Retrospective analysis of effectiveness of fingolimod in real life setting in Turkey (REFINE).

BACKGROUND: During multiple sclerosis (MS) treatment different modes of action such as lateral (interferon beta to glatiramer acetate or glatiramer acetate to interferon beta) or vertical (interferon beta/glatiramer acetate to fingolimod) drug switch can be performed. This study aims to investigate the clinical effectiveness of switching from the first-line injectable disease modifying treatments (iDMTs) to fingolimod (FNG) compared to switching between first-line iDMTs. METHODS: This is a multicenter, observational and retrospective study of patients with relapsing-remitting MS who had lateral and vertical switch. The observation period included three key assessment time points (before the switch, at switch, and after the switch). Data were collected from the MS patients' database by neurologists between January 2018 and June 2019. The longest follow-up period of the patients was determined as 24 months after the switch. RESULTS: In 462 MS patients that were included in the study, both treatments significantly decreased the number of relapses during the postswitch 12 months versus preswitch one year while patients in the FNG group experienced significantly fewer relapses compared to iDMT cohort in the postswitch 12 months period. FNG cohort experienced fewer relapses than in the iDMT cohort within the postswitch 2 year. The mean time to first relapse after the switch was significantly longer in the FNG group. DISCUSSION: The present study revealed superior effectiveness of vertical switch over lateral switch regarding the improvement in relapse outcomes. Patients in the FNG cohort experienced sustainably fewer relapses during the follow-up period after the switch compared the iDMT cohort. Importantly, switching to FNG was more effective in delaying time to first relapse when compared with iDMTs.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

Effectiveness of the transcutaneous tibial nerve stimulation and pelvic floor muscle training with biofeedback in women with multiple sclerosis for the management of overactive bladder.

BACKGROUND: Overactive bladder (OAB) is common in patients with multiple sclerosis (MS) with a limited number of treatment options. OBJECTIVE: To investigate the effect of transcutaneous tibial nerve stimulation (TTNS) and pelvic floor muscle training (PFMT) with biofeedback on OAB symptoms in female MS patients. METHODS: This study was conducted at the outpatient MS clinic in Istanbul. At baseline bladder diary, post-voiding residue (PVR), OAB, and Qualiveen Scales (QoL: Quality of Life; Siup: Specific Impact of Urinary Problems on QoL) were assessed. Patients were allocated to receive TTNS or PFMT daily for 6 weeks and reevaluated using the same tests. RESULTS: Fifty-five patients (TTNS = 28, PFMT = 27) were included. Compared with baseline, both TTNS and PFMT groups improved in terms of OAB (p = 0.0001, p = 0.0001), Qualiveen-siup (p = 0.0001, p = 0.0001), Qualiveen-QoL (p = 0.002, p = 0.006), PVR (p = 0.0001, p = 0.21), frequency (p = 0.0001, p = 0.69), nocturia (p = 0.0001, p = 0.19), urgency (p = 0.0001, p = 0.0001), and urge incontinence (p = 0.0001, p = 0.0001). Between-group comparisons showed significant differences in 24-hour frequency (p = 0.002) in favor of TTNS. CONCLUSION: Our study demonstrates the efficacy of both TTNS and PFMT for managing OAB symptoms in MS, associated with a significant impact on QoL, but did not show superiority of the methods. Further studies are needed to explore differences between these two non-invasive treatments.

Evaluating the effects of transcutaneous tibial nerve stimulation or pelvic floor muscle training on sexual dysfunction in female multiple sclerosis patients reporting overactive bladder.

AIMS: Sexual dysfunction (SD) is common in female patients with multiple sclerosis (MS) reporting overactive bladder (OAB) symptoms. The aim of the study was to evaluate the effects of transcutaneous tibial nerve stimulation (TTNS) and pelvic floor muscle training (PFMT) with biofeedback on SD in female patients with MS reporting OAB symptoms. METHODS: Patients with overactive bladder and SD were allocated to receive TTNS or PFMT daily. Overactive bladder symptoms, sexual functions, and sexual quality of life were assessed at baseline and 6th weeks. Female Sexual Function Index (FSFI), Overactive Bladder Questionnaire (OABv-8), and Sexual Quality of Life-Female (SQoL-F) questionnaires were used. RESULTS: Thirty patients (TTNS = 10, PFMT = 20) were included in the study. Compared to baseline, total FSFIOABv-8, and SQoL-F scores improved in both TTNS (p = 0.005, p = 0.011, p = 0.444, respectively) and PFMT (p = 0.002, p = 0.001, p = 0.001, respectively) groups. Between-group comparisons did not show any significant differences. CONCLUSION: This study demonstrates the efficacy of both TTNS and PFMT for improving sexual function in female MS patients with OAB symptoms, but did not show superiority of any particular method. Further studies are required to investigate the differences between these two non-invasive methods.

Validation of the Turkish version of the eight-item actionable bladder symptom screening tool in multiple sclerosis.

AIMS: This study aimed to translate the eight-item Actionable Bladder Symptom Screening Tool (ABSST) and determine its psychometric properties in Turkish speaking subjects. METHODS: The study was conducted at the multiple sclerosis (MS) outpatient clinic of the Istanbul Faculty of Medicine, Istanbul University. First, the ABSST was translated into Turkish by an expert panel. We employed the back translation method for linguistic validation. Cronbach's α and test-retest analysis were performed for reliability analysis. The overactive bladder-v8 (OAB-v8) questionnaire was also administered for concurrent validation, and expanded disability status scale (EDSS) and multiple sclerosis quality of life scale-54 (MSQL-54) were used to evaluate construct validity. RESULTS: One hundred and five patients (84 females; mean age, 39.5 ± 11.6 years; mean EDSS score, 3.2 ± 1.8) participated in the study. Mean duration of MS was 9.7 ± 8.3 years, and most (n = 96; 91.5%) had relapsing-remitting MS. The mean ABSST score was 9.7 ± 5.8 (range, 0-21). Highest scores were obtained from urgency and frequency, and the lowest from psychosocial effects of lower urinary tract (LUT) symptoms. The Cronbach's α coefficient was 0.856, and item-total score correlations ranged between 0.485 and 0.845. Correlations of ABSST scores with OAB-v8, EDSS, and MSQL-54 scales were significant (P < .001). According to the questionnaire, 38.1% (n = 40) of the patients needed a referral to a urologist or gynecologist for their LUT symptoms. CONCLUSIONS: The Turkish version of the ABSST is a valid and reliable screening tool that can be used to identify LUT symptoms in an MS clinic.

Microbiota stratification identifies disease-specific alterations in neuro-Behçet's disease and multiple sclerosis.

OBJECTIVES: Altered gut microbiota community dynamics are implicated in diverse human diseases including inflammatory disorders such as neuro-Behçet's disease (NBD) and multiple sclerosis (MS). Traditionally, microbiota communities are analysed uniformly across control and disease groups, but recent reports of subsample clustering indicate a potential need for analytical stratification. The objectives of this study are to analyse and compare faecal microbiota community signatures of ethno-geographical, age and gender matched adult healthy controls (HC), MS and NBD individuals. METHODS: Faecal microbiota community compositions in adult HC (n=14), NBD patients (n=13) and MS (n=13) were analysed by 16S rRNA gene sequencing and standard bioinformatics pipelines. Bipartite networks were then used to identify and re-analyse dominant compositional clusters in respective groups. RESULTS: We identified Prevotella and Bacteroides dominated subsample clusters in HC, MS, and NBD cohorts. Our study confirmed previous reports that Prevotella is a major dysbiotic target in these diseases. We demonstrate that subsample stratification is required to identify significant disease-associated microbiota community shifts with increased Clostridiales evident in Prevotella-stratified NBD and Bacteroides-stratified MS patients. CONCLUSIONS: Patient cohort stratification may be needed to facilitate identification of common microbiota community shifts for causation testing in disease.

Uveitis as a prognostic factor in multiple sclerosis.

Uveitis is occasionally encountered in multiple sclerosis (MS) patients. The objective of this report is to investigate whether uveitis has a prognostic impact on the clinical course of MS. Several clinical and demographic features were compared between 41 MS patients with uveitis and 100 randomly selected MS patients without uveitis. While there were no significant differences by means of gender, age of MS onset, oligoclonal band positivity and disease duration, EDSS and progression index (PI) scores of MS patients with uveitis were significantly lower than those without uveitis (p = 0.004 and <0.001, respectively). Our results suggest that uveitis might be used as a good prognostic factor.

Behçet's disease patients with multiple sclerosis-like features: discriminative value of Barkhof criteria.

OBJECTIVES: Behçet's disease (BD) is a systemic auto-inflammatory disorder of unknown cause, which may affect the central nervous system in around 5% of the patients [neuro-BD (NBD)], usually causing large lesions encompassing brainstem, diencephalon and basal ganglia regions. Occasionally NBD patients present with white matter lesions necessitating differential diagnosis from multiple sclerosis (MS). In this study, the efficacy of Barkhof criteria was tested in diagnostic differentiation of NBD and MS. METHODS: Charts and MRIs of 84 NBD patients were retrospectively evaluated. Clinical and radiological features of NBD patients fulfilling (Barkhof+) and not fulfilling Barkhof criteria (Barkhof-) were compared. RESULTS: While the Barkhof- patients (n=73) mostly displayed typical large lesions covering brainstem, diencephalon and basal ganglia regions and neurological findings consistent with brainstem involvement, all Barkhof+ (n=11) patients demonstrated MS-like white matter lesions, fulfilled McDonald's criteria and showed reduced frequency of brainstem symptoms and increased frequency of hemiparesis, hemihypesthesia and spinal cord symptoms. Moreover, the Barkhof+ group had more female patients, increased number of attacks, higher rate of oligoclonal band positivity and less patients with cerebrospinal fluid pleocytosis. CONCLUSIONS: A subgroup of BD patients with neurological complaints displays MS-like lesions, fulfills the clinical and radiological criteria of MS and presents with clinical and laboratory features resembling those of MS rather than NBD. These results suggest that Barkhof+ patients are either an overlapping group between NBD and MS, or they represent MS patients with concomitant systemic findings of BD, rather than NBD. Barkhof criteria appear to be effective in discriminating these patients.

Predictive value of early serum cytokine changes on long-term interferon beta-1a efficacy in multiple sclerosis.

BACKGROUND: In a previous study, we had evaluated short-term effects of interferon beta-1a (IFNB-1a) 44 µg s.c. three times per week treatment on serum levels of IFN-gamma (IFNG), IL-23, IL-17, IL-10, IL-9, IL-4 and TGF-beta (TGFB) and found a reduction only in IL-17 and IL-23 levels after 2 months of treatment. METHODS: Using the same multiple sclerosis (MS) cohort, we assessed the predictive value of early cytokine level changes (difference between 2nd month and baseline levels as measured by ELISA) on the efficacy of long-term IFNB-1a treatment. RESULTS: The alteration in IFNG levels of patients without any relapse was statistically lower than that of patients having one or more relapses (p = 0.019, Student's t-test). When patients with or without expanded disability severity scale (EDSS) progression were compared, none of the cytokine level changes showed a significant difference between groups. IL-17 and IL-23 level changes did not predict relapse and EDSS progression in IFNB-1a-treated MS patients. CONCLUSION: Our results show that the predictive power of early IFNG measurement on relapse occurrence may potentially extend a time span of several years.

Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort.

JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study. Overall, anti-JCV antibody prevalence was 57.6%. Anti-JCV antibody prevalence in MS patients ranged from approximately 47% to 68% across these countries: Norway, 47.4%; Denmark, 52.6%; Israel, 56.6%; France, 57.6%; Italy, 58.3%; Sweden, 59.0%; Germany, 59.1%; Austria, 66.7% and Turkey, 67.7%. Prevalence increased with age (from 49.5% in patients < 30 years of age to 66.5% in patients ≥ 60 years of age; p < 0.0001 comparing all age categories), was lower in females than in males (55.8% versus 61.9%; p < 0.0001) and was not affected by prior immunosuppressant or natalizumab use.

CACNA1H antibodies associated with headache with neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL).

BACKGROUND: Patients with the syndrome of headache with neurological deficits and lymphocytosis (HaNDL) typically present with recurrent and temporary attacks of neurological symptoms and cerebrospinal fluid lymphocytosis. AIM AND METHODS: To identify potential HaNDL-associated antibodies directed against neuronal surface and/or synapse antigens, sera of four HaNDL patients and controls were screened with indirect immunohistochemistry, immunofluorescence, cell-based assay, radioimmunoassay, protein macroarray and enzyme-linked immunosorbent assay (ELISA). RESULTS: Although HaNDL sera did not yield antibodies to any of the well-characterized neuronal surface or synapse antigens, protein macroarray and ELISA studies showed high-titer antibodies to a subunit of the T-type voltage-gated calcium channel (VGCC), CACNA1H, in sera of two HaNDL patients. CONCLUSION: Our results support the notion that ion channel autoimmunity might at least partially contribute to HaNDL pathogenesis and occurrence of neurological symptoms.

Anti-N-methyl-D-aspartate receptor encephalitis with minimal cortical impairment.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been recently identified as a fulminant encephalopathy, presenting with a variety of symptoms including behavioral change, amnesia and seizures suggesting cortical gray matter involvement. A 42-year-old woman presented with acute-onset clinical and magnetic resonance imaging (MRI) findings indicating brainstem and diencephalon involvement. Her neuropsychological examination revealed mild frontal dysfunction with no memory impairment. Detailed diagnostic workup proved negative except for serum/cerebrospinal fluid (CSF) NMDAR-antibodies and increased activity in inguinal and pelvic lymph nodes on positron-emission tomography (PET) examination. The symptoms and MRI findings completely resolved following steroid treatment. A 38-year-old woman presented with migraine-type headache and episodes of forgetfulness. Her brain MRI and neuropsychological examination were normal and diagnostic workup was unremarkable. N-methyl-D-aspartate receptor antibodies were identified in her sera and her symptoms spontaneously resolved within few months. Our cases suggest that anti-NMDAR encephalitis might present with minimal cognitive impairment, no apparent cortical gray matter involvement, a mild clinical course and without the classical clinical features of the disease.

Group exercise training for balance, functional status, spasticity, fatigue and quality of life in multiple sclerosis: a randomized controlled trial.

OBJECTIVE: To determine the effectiveness of group exercise training on balance, functional status, spasticity, fatigue and quality of life in patients with multiple sclerosis. DESIGN: A randomized single-blind controlled study. SETTING: University hospital, outpatient physical therapy department. SUBJECTS: Ambulatory patients with multiple sclerosis. INTERVENTIONS: Exercise group completed a 12-week group exercise programme under the physical therapists' supervision. Control group was included in the waiting list. MAIN MEASURES: The primary outcome measures were the Berg Balance Scale, 10-metre walk test, 10-steps climbing test and secondary outcome measures were the Modified Ashworth Scale, Fatigue Severity Scale and Multiple Sclerosis International Quality of Life. RESULTS: Ninety-nine patients completed the study. There were statistically significant improvements for all outcome measures in the group exercise group (n = 51) (p < 0.01). In the control group (n = 48), there were statistically significant negative change in the Berg Balance Scale and 10-metre walk test measures (p = 0.002, p = 0.001) and statistically significant increment only in the Fatigue Severity Scale score (p = 0.002). The Berg Balance Scale score was increased 4.33 in the exercise group, while a decreased of 2.33 in control group. The 10-metre walk test duration (second) was decreased 2.72 in exercise group, while increased 1.44 in control group. In comparing inter-groups changes, both primary and secondary outcome mesures showed significant improvements in favour of the exercise group after the training (p < 0.05). CONCLUSION: The study demonstrated that supervised group exercise training is effective in improving balance, functional status, spasticity, fatigue and quality of life in moderately affected people with multiple sclerosis, with no worsening of their clinical status.

Impact of cigarette smoking on conversion from clinically isolated syndrome to clinically definite multiple sclerosis.

Multiple sclerosis (MS) is known to be influenced by various environmental factors including cigarette smoking. To identify the impact of smoking on conversion from clinically isolated syndrome (CIS) to clinically definite MS (CDMS), 95 consecutive uniformly treated smoker (n = 31) and nonsmoker (n = 64) CIS patients were evaluated retrospectively. The smoker CIS patients did not differ from nonsmokers by means of demographic and clinical findings. In addition, there was no difference between the two groups with respect to rate and time of conversion to CDMS. However, white matter lesions were detected in magnetic resonance imagings (MRIs) of all smoking versus 54 of 64 (63.5%) nonsmoking CIS patients (p = 0.02). Our results show that smoking does not predict conversion from CIS to CDMS. However, smoking may be associated with the appearance of white matter lesions on MRI at CIS onset.

Effect of short-term interferon-ß treatment on cytokines in multiple sclerosis: significant modulation of IL-17 and IL-23.

Therapeutic effect of interferon-ß (IFN-ß) treatment has been associated with modulation of the balance between Th1, Th17, Th2 and regulatory T (Treg) cells, whereas the impact of disease modifying drugs on Th9-immunity in multiple sclerosis (MS) has not been studied. To investigate the short-term effects of IFN-ß treatment on cytokines in MS, we determined serum levels of IL-17, IL-23, IL-10, IL-4, IFN-γ, IL-9 and TGF-ß in relapsing remitting MS patients before and 2 months after IFN-ß treatment by ELISA. MS patients showed increased IL-17, IL-23 and IL-4 levels and decreased IL-9 levels as compared to healthy controls. IFN-ß treatment only reduced IL-17 and IL-23 levels, whereas the levels of other cytokines remained unchanged. IFN-ß treatment appears to exert its earliest therapeutic effect on Th17-immunity. The influence of IL-9 on MS pathogenesis needs to be further studied.

Effect of BG-12 on contrast-enhanced lesions in patients with relapsing--remitting multiple sclerosis: subgroup analyses from the phase 2b study.

BACKGROUND: In a phase 2b study in patients with relapsing-remitting MS (RRMS), BG-12 240 mg three times daily significantly reduced the number of new gadolinium-enhanced (Gd+) lesions from weeks 12 to 24 (primary end point) by 69% compared with placebo. OBJECTIVE: In this analysis, the effect of BG-12 240 mg three times daily on the number of Gd+ lesions from weeks 12 to 24 was evaluated in subgroups based on baseline disease characteristics and demographics. METHODS: Two hundred and fifty-seven patients were randomized equally to receive BG-12 (120 mg once daily or three times daily or 240 mg three times daily) or placebo. RESULTS: BG-12 240 mg three times daily significantly reduced the number of new Gd+ lesions compared with placebo in the following subgroups: Expanded Disability Status Scale (EDSS) score ≤ 2.5 (74%), EDSS score > 2.5 (63%), no Gd+ lesions (80%), ≥ 1 Gd+ lesion (55%), age < 40 years (49%), age ≥ 40 years (89%), female patients (81%), disease duration ≤ 6 years (81%) and disease duration > 6 years (54%) (all comparisons p < 0.05). CONCLUSION: BG-12 demonstrated efficacy in patients with RRMS by decreasing new Gd+ lesion development across a range of subgroups defined by baseline disease characteristics or demographics.

Switch-associated protein 70 antibodies in multiple sclerosis: relationship between increased serum levels and clinical relapse.

OBJECTIVE: To identify an antibody biomarker for multiple sclerosis (MS) that can be used as a predictor of MS relapses. METHODS: MS patients' sera were screened by a protein macroarray derived from human fetal brain cDNA library (hEX1). Sera of 90 consecutive relapsing remitting MS (RRMS) patients and age-matched 145 Behçet's disease (BD) patients, 40 infectious meningoencephalitis patients, and 70 healthy controls were screened by ELISA for serum antibodies against the selected clone. RESULTS: Sequencing of the clone with the highest signal intensity revealed switch-associated protein 70 (SWAP70) as a potential target autoantigen in RRMS. ELISA studies showed high-titer SWAP70-antibodies in 21 (23.3 %) RRMS and 7 (4.8 %) BD patients. SWAP70 antibodies were more likely to be found positive in sera obtained during or shortly after a relapse. CONCLUSION: Detection of SWAP70 antibodies during the attack period might suggest that SWAP70 is involved in MS relapse pathogenesis. Whether serum SWAP70 antibody detection may be utilized as an MS relapse predictor should be tested in prospective studies.

Comparison of the cytokine profiles of patients with neuronal-antibody-associated central nervous system disorders.

Levels of several cytokines were evaluated in the sera of patients with neuromyelitis optica (NMO) and paraneoplastic or nonparaneoplastic autoimmune encephalitis (AE) and healthy controls (HC). AE patients had higher serum interleukin-17 (IL-17), interferon-gamma (IFN-γ), and IL-12 levels than NMO patients and HC. Also, AE patients with antibodies to cell surface antigens (voltage-gated potassium channel, N-methyl-d-aspartate receptor) displayed increased serum Th17 cytokine (IL-17, IL-23) levels as compared with AE patients with antibodies to intracellular antigens (Hu, Yo), NMO patients, and HC. Aquaporin-4 (Aqp-4) antibody positive NMO patients had higher serum IL-9 levels than Aqp-4 antibody negative NMO patients. IL-17, IL-23, IL-12, and antibody levels were significantly correlated in AE patients with antibodies to cell surface antigens. Our results support the notion that different pathogenic mechanisms are involved in central nervous system diseases associated with antibodies to intracellular and cell surface neuronal antigens. T helper 1 (Th1)-/Th17-type immunities and IL-9 might be important therapeutic targets in AE and NMO, respectively.