Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Use of follow-on fingolimod for multiple sclerosis: Analysis of effectiveness and patient reported outcomes in a real-world clinical setting.

BACKGROUND: Follow-on disease modifying therapies (FO-DMTs) do not always require Phase III studies. There are concerns that cheaper FO-DMTs are only used to reduce healthcare costs. However, the well-being of people with MS (pwMS) should be a priority. We aimed to evaluate the efficacy, safety and treatment satisfaction of one of the FO- Fingolimod (FTY) used in Turkey with the approval of Turkish Ministry of Health. METHODS: PwMS under FTY were recruited from 13 centers and real-world data and answers of satisfaction and adherence statements of pwMS on FTY treatment were analyzed. RESULTS: Data of 239 pwMS were obtained. The duration of FTY treatment was 2.5 ± 0.8 (1-4) years in pwMS who were included in the study and whose treatment continued for at least one year. Significant decreases in annual relapse rate (p < 0.001), Expanded Disability Status Scale (p < 0.001) and neuroimaging findings (p < 0.001) were observed. While 64% of the patients were satisfied and 71.5% were found to adherent with this FO-FTY. CONCLUSION: This multicenter retrospective study found that the efficacy, safety and treatment adherence of a prescribed FO-FTY were consistent with the results of real-world studies. Studies including real-world data may provide guidance to address issues related to FO-FTY use.

Erratum: Clinical and Demographic Characteristics and Two-Year Efficacy and Safety Data of 508 Multiple Sclerosis Patients with Fingolimod Treatment.

[This corrects the article on p. 23 in vol. 60, PMID: 36911568.].

The Effect of Acupressure Applied to Patients With Multiple Sclerosis on Fatigue.

This study was conducted in order to examine the effect of acupressure applied to patients with multiple sclerosis on fatigue. The patients meeting the inclusion criteria were assigned to intervention (n = 30) and control (n = 30) groups. The data of the study were collected using a questionnaire and the Fatigue Severity Scale. During the study, the control group received its routine treatment; on the other hand, the intervention group received routine treatment and also the certified researcher, receiving the acupressure training, applied acupressure to the intervention group by using the points Li4, ST36 and SP6 3 times a week for a total of 4 weeks. The postacupressure fatigue mean score was 5.2 ± 0.7 in the intervention group and 5.9 ± 0.7 in the control group, and there was a significant difference in the control and intervention groups in terms of postacupressure fatigue mean scores (P < .05). According to these results of the study, it can be recommended to provide acupressure training to patients with multiple sclerosis in order to decrease the fatigue associated with multiple sclerosis.

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.

Clinical and Demographic Characteristics and Two-Year Efficacy and Safety Data of 508 Multiple Sclerosis Patients with Fingolimod Treatment.

Introduction: Fingolimod is the first oral immunomodulatory treatment used as secondary care therapy in the treatment of multiple sclerosis for the last 10 years. The objective of our study is to reveal the experiences of the first generic fingolimod active ingredient treatment in different centers across Turkey. Method: The first generic fingolimod efficacy and safety data of patients followed-up in 29 different clinical multiple sclerosis units in Turkey were analyzed retrospectively. Data regarding efficacy and safety of the patients were transferred to the data system both before the treatment and on the 6th, 12th and 24th month following the treatment. The data were analyzed using the IBM SPSS 20.00. P value of <0.05 was considered to be statistically significant. Results: A total of 508 multiple sclerosis patients, 331 of whom were women, were included in the study. Upon comparing the Expanded Disability Status values before and after the treatment, a significant decrease was observed, especially at month 6 and thereafter. Since bradycardia occurred in 11 of the patients (2.3%), the first dose had to be longer than 6 hours. During the observation of the first dose, no issues that could prevent the use of the drug occured. Side effects were seen in 49 (10.3%) patients during the course of fingolimod treatment. Respectively, the most frequent side effects were bradycardia, hypotension, headache, dizziness and tachycardia. Conclusion: The observed results regarding efficacy and safety were similar to clinical trial data in the literature and real life data in terms of the first equivalent with fingolimod active ingredient.

The effect of cognitive performance on self-management behavior of multiple sclerosis patients.

BACKGROUND: Difficulties of self-management in people with MS (pwMS) is considered as one of the most important factors contributing to low rehabilitation efficacy, more severe long-term complications and increase in healthcare costs. Despite the emergence of research in the last decade documenting causes, types, and course of cognitive difficulties in MS disease subtypes, limited evidence is available in the literature for direct comparison of self-management and cognitive deficits. In this study we aimed to investigate the relationship between cognitive performance and self-management in pwMS. METHODS: PwMS who applied to neurology out-patient clinics of seven different centers were included into study. Multiple Sclerosis Self-Management Scale- Revised (MSSM-R) was used for the assessment of self-management behaviors and Multiple Sclerosis inventory cognition scale (MUSIC) was used for the assessment of cognitive performance and fatigue. RESULTS: In this study, 194 (144 female and 50 male) pwMS participated (mean age = 38.9 years). The course of the disease was RRMS in 173 patients and mean EDSS was 2.0. 68.5% of the participants were married, 32.5% were employed, and 57.2% had secondary education. The MSSM-R mean score of the study group was 42.6 ± 10.4 (1-81). There was a positive correlation between MSSM-R and MUSIC-cog scores (r = 0.21, p = 0.003). A hierarchical multiple regression revealed that income level (ß = 0.196, t = 2.692, p = 0.008) and cognitive performance (ß = 0.167, t = 2.063, p = 0.041) together with control variables (gender, age, educational status, employment status, duration of disease, EDSS and fatigue) explained 5.5% of the variance in self-management. CONCLUSION: Cognitive performance is a predictor of self-management in pwMS. Better self-management behavior is also related with employment and income level in pwMS. Studies evaluating patients' cognitive abilities and evaluating the effectiveness of adapted self-management training programs are needed.

Comparative analysis of fingolimod versus teriflunomide in relapsing-remitting multiple sclerosis.

BACKGROUND: Fingolimod and teriflunomide are commonly used in the treatment of relapsing-remitting multiple sclerosis (RRMS). These have not been compared in controlled trials, but only in observational studies, with inconclusive results. Comparison of their effect on relapse and disability in a real-world setting is therefore needed. OBJECTIVES: The objective of this study was to compare the efficacy of fingolimod and teriflunomide in reducing disease activity in RRMS. METHODS: This multicenter, retrospective observational study was carried out with prospectively collected data from 15 centers. All consecutive RRMS patients treated with teriflunomide or fingolimod were included. Data for relapses, Expanded Disability Status Scale (EDSS) scores and brain magnetic resonance imaging (MRI) scans were collected. Patients were matched using propensity scores. Annualized relapse rates (ARR), disability accumulation, percentage of patients with active MRI and treatment discontinuation over a median 2.5-year follow-up period were compared. RESULTS: Propensity score matching retained 349 out of 1388 patients in the fingolimod group and 349 out 678 in the teriflunomide group for final analyses. Mean ARR decreased markedly from baseline after 1 and 2 years of treatment in both the fingolimod (0.58-0.17 after 1 year and 0.11 after 2 years, p < 0.001) and teriflunomide (0.56-0.29 after 1 year and 0.31 after 2 years, p < 0.001) groups. Mean ARR was lower in fingolimod-treated patients than in those treated with teriflunomide at years 1 (p = 0.02) and 2 (p = 0.004). Compared to teriflunomide, the fingolimod group exhibited a higher percentage of relapse-free patients and a lower percentage of MRI-active patients after 2.5-year follow-up. Disability worsening was similar between the two groups. Patients were less likely to discontinue fingolimod than teriflunomide (p < 0.001). CONCLUSION: Fingolimod was associated with a better relapse control and lower discontinuation rate than teriflunomide. The two oral therapies exhibited similar effects on disability outcomes.

Fatigue in Multiple Sclerosis: Is it related to cytokines and hypothalamic-pituitary-adrenal axis?

BACKGROUND: Fatigue is a common symptom of Multiple Sclerosis (MS) that diminishes the quality of life of patients, but its exact mechanism remains poorly understood. There is not a generally adopted scale to determine MS fatigue. Studies that investigated physiopathology of fatigue symptom have shown dysregulation of hypothalamic-pituitaryadrenal (HPA) axis. In the current study, we aimed to compare the results obtained with two separate scales, namely the Fatigue Severity Scale (FSS) and the Neurological Fatigue Index-Multiple Sclerosis (NFI-MS), and assess the relationship between fatigue and serum IL-1ß, TNF-α, IL-35, IL-2, IL-10, ACTH, cortisol, α-MSH, ß-MSH, γ-MSH and CLIP (Corticotropinlike intermediate lobe peptide) in MS patients categorized as fatigued and non-fatigued on the basis of FSS scores. METHODS: For the study, a total of 54 (29 females, 25 males) patients diagnosed with RRMS including 26 with fatigue symptom (48.1%), and 26 healthy controls (13 females, 13 males) were enrolled. A FSS score ≥36 was considered as cut-off score to separate fatigued patients from nonfatigued patients. RESULTS: A significant positive correlation was determined between FSS score and NFI-MS scale, NFI-MS 1, NFI-MS 2, NFI-MS 3 and NFI-MS 4 scores. IL-1ß, IL-10 and TNF-α levels did not differ between patient and control groups. IL-35 and IL-2 levels were significantly higher among MS patients (p<0.01). However, no difference was observed between fatigued and nonfatigued patients in the cytokines and HPA parameters studied. ACTH, cortisol and α-MSH were significantly higher in MS group (p=0.02, p<0.01 and p<0.01, respectively). CLIP level was significantly low in MS patient group (p<0.01). CONCLUSION: NFI-MS scale is equally sensitive as FSS scale for assessment of MS fatigue; thus, it may also be widely used to evaluate that symptom. Generally HPA axis is hyperactive in MS patients, but it is not correlated with fatigue in our study. For the first time, levels of CLIP (a type of melanocortin) are studied, and determined to be lower among MS patients. Elevated levels of IL-35 and IL-2 suggest that these cytokines may have a prominent role in MS pathophysiology and can be investigated as potential targets for development of novel therapies.

Circulating IGF-1, IGFB-3, GH and TSH levels in multiple sclerosis and their relationship with treatment.

OBJECTIVES: Improving the proficiency of oligodendrocytes in their ability to repair myelin damage is one of the major goals of multiple sclerosis treatment. Insulin-like growth factor-1 (IGF-1) is one of several polypeptides that are considered to have potential benefits in that sense. In the present study, we aimed to determine serum levels of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3), thyroid stimulating hormone (TSH) and growth hormone (GH) among treated and non-treated patients with Relapsing-Remitting Multiple Sclerosis (RRMS) and a healthy control group. METHODS: The study enrolled 100 RRMS patients and 100 age- and sex-matched control subjects diagnosed with definite multiple sclerosis (MS). Serum GH, IGF-1, IGFBP-3, and TSH levels were studied. RESULTS: The number of relapses and Expanded Disability Status Scale were negatively correlated and IGFBP-3 and GH were positively correlated with IGF-1. A statistically significant difference was not observed when patients were divided into two subgroups as patients treated with a MS-specific therapy (n = 54) and non-treated patients (n = 46). TSH and IGFBP-3 values were significantly lower in patient group vs. CONCLUSION: While no difference was determined with in IGF-1 levels, low levels of IGF-1 was in correlation with the least levels of IGFBP-3. To understand the relation between IGF-1 and IGFBP-3, the role of low levels of IGFBP-3 and TSH may be studied with clinic isolated syndrome patients and the evolution of these patients to definite MS.

Plasma urotensin-2 level and Thr21Met but not Ser89Asn polymorphisms of the urotensin-2 gene are associated with migraines.

BACKGROUND: Urotensin-II (U-II) is a peptide recognized by its potent vasoconstrictor activity in many vascular events, however the role of urotensin-II in migraine has not been considered yet. The molecular mechanisms and genetics of migraine have not been fully clarified yet, but it is well-known that vascular changes considerably contribute in pathophysiology of migraine and also its complications. The aim of this study was to analyze the plasma U-II levels along with genotype distributions and allele frequencies for UTS2 Thr21Met and Ser89Asn polymorphisms among the patients with migraine without aura (MWoA). METHODS: One hundred eighty-six patients with MWoA and 171 healthy individuals were included in this study. Plasma U-II levels were measured in attack free period. The genotype and allele frequencies for the Thr21Met (T21M) and Ser89Asn (S89N) polymorphisms in the UTS2 gene were analyzed. RESULTS: Plasma U-II levels were significantly higher in MWoA patients (p = 0.002). We detected a significant association between the T21M polymorphism in the UTS2 gene and migraine (53.8 % in patients, 40.4 % in controls, p = 0.035), but not with S89N polymorphism (p = 0.620). A significant relationship was found between U-II levels and MIDAS score (ß = 0.508, p = 0.001). CONCLUSION: Our study suggests that U-II may play a role in migraine pathogenesis; also Thr21Met polymorphism was associated with the risk of migraine disease. Further studies are needed for considering the role of U-II in migraine pathophysiology and for deciding if UTS2 gene may be a novel candidate gene in migraine cases.

The Effect of Circadian Melatonin Levels on Inflammation and Neurocognitive Functions Following Coronary Bypass Surgery.

PURPOSE: In this study, the relationship between the plasma levels of melatonin and intercellular adhesion molecule-1 (ICAM-1), which plays role in several intercellular interactions including inflammatory and immune responses, and early neurocognitive functions associated with ischaemia-reperfusion injury during open heart surgery is examined. METHODS: Forty patients who were to undergo elective coronary artery bypass grafting (CABG) were divided into two groups, those who underwent their operations at 8 AM (group I; n = 20) and those who underwent their operations at 1 PM (group II; n = 20). Blood samples were collected prior to surgery (S1), when the aortic cross clamp was removed (S2) and 4 (S3) and 24 h after the surgery (S4). Neuropsychiatric assessment was conducted one day before and seven days after surgery. RESULTS: Melatonin levels measured during and after surgery were also significantly higher in Group 1. ICAM-1 levels were significantly lower in Group 1 at S2 and S3. Significant deterioration was observed in postoperative neurocognitive function compared with preoperative functions in Group 2 more than Group 1. CONCLUSION: We hypothesise that the greater preservation of neurocognitive functions in the morning patients is associated with elevated melatonin levels, which reduce the damage from ischaemia-reperfusion injury.

Contribution of KCNJ10 gene polymorphisms in childhood epilepsy.

The purpose of this study was to investigate the possible association between childhood epilepsy and KCNJ10 gene polymorphisms (rs61822012 and rs2486253). A total of 200 epileptic cases and 200 healthy controls enrolled to this study. Genomic DNAs from the patients and control cases were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism methods. There were significant associations between the G/T genotype of KCNJ10 gene rs2486253 polymorphism in the idiopathic generalized epilepsy group (P = .037) and in subjects with generalized tonic-clonic seizures (P = .0015). T allele was also increased in patients with generalized tonic-clonic seizures (P = .0158). However, no statistically significant association was found between rs61822012 polymorphism and epilepsy. Our data suggest that G/T genotype of the KCNJ10 gene rs2486253 polymorphism affects risk for development of common types of childhood epilepsy. The T allele of this polymorphism was found to be a seizure-susceptibility allele for tonic-clonic epilepsy.

Investigation of the Rho-kinase 2 gene Thr431Asn polymorphism in migraine.

BACKGROUND: Migraine has a complex etiology determined by genetic and environmental factors, but the molecular mechanisms and genetics of this disease have not yet been fully clarified. AIM: This case/control study was designed to analyze the genotype distributions and allele frequencies for the Rho-kinase 2 (ROCK2) gene Thr431Asn polymorphism among the migraine patients. MATERIALS AND METHODS: A total of 155 migraine patients and 155 healthy age and sex matched controls were included in this study. Genomic deoxyribonucleic acid from migraine patients and controls was analyzed by real-time polymerase chain reaction. RESULTS: Neither genotype distributions nor the allele frequencies for the Thr431Asn polymorphism showed a significant difference between the groups. In addition, there were no marked differences in genotype and allele frequencies for the migraine without aura and migraine with aura subgroups when compared with control group. CONCLUSION: This is the first study to show that the ROCK2 gene Thr431Asn polymorphism is not a risk factor for the migraine in the Turkish population.

Prevalence of resistant occipital lobe epilepsy associated with celiac disease in children.

PURPOSE: Celiac disease (CD) is a chronic, inflammatory autoimmune disorder caused by intolerance to ingested gluten. Increased frequency of CD has been reported in occipital lobe epilepsy. The aim of the present study is to investigate the frequency of CD among children followed up due to epilepsy and diagnosed with epileptic activity in the occipital lobe in at least one electroencephalography (EEG) test. METHODS: For this research, 90 pediatric epilepsy patients with epileptic activity in the occipital lobe were enrolled in the study group, while the control group comprised of 100 healthy children. In addition to the EEG examination, tissue transglutaminase (tTG) antibody was determined on duodenal biopsy. RESULTS: None of the healthy children in the control group was positive in terms of the tTG antibody test used to scan CD. In the group with epileptic activity in the occipital lobe, two patients out of 90 were tTG antibody positive. The seroprevalence was 1/45 (2.22 %) in this group. These two patients were diagnosed with CD based on the endoscopic duodenal biopsy. In these patients, the seizures were uncontrollable through monotherapy. CONCLUSIONS: Our results showed that the prevalence of CD is observed to be higher than the normal population among the patients with occipital lobe epilepsy. This type of seizure disorder seems to be more resistant to monotherapy, compared with other types of occipital epilepsy. Therefore, screening for CD is recommended in children with resistant epileptic activity in the occipital lobe.

Lack of association between the C276T polymorphism of the neuronal nitric oxide synthase gene and migraine.

A migraine attack is a spectacularly complex brain event that can produce a wide array of neurological and systemic symptoms. The molecular mechanisms and genetics of migraine have not yet been clarified. The objective of this study was to analyze the genotype distributions and allele frequencies for the C276T polymorphism of the neuronal nitric oxide synthase (nNOS) gene among the patients with migraine. The diagnosis of migraine was made clinically based on questionnaires. One hundred and twenty patients with migraine were genotyped for the C276T polymorphism of the nNOS gene and compared with 185 age-matched healthy controls. Genomic DNA from migraine patients and controls was analyzed by polymerase chain reaction (PCR). A PCR-restriction fragment-length polymorphism analysis of nNOS gene polymorphism was performed, and the results were compared. Neither genotype distributions nor the allele frequencies for the C276T polymorphism showed a significant difference between the groups. Additionally, there was no marked differences in genotype distribution or allele frequencies for the migraine without aura and migraine with aura subgroups when compared to control group. These results suggested that migraine of the Turkish population seemed to develop without any alterations in nNOS C276T polymorphism. Our data showed that there is no marked association between the C276T polymorphism of the nNOS gene and migraine.

Simultaneous cranial subarachnoid hemorrhage and spinal subdural hematoma.

We report a rare case of simultaneous cranial subarachnoid and spinal subdural hematoma (SDH) in a 42-year-old man who was on Warfarin therapy after cardiac bypass surgery. Computed tomography at presentation revealed a cranial subarachnoid hemorrhage, and spinal Magnetic Resonance Imaging (MRI) showed a spinal SDH extending from the T6 to L5 segments. He had paraparesis due to spinal cord compression. The patient was managed conservatively due to his poor general condition and was infused with intravenous steroid therapy, but he experienced sudden cardiac arrest 5 hours later after being admitted to the hospital. This case is of interest because of its first presentation of spinal subdural hematoma and cranial subarachnoid hemorrhage simultaneously and it is also the second longest vertebral segmental spread in the literature.