parallel-group, multi-center Phase 3 trial conducted in Iran in participants with RRMS. Participants received 125 µg of subcutaneous peginterferon beta-1a every two weeks or 30 µg of intramuscular interferon beta-1a once a week for up to 96 weeks. The primary outcome was the non-inferiority of peginterferon beta-1a to interferon beta-1a in reducing annualized relapse rate (ARR). Other outcomes included the number of patients with 12-week confirmed disability progression, the number of new or newly-enlarging T2 hyperintense lesions, the number of gadolinium-enhancing lesions, the number of new T1 hypointense lesions, the volume of new or newly-enlarging T2 hyperintense lesions, changes in brain volume, immunogenicity, and safety assessments. RESULTS: A total of 168 patients who met the eligibility criteria were enrolled and assigned to two arms of the study, each consisting of 84 participants. Totally, 41 participants (24 patients in the peginterferon beta-1a group and 17 patients in the interferon beta-1a group) were withdrawn from the study. The withdrawn patients were included in the per-protocol analysis for the period of time they were in the study. In 96 weeks, in the per-protocol population, the ARR was 0.05 in the peginterferon beta-1a group versus 0.11 in the interferon beta-1a group, which does not reflect a statistically significant difference (p=0.09; 95 % CI, 0.18-1.14). Considering the upper limit of the one-sided 95 % CI of the rate ratio of peginterferon beta-1a compared to interferon beta-1a, as well as the non-inferiority margin, it can be concluded that the primary outcome was met. The results were also comparable for other efficacy and safety outcomes. CONCLUSION: The results demonstrate the non-inferiority of peginterferon beta-1a to interferon beta-1a with similar efficacy in 96-week ARR in RRMS patients. Both arms were also comparable in other efficacy outcomes and safety profiles with no statistically significant differences. These findings support considering peginterferon beta-1a as a safe and efficient option in patients with RRMS. This study was registered on Iranian Registry of Clinical Trials (IRCT201612306135N8) and clinicaltrials.gov (NCT05242133).

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.

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.

Brain MRI Volumetric Assessment of Patients With Multiple Sclerosis: The Volume of Basal Ganglia, Thalamus, and Posterior Fossa.

Introduction: Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system, which is associated with brain atrophy and volume changes in some brain structures. This study aimed to compare the volume of the basal ganglia, thalamus, cerebellum, and brainstem in patients with relapsing-remitting MS with that of the control group using magnetic resonance imaging (MRI). Methods: In this cross-sectional study, MRI brain scans were obtained from 25 patients with relapsing-remitting MS and 25 healthy control subjects. Volumetric analyses were performed using Brain Suite software. Results: The mean age of the MS and the control groups was 33.96±8.75 and 40.40±8.72, respectively. No statistically significant difference was found in gender (P=0.747). The bilateral putamen and caudate nuclei volumes were significantly higher in the case group than in the control group (P<0.001). Moreover, lower the volume of the brainstem, cerebellum, bilateral thalamus, and globus pallidus were identified in the MS patients compared to the control group (P<0.001). There was an inverse correlation between the disease and treatment duration with the thalamus and cerebellum volume in MS patients (P=0.001). Treatment duration also had an inverse correlation with brainstem volume (P=0.047). Conclusion: The volume of some structures of the brain, including globus pallidus, thalamus, cerebellum, and brainstem is lower in MS and can be one of the markers of disease progression and disability among MS patients. Highlights: Due to the degenerative process in multiple sclerosis, some cerebral structures may face volume change.The present study demonstrated that the volume of globus pallidus, thalamus, cerebellum, and brainstem is lower in MS patients compared to the controls. Plain Language Summary: Multiple sclerosis (MS) is defined as an inflammatory disease involving the white matter of the brain, but experience has shown that many non-white matter structures also change in MS. In this study, we aimed to examine some parts of the brain, such as the thalamus, basal ganglia, brainstem, and cerebellum, for volume changes. The results showed that all these structures can have a smaller volume in MS patients than in healthy people. Especially in the case of the thalamus and cerebellum, this difference increases with increasing the disease duration. Changes in the size of these structures can be the result of degeneration of the neurons in these areas. These changes can cause significant disability in patients; however, there may not be significant changes in the number of plaques in patients. Attention to these changes can be essential in interpreting patients' clinical changes, including motor and cognitive disabilities.

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.

Characteristics of COVID-19 in patients with multiple sclerosis.

BACKGROUND: Regarding the high prevalence of multiple sclerosis (MS) and COVID-19 in Iran, a multicenter study of COVID-19 in Iranian MS patients with is carried out to address the concerns of this population. METHODS: Data on MS patients with COVID-19 from nine provinces of Iran were entered in a web-based registry system, between July 2020 and March 2021. Among the COVID-19 symptoms, dyspnea, altered mental status, or those resulting in hospital admission were considered severe. RESULTS: A total of 397 eligible patients were identified. In addition, 310 (78%) were female. The mean age was 36.5 ± 9.5. 294 (74%) patients had relapsing- remitting form. Also, four patients (1%) expired due to COVID-19 infection. The mean duration of admission in hospitalized patients was 9 (± 5.3) days. MRI was performed on 111 (28%) patients after developing COVID-19. MRI changes were observed in 27 (24%) of these cases. MS drug was changed in 26 (6%) patients. Steroid use in the past three months (OR: 2.43, 95% CI: 1.003-5.88) (p value: 0.049) and antiCD20s (OR: 4.03, 95% CI: 2.41-6.68) (p value < 0.001) showed significant association with severe COVID-19 symptoms. CONCLUSION: The death rate of COVID-19 among MS patients (1%) is lower than the overall death rate of the pandemic in Iran (3%). Those who received steroid in the past three months may be at increased risk of more severe forms of COVID-19. There are still doubts about the effect of anti CD20s on COVID-19 severity.