Earlier age of symptom onset in younger generation of familial cases of multiple sclerosis.

AIM: The aim of this study was to assess the prevalence of familial MS (fMS) in Belgrade MS population, discern the differences between the persons with fMS and sporadic MS, and to detect the presence of anticipation phenomenon in fMS patients. METHODS: The data on the demographic and clinical characteristics of MS patients was obtained from the Belgrade MS population Registry. In cases of vertical transmission of MS, the family members were divided into the younger and older generation, in order to assess the potential presence of anticipation phenomenon. To adjust for follow-up time bias, a secondary analysis including only patients who had the onset of symptoms before 39 years (75.percentile), and those who were 39 + years, was performed. RESULTS: The prevalence of fMS in Belgrade MS population is 6.4%. FMS cases had earlier age at MS symptom onset (30.4 vs. 32.3 years) compared to sporadic MS cohort. When comparing fMS cases across generations, the younger generation had significantly lower age at onset compared with the older one (25.8 vs. 35.7 years, p < 0.001). After adjustment for the different length of the follow-up, the difference in age at symptom onset between the groups was reduced, but it still existed and was statistically significant (30.0 years in younger vs. 36.4 years in older generation, p = 0.040). CONCLUSION: In our study, the analysis of fMS cases across generations, showed an earlier age of symptom onset in the younger generation, even after adjustment. These results indicate the possibility of existence of anticipation phenomenon.

Whole exome sequencing in Serbian patients with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with a high genetic and clinical heterogeneity. Numerous HSP patients remain genetically undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel variants and genes is needed. Our previous study analyzed 74 adult Serbian HSP patients from 65 families using panel of the 13 most common HSP genes in combination with a copy number variation analysis. Conclusive genetic findings were established in 23 patients from 19 families (29%). In the present study, nine patients from nine families previously negative on the HSP gene panel were selected for the whole exome sequencing (WES). Further, 44 newly diagnosed adult HSP patients from 44 families were sent to WES directly, since many studies showed WES may be used as the first step in HSP diagnosis. WES analysis of cohort 1 revealed a likely genetic cause in five (56%) of nine HSP families, including variants in the ETHE1, ZFYVE26, RNF170, CAPN1, and WASHC5 genes. In cohort 2, possible causative variants were found in seven (16%) of 44 patients (later updated to 27% when other diagnosis were excluded), comprising six different genes: SPAST, SPG11, WASCH5, KIF1A, KIF5A, and ABCD1. These results expand the genetic spectrum of HSP patients in Serbia and the region with implications for molecular genetic diagnosis and future causative therapies. Wide HSP panel can be the first step in diagnosis, alongside with the copy number variation (CNV) analysis, while WES should be performed after.

Exclusive breastfeeding may be a protective factor in individuals with familial multiple sclerosis. A population registry-based case-control study.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease that affects the central nervous system, which most likely results from the interplay between environmental and genetic factors. The aim of our study was to assess the effect of breastfeeding on the risk of developing familial multiple sclerosis (fMS) in persons with positive MS history, being the first such investigation performed in fMS cohort. METHODS: A case-control study based on the Belgrade population MS Registry was conducted. Cases for the sporadic MS (sMS) control group were randomly selected from the Registry, and matched with individuals with fMS at a ratio of 1:1. Spouses of the persons with fMS were included as a healthy control (HC) group. A specific questionnaire that was previously validated was used to obtain the data. To evaluate risk factors associated with breastfeeding for fMS occurrence compared with sMS and HC, multinomial regression analysis was performed to compute the relative risk ratios (RRR) along with 95% confidence intervals (95% CI). The analysis was afterwards repeated, stratified by sex. Both models were adjusted for potential confounding factors. RESULTS: A total of 393 participants were included in our case-control study, 131 per group. There were more individuals who were exclusively breastfed longer than six months in the sMS group compared to fMS group (RRR 2.01, 95% CI 1.22-3.32). After stratification by sex, exclusive breastfeeding was shown to be a protective factor for fMS only in male population, for individuals breastfed ≥4 months. The results of both the main and stratified analysis remained robust after adjustment. CONCLUSION: Our study findings indicate that breastfeeding reduces the risk of MS in infants with family history of the disease, although this protective effect may be limited to the male population. Further investigation into the differences in risk factors between fMS and sMS is warranted to gain a more comprehensive understanding of the disease.

The impact of the comorbid seizure/epilepsy on the health related quality of life in people with multiple sclerosis: an international multicentric study.

Introduction: The health-related quality of life (HRQoL) of people with (Pw) multiple sclerosis (MS) is usually deteriorated. It has been recently suggested that comorbidities may have the negative influence on the quality of life of the PwMS, but according to the best of our knowledge, only one study investigated, although in a very small cohort, the impact of individual comorbidity on the quality of life of PwMS. The aim of our investigation was to assess, in an international, multicentric study, the impact of comorbid seizure/epilepsy on the HRQoL in PwMS. Methods: We conducted cross-sectional study at numerous neurological centers in Serbia, Croatia, Bulgaria, Montenegro, Northern Macedonia, and Bosnia and Herzegovina (Federation of Bosnia and Herzegovina and Republic of Srpska). For each patient, demographic and clinical data were collected, including Expanded disability status scale (EDSS) score. Beck Depression Inventory (BDI) and the 36-Item Short Form Health Survey (SF-36) questionnaires were administered to all patients. Results: The study comprised 326 PwMS in total, 127 PwMS with seizure/epilepsy and 209 PwMS without. Both mean Physical health composite (PHC) and mental health composite (MHC) scores, were statistically significantly higher in PwMS without seizure/epilepsy, implicating worse quality of life in PwMS with comorbid seizure/epilepsy. Presence of seizure/epilepsy in pwMS was statistically significant independent predictor of both PHC and MHC, in multivariate linear regression model after adjustment for potential confounding variables. The hierarchical multivariate regression analysis was performed in order to establish the most important predictors of the PHC and MHC of the SF-36, in PwMS with seizure/epilepsy; older age, higher level of disability, as measured by EDSS, higher depression score, drug-resistant epilepsy and shorter time since last seizure were found to significantly predict worse MHC score in PwMS with seizure/epilepsy. Discussion: Our results point to the possible role of theinterventions related to the adequate control of epilepsy along with improvement of the mental health status to be important in order to reduce MS burden in the PwMS with comorbid seizure/epilepsy.

Impact of the autonomic dysfunction on the quality of life in people with NMOSD and MS: An international cross-sectional study.

BACKGROUND: A substantial autonomic nervous system (ANS) dysfunction has been described in multiple sclerosis (MS) and recently, also in neuromyelitis optica spectrum disorder (NMOSD). The prevalence of ANS symptoms contributes to the chronic symptom burden in both diseases. The aim of our study was to assess ANS dysfunction in people with (pw) NMOSD and MS, using the Composite Autonomic Symptom Score-31 (COMPASS-31), and additionally, to evaluate if ANS dysfunction have impact on the quality of life of these patients. METHODS: We conducted cross-sectional study at three national referral neurological clinics in Serbia, Croatia, and Montenegro. A total of 180 consecutive subjects, 80 pwNMOSD and 100 pwMS, followed-up at these clinics, were enrolled in the study. Subjects included in the study completed: the validated versions of the COMPASS-31 and the Multiple Sclerosis Quality of Life-54 (MSQoL-54), and the Beck Depression Inventory (BDI). RESULTS: This study demonstrated that the total COMPASS-31 score > 0.0, implicating the presence of ANS dysfunction, was detected in almost all NMOSD and MS study participants tested (80/80, and 97/100, respectively). Our findings showed that autonomic symptom burden was statistically significantly correlated with decreased quality of life, in both NMOSD and MS cohorts. The independent predictors of the better quality of life in pwNMOSD were lower autonomic burden, particularly the absence of the orthostatic intolerance (p = 0.005), along with lower EDSS and BDI score (p ≤ 0.001). Similarly, in pwMS, independent predictors were EDSS, BDI, orthostatic intolerance, and the total COMPASS-31 (p ≤ 0.001). CONCLUSION: Our study demonstrated that a significant proportion of persons with both NMOSD and MS have considerable dysautonomic symptom burden which is correlated with the decreased quality of life. Further investigations are warranted in order to optimize treatment interventions in MS and NMOSD.

Cladribine tablets in people with relapsing multiple sclerosis: A real-world multicentric study from southeast European MS centers.

BACKGROUND: Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS). OBJECTIVES: To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS). METHODS: A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries. RESULTS: We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment. CONCLUSION: Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals.

VALIDATION OF THE BRIEF INTERNATIONAL COGNITIVE ASSESSMENT FOR MULTIPLE SCLEROSIS (BICAMS) IN A LARGE COHORT OF RELAPSING-REMITTING MS PATIENTS.

Cognitive impairment is one of the most frequently reported symptoms in persons with multiple sclerosis (MS). The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been recommended as a standardized international screening and monitoring tool for brief cognitive assessment. The aim of our study was to assess the reliability and validity of the Serbian version of the BICAMS. A total of 500 relapsing-remitting MS (RRMS) patients and 69 age-, gender- and education-matched healthy control (HC) subjects were examined. All participants performed the BICAMS test battery, which includes the oral version of the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test second edition (CVLT-II), and Brief Visuospatial Memory Test Revised (BVMTR). A randomly selected subset of patients were retested one to three weeks after baseline. Statistically significant differences between patients and HCs were evident on the SDMT and BVMTR (p<0.001). HCs had higher CVLT-II scores but this difference did not reach statistical significance (p=0.063). Cognitive impairment, defined as an abnormal test score on ≥1 subtest, was found in 62.9% of MS patients. There were statistically significant correlations between BICAMS scores and age, education, EDSS and disease duration in patient sample. Test-retest reliability was confirmed with Pearson correlation coefficient of 0.70 in all measures. This study supported the reliability and validity of the Serbian BICAMS, although the CVLT-II version tested here lacked sensitivity to detect MS compared to healthy volunteers.

Phenotypic and Genetic Heterogeneity of Adult Patients with Hereditary Spastic Paraplegia from Serbia.

Hereditary spastic paraplegia (HSP) is among the most genetically diverse of all monogenic diseases. The aim was to analyze the genetic causes of HSP among adult Serbian patients. The study comprised 74 patients from 65 families clinically diagnosed with HSP during a nine-year prospective period. A panel of thirteen genes was analyzed: L1CAM (SPG1), PLP1 (SPG2), ATL1 (SPG3A), SPAST (SPG4), CYP7B1 (SPG5A), SPG7 (SPG7), KIF5A (SPG10), SPG11 (SPG11), ZYFVE26 (SPG15), REEP1 (SPG31), ATP13A2 (SPG78), DYNC1H1, and BICD2 using a next generation sequencing-based technique. A copy number variation (CNV) test for SPAST, SPG7, and SPG11 was also performed. Twenty-three patients from 19 families (29.2%) had conclusive genetic findings, including 75.0% of families with autosomal dominant and 25.0% with autosomal recessive inheritance, and 15.7% of sporadic cases. Twelve families had mutations in the SPAST gene, usually with a pure HSP phenotype. Three sporadic patients had conclusive findings in the SPG11 gene. Two unrelated patients carried a homozygous pathogenic mutation c.233T>A (p.L78*) in SPG7 that is a founder Roma mutation. One patient had a heterozygous de novo variant in the KIF5A gene, and one had a compound heterozygous mutation in the ZYFVE26 gene. The combined genetic yield of our gene panel and CNV analysis for HSP was around 30%. Our findings broaden the knowledge on the genetic epidemiology of HSP, with implications for molecular diagnostics in this region.

Occurrence of malignant diseases in patients with multiple sclerosis: population-based MS Registry data.

INTRODUCTION: Among different comorbidities occurring in multiple sclerosis (MS), the presence of malignant diseases in these patients is of the particular importance. The aim of this study was to determine the malignant diseases burden in a whole cohort of patients with MS in the Belgrade region, based on the Belgrade population registry data. MATERIAL AND METHODS: This study comprises 2725 MS patients from the MS Registry, which represents a source for all necessary demographic and clinical data. Firstly, the Registry was searched for all persons with MS who had cancer comorbidity, during the period 1996-2019. Diagnosis of cancer was validated by the patients' medical documentation. In order to investigate factors associated with the occurrence of any type of the cancer and/ or breast cancer only, in persons with MS, different logistic regression analyses were performed. RESULTS: A total of 64 persons with 69 malignant diseases were observed (prevalence 2.53%). The most frequent malignancies in males were skin cancer (50.0%) and in females, breast cancer (23.2%). The cumulative incidence of cancer comorbidity in persons with MS was 324.9 new cases per 100,000 person-years for the total population (137.6/100,000 in males and 403.6 per 100,000 in females). Comparison of cancer incidence rate between MS and general Belgrade population revealed lower risk for malignancy occurrence in the MS population in total (standardized incidence ratio, SIR = 0.58, 95% CI 0.16-1.49). CONCLUSIONS: Our findings demonstrate that MS patients in the Belgrade region have lower risk for the development of malignancy than age- and sex-matched general population.

Sudomotor dysfunction in people with neuromyelitis optica spectrum disorders.

BACKGROUND AND PURPOSE: The aim was to determine the extent of sudomotor dysfunction in people with neuromyelitis optica spectrum disorder (pwNMOSD) and to compare findings with a historical cohort of people with relapsing-remitting multiple sclerosis (pwRRMS). METHODS: Forty-eight pwNMOSD were enrolled from four clinical centers. All participants completed the Composite Autonomic Symptom Score 31 to screen for symptoms of sudomotor dysfunction. Sudomotor function was assessed using the quantitative sudomotor axon reflex test. The results were compared with a historical cohort of 35 pwRRMS matched for age, sex and disease duration. RESULTS: Symptoms of sudomotor dysfunction, defined by a score in the Composite Autonomic Symptom Score 31 secretomotor domain >0, were present in 26 (54%) of pwNMOSD. The quantitative sudomotor axon reflex test confirmed a sudomotor dysfunction in 25 (52.1%) of pwNMOSD; in 14 of them (29.2%) sudomotor dysfunction was moderate or severe. No difference was observed between pwNMOSD and pwRRMS in any of the studied parameters. However, symptomatic sudomotor dysfunction was more frequent in pwNMOSD (n = 8, 22.9%) compared to pwRRMS (n = 1, 3%; p = 0.028). In a multivariable logistic regression analysis, statistically significant predictors for symptomatic sudomotor failure were age and diagnosis of neuromyelitis optica spectrum disorder. CONCLUSIONS: Sudomotor dysfunction is common in pwNMOSD and more often symptomatic compared to pwRRMS.

Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study.

OBJECTIVES: To evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability. METHODS: In this cross-sectional study, 270 healthy controls and 434 patients with multiple sclerosis were retrospectively selected from 7 European sites. T1w/T2w ratio was obtained from brain T2w and T1w scans after intensity calibration using eyes and temporal muscle. RESULTS: In healthy controls, T1w/T2w ratio increased until 50-60 years both in white and grey matter. Compared with healthy controls, T1w/T2w ratio was significantly lower in white matter lesions of all multiple sclerosis phenotypes, and in normal-appearing white matter and cortex of patients with relapsing-remitting and secondary progressive multiple sclerosis (p≤0.026), but it was significantly higher in the striatum and pallidum of patients with relapsing-remitting, secondary progressive and primary progressive multiple sclerosis (p≤0.042). In relapse-onset multiple sclerosis, T1w/T2w ratio was significantly lower in white matter lesions and normal-appearing white matter already at Expanded Disability Status Scale (EDSS) <3.0 and in the cortex only for EDSS ≥3.0 (p≤0.023). Conversely, T1w/T2w ratio was significantly higher in the striatum and pallidum for EDSS ≥4.0 (p≤0.005). In primary progressive multiple sclerosis, striatum and pallidum showed significantly higher T1w/T2w ratio beyond EDSS=6.0 (p≤0.001). In multiple sclerosis, longer disease duration, higher EDSS, higher brain lesional volume and lower normalised brain volume were associated with lower lesional and cortical T1w/T2w ratio and a higher T1w/T2w ratio in the striatum and pallidum (ß from -1.168 to 0.286, p≤0.040). CONCLUSIONS: T1w/T2w ratio may represent a clinically relevant marker sensitive to demyelination, neurodegeneration and iron accumulation occurring at the different multiple sclerosis phases.

MR T2-relaxation time as an indirect measure of brain water content and disease activity in NMOSD.

OBJECTIVE: Since astrocytes at the blood-brain barrier are targeted by neuromyelitis optica spectrum disorder (NMOSD), this study aims to assess whether patients with NMOSD have a subclinical accumulation of brain water and if it differs according to disease activity. METHODS: Seventy-seven aquaporin-4-positive patients with NMOSD and 105 healthy controls were enrolled at two European centres. Brain dual-echo turbo spin-echo MR images were evaluated and maps of T2 relaxation time (T2rt) in the normal-appearing white matter (NAWM), grey matter and basal ganglia were obtained. Patients with a clinical relapse within 1 month before or after MRI acquisition were defined 'active'. Differences between patients and controls were assessed using z-scores of T2rt obtained with age-adjusted and sex-adjusted linear models from each site. A stepwise binary logistic regression was run on clinical and MRI variables to identify independent predictors of disease activity. RESULTS: Patients had increased T2rt in both white and grey matter structures (p range: 0.014 to <0.0001). Twenty patients with NMOSD were defined active. Despite similar clinical and MRI features, active patients had a significantly increased T2rt in the NAWM and grey matter compared with those clinically stable (p range: 0.010-0.002). The stepwise binary logistic regression selected the NAWM as independently associated with disease activity (beta=2.06, SE=0.58, Nagelkerke R2=0.46, p<0.001). CONCLUSIONS: In line with the research hypothesis, patients with NMOSD have increased brain T2rt. The magnitude of this alteration might be useful for identifying those patients with active disease.

Humoral response to SARS-CoV-2 infection and vaccines against COVID-19 in patients with neuromyelitis optica spectrum disorders: Impact of immunosuppressive treatment.

The aim of this study was to evaluate the humoral response to the SARS-CoV-2 infection and vaccination in the NMOSD patients, treated with various immunosuppresants (ISs). Serum IgG against the complete sequence of the receptor binding domain of the spike protein was measured using ELISA SARS-CoV-2 IgG, INEP, Belgrade. Seroconversion occurred in 8/10 patients with COVID-19, and in 5/9 after vaccination. One out of four patients treated with inebilizumab seroconverted (after COVID-19); antibodies were not detected in any of the remaining 3 patients who were vaccinated. Antibodies developed after COVID-19 in 4/5 patients treated with azathioprine and all treated with mycophenolate-mofetil, and after vaccination, in 5/6 patients treated with these ISs. Post-vaccination humoral response was impaired in our NMOSD patients treated with B-cell depleting therapies; seroconversion occurred in almost all patients treated with conventional synthetic disease modifying ISs.

COVID-19 and vaccination against SARS-CoV-2 in patients with neuromyelitis optica spectrum disorders.

BACKGROUND: Reports on outcomes of COVID-19 in patients with neuromyelitis optica spectrum disorder (NMOSD) are scarce, as well as those related to the safety profile of the vaccines in this population. The aim of this survey is to present demographic and clinical characteristics of patients with NMOSD who developed COVID-19 and safety data of the COVID-19 vaccines in these persons. METHODS: This study comprise all patients from the Hospital registry of NMOSD, of the Clinic of Neurology in Belgrade, who fulfilled the 2015 NMOSD diagnostic criteria, and who after invitation by phone call, from April 10 to May 10, 2021, accepted to participate and provide information regarding COVID-19 and vaccination against Sars-CoV-2 (n = 53). RESULTS: Sixteen out of 53 enrolled NMOSD patients were diagnosed with COVID-19. In three cases (18.8%), severity of COVID-19 clinical manifestations warranted hospitalization, and one of these patients, died due to COVID-19 (case fatality ratio = 6.25%), after invasive mechanical ventilation. The remaining two patients had grade II COVID -19 severity and were hospitalized because of pneumonia, not requiring supplemental oxygen. Median EDSS in patients requiring hospitalization was 4.5, and in the non-hospitalized group, it was 3.0. Nine out of 53 patients received two doses of vaccine against Sars-Cov-2 (8 Sinopharm and one Pfizer). Pain at the site of application was the only vaccine-related adverse effect. CONCLUSIONS: Our survey indicates overall favourable COVID-19 outcome and encouraging safety profile of the vaccines in persons with NMOSD, in our cohort. Prospective studies are warranted to confirm these data.

Impact of comorbidities on the disability progression in multiple sclerosis.

OBJECTIVES: Investigation of the comorbidity burden in persons with multiple sclerosis (PwMS) has become increasingly important. The aim of this study was to investigate the relationships of cardiovascular disease (CVD) comorbidities and type 2 diabetes with the disability progression. MATERIALS & METHODS: The retrospective cohort study was conducted at the Clinic of Neurology, Belgrade. The Belgrade MS population Registry, which comprises 2725 active MS cases, was used as the source of data. The mean duration of the disease was 21.6 ± 12.5 years. Expanded Disability Status Scale (EDSS) was followed in all PwMS in the Registry. In the statistical analysis, the Cox proportional hazard regression analysis and Kaplan-Meier curve were performed. RESULTS: Hypertension statistically significantly contributed to more rapid reaching investigated levels of irreversible disability (EDSS 4.0, 6.0, and 7.0), while the presence of any of the investigated CVD comorbidities and type 2 diabetes significantly contributed to faster reaching EDSS 4.0 and EDSS 6.0. In a multivariable model, progression index (PI) was singled out (HR = 3.171, p < .001), indicating that higher progression index (PI) was an independent predictor of CVD occurrence in MS patients. In the case of type 2 diabetes, PI (p < .001) and MS phenotype (p = .015) were statistically significant in multivariable Cox regression analysis. CONCLUSIONS: Our study confirms the impact of CVD comorbidities and type 2 diabetes in MS on the progression of disability as measured by EDSS in the large cohort of PwMS from the population Registry.

Application of deep-learning to the seronegative side of the NMO spectrum.

OBJECTIVES: To apply a deep-learning algorithm to brain MRIs of seronegative patients with neuromyelitis optica spectrum disorders (NMOSD) and NMOSD-like manifestations and assess whether their structural features are similar to aquaporin-4-seropositive NMOSD or multiple sclerosis (MS) patients. PATIENTS AND METHODS: We analyzed 228 T2- and T1-weighted brain MRIs acquired from aquaporin-4-seropositive NMOSD (n = 85), MS (n = 95), aquaporin-4-seronegative NMOSD [n = 11, three with anti-myelin oligodendrocyte glycoprotein antibodies (MOG)], and aquaporin-4-seronegative patients with NMOSD-like manifestations (idiopathic recurrent optic neuritis and myelitis, n = 37), who were recruited from February 2010 to December 2019. Seventy-three percent of aquaporin-4-seronegative patients with NMOSD-like manifestations also had a clinical follow-up (median duration of 4 years). The deep-learning neural network architecture was based on four 3D convolutional layers. It was trained and validated on MRI scans of aquaporin-4-seropositive NMOSD and MS patients and was then applied to aquaporin-4-seronegative NMOSD and NMOSD-like manifestations. Assignment of unclassified aquaporin-4-seronegative patients was compared with their clinical follow-up. RESULTS: The final algorithm differentiated aquaporin-4-seropositive NMOSD and MS patients with an accuracy of 0.95. All aquaporin-4-seronegative NMOSD and 36/37 aquaporin-4-seronegative patients with NMOSD-like manifestations were classified as NMOSD. Anti-MOG patients had a similar probability of being NMOSD or MS. At clinical follow-up, one unclassified aquaporin-4-seronegative patient evolved to MS, three developed NMOSD, and the others did not change phenotype. CONCLUSIONS: Our findings support the inclusion of aquaporin4-seronegative patients into NMOSD and suggest a possible expansion to aquaporin-4-seronegative unclassified patients with NMOSD-like manifestations. Anti-MOG patients are likely to have intermediate brain features between NMOSD and MS.

Performance of the 2017 and 2010 Revised McDonald Criteria in Predicting MS Diagnosis After a Clinically Isolated Syndrome: A MAGNIMS Study.

BACKGROUND AND OBJECTIVES: To compare the performance of the 2017 revisions to the McDonald criteria with the 2010 McDonald criteria in establishing multiple sclerosis (MS) diagnosis and predicting prognosis in patients with clinically isolated syndrome (CIS) suggestive of MS. METHODS: CSF examination and brain and spinal cord MRI obtained ≤5 months from CIS onset and a follow-up brain MRI acquired within 15 months from CIS onset were evaluated in 785 patients with CIS from 9 European centers. Date of second clinical attack and of reaching Expanded Disability Status Scale score (EDSS) ≥3.0, if they occurred, were also collected. Performance of the 2017 and 2010 McDonald criteria for dissemination in space (DIS), dissemination in time (DIT) (including oligoclonal bands assessment), and DIS plus DIT for predicting a second clinical attack (clinically definite MS [CDMS]) and EDSS ≥3.0 at follow-up was evaluated. Time to MS diagnosis for the different criteria was also estimated. RESULTS: At follow-up (median 69.1 months), 406/785 patients with CIS developed CDMS. At 36 months, the 2017 DIS plus DIT criteria had higher sensitivity (0.83 vs 0.66), lower specificity (0.39 vs 0.60), and similar area under the curve values (0.61 vs 0.63). Median time to MS diagnosis was shorter with the 2017 vs the 2010 or CDMS criteria (2017 revision, 3.2; 2010 revision, 13.0; CDMS, 58.5 months). The 2 sets of criteria similarly predicted EDSS ≥3.0 milestone. Three periventricular lesions improved specificity in patients ≥45 years. DISCUSSION: The 2017 McDonald criteria showed higher sensitivity, lower specificity, and similar accuracy in predicting CDMS compared to 2010 McDonald criteria, while shortening time to diagnosis of MS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the 2017 McDonald Criteria more accurately distinguish CDMS in patients early after a CIS when compared to the 2010 McDonald criteria.

Humoral response to SARS-CoV-2 COVID-19 vaccines in patients with multiple sclerosis treated with immune reconstitution therapies.

BACKGROUND: It has been generally accepted that people with MS (PwMS) should be vaccinated against COVID-19. The aim of our investigation was to evaluate the humoral response to natural SARS-CoV-2 infection and to two COVID-19 vaccines (BNT162b2 Pfizer-BioNTech and Beijing/Sinopharm BBIBP-CorV) in our cohort of PwMS under high efficacy disease modifying therapies (DMTs), cladribine and alemtuzumab. METHODS: Twenty two PwMS treated at the Clinic of Neurology, in Belgrade, who developed COVID-19 and/or were vaccinated against SARS-CoV-2, during treatment with cladribine and alemtuzumab, were included. Out of 18 patients treated with cladribine, 11 developed COVID-19, and 11 were vaccinated against SARS-CoV-2 (four with mRNA vaccine, 7 with Sinopharm). Four MS patients under alemtuzumab were vaccinated against SARS-CoV-2; three with mRNA, and one with Sinopharm vaccine. SARS-Cov-2 IgG response was measured using ELISA anti-spike protein-based serology (INEP, Belgrade, Serbia). RESULTS: All 7 patients under cladribine treatment who suffered from COVID-19, developed IgG antibodies, 2.0-5.5 months after last symptoms. All four (100%) patients under cladribine who were vaccinated with Pfizer-BioNTech vaccine, and three out of seven (42.9%) vaccinated with Sinopharm, developed antibodies. All 4 patients under alemtuzumab developed antibodies after vaccination. In all cases, seroprotection occurred, irrespective of timing of vaccination and absolute lymphocyte count. CONCLUSION: Our findings in a small number of highly active PwMS in whom, lymphodepleting, immune reconstitution therapies, were applied in order to successfully manage MS, indicate that in a number of these patients it was possible to develop at the same time seroprotection in these patients after COVID-19 vaccination in these complex circumstances.