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.

Detailed Evaluation of Macular Ganglion Cell Complex in Patients with Multiple Sclerosis.

INTRODUCTION: Retinal nerve fiber layer thickness has been used for monitoring of disease activity in patients with multiple sclerosis (MS). Macular ganglion cell complex (GCC) layer of retina also can be measured by OCT and has been suggested as a potential biomarker in MS. In this study we investigated the macular GCC and its role as a potential biomarker in patients with Multiple Sclerosis (MS). METHODS: A prospective cohort-study, subjects consisted of Relapsing-Remitting MS patients (n=62) and healthy controls (n=60). Eyes of MS patients were divided into two subgroups according to the history of the optic neuritis (ON). Standard peripapillary-RNFL and macular scan protocol, and retinal auto-segmentation of spectral-domain OCT were performed. Macular RNFL (mRNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL), and GCC (the sum of these former three layers) were recorded. The macula was divided into nine sectors using the ETDRS grid (4×9=36 variables). RESULTS: In total, 50 eyes of 36 patients had previous ON attacks. 35/36 GCC parameters were thinner in MS patients and subgroups compared to the control group (p<0.05). When the eyes with and without a history of optic neuritis were compared, 25 of 36 parameters were thinner in those with ON. There were strong correlations between visual acuity-GCC parameters and EDSS scores in patients with a history of optic neuritis. However, no such relationship was found in those without an ON story. CONCLUSION: Ganglion cell complex gets thinner in patients with MS with a decreasing order of GCL, IPL, and mRNFL. The examination of GCC in detail could be a beneficial biomarker for MS.

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.

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.

Bruch's membrane opening-minimum rim width: An alternative OCT biomarker study for multiple sclerosis.

PURPOSE: Bruch's membrane opening-minimum rim width (BMO-MRW) and RNFL measured using anatomic positioning system (APS-RNFL) are novel OCT methods and remained unexplored in MS patients.To investigate the novel parameters of spectral-domain OCT as an alternative biomarker in patients with multiple sclerosis (MS). METHODS: Retrospective cohort study; participants consisted of relapsing-remitting MS (RRMS) patients and healthy controls (HC). Eyes were classified according to the presence of MS and previous optic neuritis (ON). Measurements of standard peripapillary RNFL (S-RNFL), BMO-MRW, and APS-RNFL were performed. RESULT: A total of 244 eyes of 122 participants (MS-patients: 63, HC: 59) were included in the study. Fifty-one eyes had a history of previous ON. In almost all measured parameters, neuroretinal rim thicknesses were observed the thinnest in eyes with ON history between all subgroups. S-RNFL and APS-RNFL techniques showed the difference in neuroretinal rim thickness in all three subjects (ON+, ON-, and HC). However, BMO-MRW, on the other hand, could not distinguish between ON(-) patients and HC. The relationship between OCT parameters and EDSS were observed only in eyes with an ON history in all three techniques. A meaningful model with 78% accuracy was obtained by using only the OCT parameters as risk factors. In the ROC analysis, no parameters were found to have acceptable high sensitivity and specificity. BMO-MRW was statistically weaker in every aspect than other RNFL techniques. CONCLUSION: The novel APS-RNFL technique appears to be a bit more reliable alternative to S-RNFL technique to support therapeutic decision-making in MS. BMO-MRW has not been found as a successful alternative to S-RNFL.

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.

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.

Impact of fingolimod on CD4+ T cell subset and cytokine profile of relapsing remitting multiple sclerosis patients.

Fingolimod inhibits the egress of lymphocytes from lymphatic tissues and also directly affects their functions by modulation of the sphingosine-1-phosphate receptor 1 (S1P1). Our aim was to evaluate the impact of fingolimod on diverse CD4+ T cell subsets, and cytokines. Sixty-six relapsing remitting multiple sclerosis (RRMS) patients were treated with oral fingolimod (0.5 mg) for 6 months, and blood samples were collected at baseline, 3 months, and 6 months. Serum levels of seven cytokines and five chemokines were measured by multiplex immunoassay, and frequencies of peripheral blood mononuclear cell subsets were assessed by flow cytometry, and compared with those of 60 healthy controls. CCL2 (p = 0.039), and CCL5 (p = 0.001) levels were significantly higher in fingolimod-treated patients than healthy controls, whereas end-of-study serum levels of IL-6, IL-8, IL-17A, IL-22, IL-23, TNF-α, CXCL10, and CXCL13 were comparable to the baseline levels. Six months of fingolimod treatment reduced CD3+ T cell (mean ±â€¯standard deviation, 72.9% ±â€¯5.5 vs. 60.1% ±â€¯11.1, p < 0.001), CD4+ T cell (62.2% ±â€¯8.5 vs. 24.6% ±â€¯12.9, p < 0.001), CD4+CD25hi regulatory T cell (Treg) (3.4% ±â€¯1.3 vs. 2.0% ±â€¯1.4, p < 0.01), and CD19+ B cell (13.2% ±â€¯5.8 vs. 5.3% ±â€¯2.7, p < 0.001) frequencies, while CD8+ T cells (31.8% ±â€¯7.8 vs. 57.8% ±â€¯13.2, p < 0.001) were increased, and NK and NKT cells remained unchanged. The proportions of intracytoplasmic IL-4, IL-10, IFN-γ, and TNF-α-producing T cells were increased, whereas IL-17-producing cells remained relatively constant as measured by flow cytometry. Fingolimod appears to primarily diminish lymphocyte subsets involved in antigen presentation (CD19+ B and CD4+ T cells) rather than immune cells (CD8+ T, NK, and NKT cells) in charge of host defense against pathogens. In contrast, a relative increase is observed in pro- and anti-inflammatory cytokine-producing T helper subsets (IFN-γ, TNF-α, IL-4, and IL-10-producing CD4+ T cells), suggesting that effector T cells are suppressed to a lesser degree by S1P1 modulation.

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.

Validity and Reliability of the Turkish Version of the Monitoring My Multiple Sclerosis Scale.

INTRODUCTION: This research was conducted to adapt the Monitoring My Multiple Sclerosis (MMMS) scale, which is a scale used for self-evaluation by multiple sclerosis (MS) patients of their own health and quality of life, to Turkish and to determine the psychometric properties of the scale. METHODS: The methodological research was conducted in the outpatient MS clinic of a university hospital between January and September 2013. The sample in this study consisted of 140 patients aged above 18 who had a diagnosis of definite MS. Patients who experienced attacks in the previous month or had any serious medical problems other than MS were not included in the group. The linguistic validity of MMMS was tested by a backward-forward translation method and an expert panel. Reliability analysis was performed using test-retest correlations, item-total correlations, and internal consistency analysis. Confirmatory factor analysis and concurrent validity were used to determine the construct validity. The Multiple Sclerosis Quality of Life-54 instrument was used to determine concurrent validity and the Expanded Disability Status Scale, Hospital Anxiety and Depression Scale, and Mini Mental State Examination were used for further determination of the construct validity. RESULTS: We determined that the scale consisted of four factors with loadings ranging from 0.49 to 0.79. The correlation coefficients of the scale were determined to be between 0.47 and 0.76 for item-total score and between 0.60 and 0.81 for items and subscale scores. Cronbach's alpha coefficient was determined to be 0.94 for the entire scale and between 0.64 and 0.89 for the subscales. Test-retest correlations were significant. Correlations between MMMS and other scales were also found to be significant. CONCLUSION: The Turkish MMMS provides adequate validity and reliability for assessing the impact of MS on quality of life and health status in patients.

Clinical and genetic features of PKAN patients in a tertiary centre in Turkey.

OBJECTIVE: Pantothenate kinase-associated neurodegeneration (PKAN) is caused by mutations of the pantothenate kinase 2 (PANK2) gene. The major clinical sign of PKAN is dystonia and the eye-of-the-tiger pattern on the MRI has been a clue for the diagnosis. We aim to discuss clinical and genetic findings of 22 PKAN patients from 13 families. METHODS: Twenty-two patients were clinically diagnosed with PKAN and screened for PANK2 mutations. The patients were classified according to their onset age and progression rate. RESULTS: Mutation screening revealed 5 novel and 7 previously reported sequence variants in PANK2. The variants identified were in the form of missense changes, small exonic deletions and intronic mutations with a probable splicing effect. The presenting features were dystonia and gait disturbance in early onset patients, whereas the presenting symptoms were variable for the late onset group. The progression rate of the disease was not uniform. CONCLUSION: The current report is the first patient series of PKAN from Turkey that expands the clinical and genetic spectrum of the disease.

Validity and Reliability of the Turkish Version of the Multiple Sclerosis-Related Symptom Checklist.

INTRODUCTION: Multiple sclerosis (MS) is a disease that causes different symptoms in each attack and has an individual-specific course. Detailed questioning and recording of MS symptoms is important for developing a management plan for individual-specific symptoms. The present study was planned to evaluate the validity and reliability of the Turkish version of "Multiple Sclerosis-Related Symptom Checklist" (MS-RS), which has been developed for patients to personally follow-up the symptoms they experience. METHODS: The study was conducted in the outpatient MS clinic of the Istanbul University Istanbul Faculty of Medicine between January and October 2013 and included a sample group of 148 patients who were aged >18 years, could easily communicate, had a definite diagnosis of MS, and had no other medical problems besides MS. The data were collected using patient information forms, including sociodemographic and MS-RS forms. To assess the linguistic validity, the Likert-type scale with 26 items was first applied to a group of 30 patients. Confirmatory factor analysis was used to test the construct validity. Furthermore, the correlation of the scale with the Expanded Disability Status Scale (EDSS), Hospital Anxiety and Depression Scale (HADS), Mini-Mental Status Evaluation (MMSE) scale, and Multiple Sclerosis Quality of Life Scale-54 (MSQL-54) was evaluated. RESULTS: The scale comprised five factors with factor loading values between 0.39 and 0.86. The item-total correlation coefficients revealed values of 0.27-0.88. The Cronbach's alpha reliability coefficient for the whole scale was determined to be 0.89 and for the subscales to be 0.60-0.85. The test-retest analysis revealed no difference between the scale and its subscales in terms of invariance with time (p>0.05). Moreover, MS-RS was significantly correlated with EDSS, HADS, MMSE, and MSQL-54. CONCLUSION: The Turkish version of MS-RS is a valid and reliable scale that can be used in the Turkish population.