NOTCH3 Variants in Patients with Suspected CADASIL.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease. It is clinically, radiologically, and genetically heterogeneous and is caused by NOTCH3 mutations. Methods: In this study, we analyzed NOTCH3 in 368 patients with suspected CADASIL using next-generation sequencing. The significant variants detected were reported along with the clinical and radiological features of the patients. Results: Heterozygous NOTCH3 changes, mostly missense mutations, were detected in 44 of the 368 patients (~12%). Conclusions: In this single-center study conducted on a large patient group, 30 different variants were detected, 17 of which were novel. CADASIL, which can result in mortality, has a heterogeneous phenotype among individuals in terms of clinical, demographic, and radiological findings regardless of the NOTCH3 variant.

The expression and prognostic value of miR-146a and miR-155 in Turkish patients with multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory, autoimmune demyelinating, and neurodegenerative disorder of the central nervous system. Interactions between environmental factors, predisposition genes, and determining genes appear to be involved in its etiology. Epigenetic mechanisms such as microRNA-mediated gene regulation can determine the susceptibility and severity of autoimmune diseases. Therefore, to determine the role of miR-146a and miR-155 in MS and its developmental stages, the expression levels in the serum of MS and clinically isolated syndrome (CIS) patients were compared with those of healthy controls. In the present study, the expression levels of miR-146a and miR-155 were assessed using quantitative Real-Time PCR in blood samples of 15 CIS patients and 61 relapsing-remitting multiple sclerosis (RRMS) patients alongside 32 healthy patients as controls. Furthermore, any associations with the clinicopathologic variables of the patients were also evaluated. Dysregulations were found only in the miR-146a and miR-155 expressions in the RRMS-Control group. When the RRMS patients were evaluated in terms of the characteristics of sex, annual attack rate, age of diagnosis, duration of follow-up, and immunomodulatory treatments used, no significant differences were observed. However, significant dysregulations were identified in miRNA expression in the vitamin D level, EDSS values, and the number of attacks. ROC curve analysis showed that miR-146a and miR-155 were significant in the RRMS-Control group for the area under the curve (AUC). It is possible that miR-146a may be associated with vitamin D deficiency and disease disability, while miR-155 may be associated with the number of attacks.

Comparison of Brain Atrophy, Cognition and Optical Coherence Tomography Results Between Multiple Sclerosis Patients and Healthy Controls.

INTRODUCTION: Cognitive impairment is also an important cause of disability in MS in addition to motor, sensory, visual, and cerebellar affections. The aim of this study is to show the relation between the cognitive disability in MS with brain atrophy and retinal nerve fiber layer (RNFL). METHODS: Forty-three multiple sclerosis (MS) patients, and 15 healthy individuals as controls were included in the study. MS patients were divided into three groups as relapsing-remitting MS (RRMS), relapsing-remitting with optic neuritis (RRMS+ON), and secondary-progressive MS (SPMS). An experienced psychologist performed modified Wechsler Memory Scale Revised form (WMS-R), Lines Orientation test, Stroop Color Word Interference test (STROOP), Standard Raven Progressive Matrices (SRPM), Benton Facial Recognition Test, verbal fluency test, and Paced Auditory Serial Addition tests in all cases. Optic coherence tomographies (OCT) were done. Cranial subcortical volumes of all subjects were measured using 3-dimensonal T1A imagines obtained by the cranial subcortical 1.5 tesla MR device (fully automatic Freesurfer program). Brain parenchymal fractions were calculated by proportioning the obtained volume measurements to the total intracranial volume. RESULTS: Fifty-eight subjects (65.5% female, 34.5% male) were enrolled in the study. There were significant differences among the groups in terms of parenchymal thickness, volumes of third ventricle, and white matter. There was a significant correlation between the volumes of the deep gray matter, mesial temporal structures and lateral ventricular volumes, and the test results of the WMS-R. OCT scores of all MS patients, whether or not they experienced optic neuritis, had increased, being worse especially in the SPMS group. Correlation between RNFL and the brain parenchymal fractions of the patients were statistically significant. CONCLUSION: Manual methods instead of automatic segmentation method are being more commonly used in the studies with brain atrophy and MS in our country. A significant correlation between OCT scores and brain atrophy is shown with our present study, and this is followed as a reflection of decrease in cognitive tests that provides valuable and reliable knowledge for the literature.

Prevalence of and risk factors for cognitive impairment in patients with relapsing-remitting multiple sclerosis: Multi-center, controlled trial.

BACKGROUND: Cognitive impairment (CI) is a common problem in multiple sclerosis (MS), may occur either in early or late phase of the disease, and impairs quality of life. OBJECTIVES: This study aimed to determine the prevalence of CI and related risk factors in relapsing-remitting MS (RRMS) patients in Turkey. METHODS: The present cross-sectional, multi-center, and nationally representative study included RRMS patients. Sociodemographic characteristics, cognitive functions and additional outcomes were compared between patients with and without CI. RESULTS: The analyses included 487 RRMS patients. According to the BRB-N battery results, CI prevalence was 53.7%. There was a negative significant correlation of BRB-N subtests with age, disease duration, and EDSS and MSNQ-patient rated scores. On the logistic regression analysis, increased age, living in village/rural area, high income level, and high EDSS score were significant increasing risk factors in the development of CI. CONCLUSIONS: This is the first national cognitive data obtained from MS in Turkey, which is a country between Europe and Asia and thus has characteristics of both continents. The similarity of the results of the present study obtained from Turkey to the Western-based data indicates that CI is universal in MS and the main factors affecting CI have not changed.

Early Stage Alterations in CA1 Extracellular Region Proteins Indicate Dysregulation of IL6 and Iron Homeostasis in the 5XFAD Alzheimer's Disease Mouse Model.

In recent years, an increasing number of research papers revealed that the compositional and volumetric alterations in the extracellular matrix are the consequences of aging and may be related to Alzheimer's disease (AD). In this study, we aimed to demonstrate the alterations in hippocampal extracellular fluid proteins in vivo using the 5XFAD mouse model. Samples were obtained from hippocampi of 5XFAD mice (n = 6) and their non-transgenic littermates by intracerebral push-pull perfusion technique at 3 months of age, representing the pre-pathological stage of the AD. Proteins in the hippocampal perfusates were analyzed by Ultra Performance Liquid Chromatography-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UPLC-ESI-qTOF-MS/MS). 178 proteins were identified and 19 proteins of them were found to be statistically significantly altered (p≤0.05, fold change ≥40%, unique peptide count ≥3) in the hippocampal CA1 extracellular fluid of the 5XFAD mouse model. Ingenuity pathway analysis of the protein expression results identified IL6 as an upstream regulator. The upregulation of IL6 was validated by immunohistochemical staining of the hippocampus and cortex of the 5XFAD mice prior to Aß plaque formation. Furthermore, the iron level in the hippocampus was measured by inductively coupled plasma-mass spectrometry as IL6 is mentioned in several studies to take part in iron homeostasis and inflammation and found to be increased in 5XFAD mice hippocampus. Alterations in extracellular matrix proteins in addition to increasing amount of hippocampal IL6 and iron in the early stages of AD may reveal inflammation-mediated iron dyshomeostasis in the early stages of neurodegeneration.

Recent Advances in the Treatment for Multiple Sclerosis; Current New Drugs Specific for Multiple Sclerosis.

Since the first approved parenteral drug for the treatment of multiple sclerosis (MS) in 1993 (interferon [IFN] beta, and later glatiramer acetate [GA]), today there are both parenteral and oral treatment options for MS. After IFN beta preparations, glatiramer acetate was developed; and, until the approval of natalizumab in 2006, those dominated the treatment of MS. Later on, among oral drug options, cladribine made a promising entry; however, due to safety concerns, it was withdrawn soon. Afterwards, with the understanding of the role of sphingosine-1 phosphate (S1P) receptors in the pathogenesis of MS, fingolimod was approved in 2010, which was followed by other oral agents such as teriflunomide and dimethyl fumarate. Recently newer IV treatment options such as alemtuzumab, rituximab and ocrelizumab have widened the treatment arena. Recently, after submitting new efficacy and safety data, cladribine was approved for MS by EMA, in 2017. Moreover, seven years after its rejection due to safety reasons, in August 2018 FDA accepted to re-evaluate the data of cladribine as a treatment option for relapsing remitting MS (RRMS). Another oral treatment option, Laquinimod, was not approved because it could not be shown to slow disability progression despite favourable effect in relapsing MS. Newer generation S1P receptor modulators are being investigated currently, and they are expected to come into the treatment arena soon. In this article, mechanisms of actions, clinical trial results, and side effects of the newer drugs used for MS, are reviewed. IFN beta and glatiramer acetate were not included since they have clinical experience nearing 30 years.

Performance and Capacity Measurement of the Lower Extremities in Multiple Sclerosis -How to Approach?

Walking limitations play a key role in the development of disability in multiple sclerosis (MS) patients. Vast majority of patients, even in the very early stages of the disease, experience walking disturbances. Measuring capacity and performance in lower extremities enables us to 1) monitor disease pregression; 2) evaluate treatment responses; 3) determine the necessity of new treatment strategies on time. The purpose of this review is to highlight the importance of regular walking assessments in MS patients, give idea about which measurement tools to choose, and provide insight for future investigations in the light of new technological developments.

Caregiver Burden in Different Stages of Alzheimer's Disease.

With an increasing number of patients being diagnosed with Alzheimer's disease (AD) daily, it has become one of the major problems in public health. The increase in the number of dementia patients in low- and middle-income countries is expected to be much more than that in developed countries. As a result, the economic burden of dementia, both worldwide and in Turkey, is growing. Moreover, AD leads to emotional burdens and psychological distress in family member(s) and caregiver(s) alongside the patient. Each stage of AD imposes different responsibilities on caregivers, increasing their burden. The suffering and emotional burdens of caregivers from these responsibilities lead to a decreased quality of life and disturbed body physiology. Incapacity, despair, weariness, and loneliness are the hidden emotions of this iceberg. This review aims to gather the results of studies on caregiver burden in different stages of AD, attract attention to those results that may have been ignored in Turkey, and shed light on the solutions required to overcome the problems in caregiving of AD patients.

Targeting Apoptosis Through Foxp1, and N-cadherin with Glatiramer Acetate in Chick Embryos During Neural Tube Development.

AIM: To demonstrate the effect of glatiramer acetate (GA) in chick embryos on neural tube (NT) development, and to explore its effects of Foxp1, apoptosis, and N-cadherin. MATERIAL AND METHODS: One hundred fertile, specific pathogen free eggs were divided into 5 groups for this study. The eggshell was windowed specifically at 24 hours of incubation. The embryos in Group 1 (n=20) were treated with 10 µl physiological saline; in Group 2 the embryos (n=20) were given 10 µl GA (equal to daily human therapeutic dose); 20 µl GA (equal to twice daily human therapeutic dose) was injected to embryos in Group 3 (n=20); in Group 4 and 5, 30 µl and 40 µl GA were administered to the embryos (n=20) (equal to x3 and x4 daily human therapeutic dose, respectively). Each egg was re-incubated for 24 hours more. Then, histological and immunohistochemical evaluation of the subjects were done. RESULTS: The embryos with NT defect showed FOXP1 expression without N- cadherin or staining with N-cadherin in another location in our study. We interpreted this result as GA leading to an NT closure defect by increasing FOXP expression. Moreover, we also showed the reverse relation between FOXP1 and N-cadherin at the immunohistochemical level for the first time. CONCLUSION: GA affects the spinal cord development through FOXP in the chick embryo model at high doses.

Association of MDR1, CYP2D6, and CYP2C19 gene polymorphisms with prophylactic migraine treatment response.

Prophylactic therapy response varies in migraine patients. The present study investigated the relationship between the resistance to the drugs commonly used in prophylactic therapy and the possible polymorphic variants of proteins involved in the metabolism of these drugs. Migraine patients with the MDR1 3435TT genotype exhibited a better treatment response to topiramate than migraine patients with the CC and CT genotypes (p=0.020). The MDR1 C3435T polymorphism was also found to be a higher risk factor for topiramate treatment failure in a comparison of the number of days with migraine (ß2=1.152, p=0.015). However, there was no significant relationship between the treatment response to topiramate and either the CYP2D6 or CYP2C19 polymorphism, and there were no significant correlations between the treatment responses to amitriptyline, propranolol, and valproic acid and the MDR1, CYP2D6 and CYP2C19 gene polymorphisms. This is the first study to investigate the effect of the polymorphic variants on prophylactic therapy response in migraine patients.

A case of hyperkinetic movement disorder associated with LGI1 antibodies.

Encephalitis associated with leucine-rich glioma inactivated 1 (LGI1) antibodies is often encountered in elderly male patients and may infrequently present with isolated syndromes. A 6-year-old boy was admitted with acute onset severe oral and facial stereotypic and choreiform movements. On his neurologic examination, he had repetitive and rhythmic movements in orolingual muscles including tongue protrusion, limb chorea and minimal facial stereotypic movements. Anti-streptolysin O (ASO) titers were found severely elevated in several measurements. Well-characterized antibodies against ion channels and synapse proteins were negative whereas LGI1 antibody was positive in both serum and CSF. Marked clinical improvement was observed after immunotherapy. Here, we present the first pediatric case with LGI1 antibody associated hyperkinetic movement disorders and emphasize the importance of investigating neuronal autoantibodies in patients with isolated and treatment resistant movement disorders.

Persistent headache in a postpartum patient: the investigation and management.

Postdural puncture headache (PDPH) is the most common complication of obstetric regional anaesthesia and the most likely cause of headache in a woman who underwent epidural anaesthesia during delivery. Cerebral venous sinus thrombosis (CVST) is an uncommon cause of postpartum headache. Anaesthesia in obstetrics may lead to long-lasting intracranial hypotension resulting in CVST. CVST is a serious pathology with high mortality if misdiagnosed, but its correct and rapid diagnosis offers the opportunity for early treatment. Cranial magnetic resonance imaging (MRI) is an important modality in the diagnosis of both CVST and intracranial hypotension. The latter condition may be treated either by an epidural blood patch or bed rest and hydration. We report a case of a 36-year-old woman who developed CVST and multiple venous infarcts after an attempted epidural procedure during delivery. She was treated conservatively with bed rest, hydration and low-molecular-weight heparin and the patient recovered completely.

Sporadic Creutzfeldt-Jacob Disease: An 8-Year Experience from a Single Center in Turkey.

INTRODUCTION: Our aim was to conduct a retrospective review to demonstrate the clinical, radiological, and electrophysiological features of patients with sporadic Creutzfeldt-Jacob disease (sCJD). METHOD: A total of 10 patients (5 female and 5 male, with a mean age of 45 years from a range of 40 to 67 years) out of 8.259 adult patients hospitalized from January 2000 to December 2008 were diagnosed with sCJD. RESULTS: Eight of the patients were diagnosed on the basis of clinical, radiological, electroencephalography (EEG), and cerebrospinal fluid (CSF) findings. Two other patients also had a pathological diagnosis. The most common signs and symptoms were behavioral disturbances, movement disorders, cognitive decline, myoclonus, psychosis, focal neurological deficit, and aphasia. Nine of the patients had periodic sharp wave discharges on EEG. Seven patients were positive for the 14.3.3 protein in the CSF. Five patients had pulvinar signs-a bilateral increased signal in the pulvinar thalami-on cranial magnetic resonance imaging. Eight patients were diagnosed with probable sCJD; two were diagnosed with definite sCJD. All of the patients died as a result of the disease within 24 months after the onset of symptoms. DISCUSSION: sCJD should be considered in the diagnosis of patients who present with rapidly progressive dementia. Clinical and radiological data appear to be sufficient for the diagnosis. However, detailed molecular examinations of the subtypes of the disease may be required for early diagnosis of cases given the wide spectra of CJD.

Assessment of Quality of Life in Migraine.

Quality of life is the perception of an individual's position in life associated with his objectives, expectations, interests, and standard's of life. Health-related quality of life, on the other hand, includes satisfaction with his health and emotional reaction to his state of health. Primary headaches are encountered commonly in adults during their most productive years like end of puberty and at the beginning of 50's. Migraine alone is responsible for 1.3% of years with disability in the world, all headaches together being responsible for twice of this load. Headaches both worsen quality of life of individuals and place a significant burden on the society. This review will focus on the effects of primary headaches, especially migraine, on quality of life and tools used to evaluate these effects.

Shape analysis of the corpus callosum and cerebellum in female MS patients with different clinical phenotypes.

The aim of this study was to investigate the shape differences in the corpus callosum (CC) and cerebellum of female relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) patients compared with healthy controls. This study was conducted using the magnetic resonance imaging scans of 15 control subjects, 26 RRMS, and 14 SPMS patients. The data obtained from the landmark coordinates were analyzed with statistical shape analysis. The landmarks that were chosen to determine the shape differences of the CC and cerebellum have been identified and used in previous studies. In addition to these landmarks, constructed landmarks were determined and used to assess regional shape differences better. The shapes of the CC and cerebellum showed statistically significant differences from the controls when compared with both the RRMS and SPMS patients. It was found that the deformation observed from controls to SPMS was greater than the deformation from controls to RRMS, both for the CC and cerebellum. In conclusion, this study revealed CC and cerebellar shape change in RRMS and SPMS, and showed that deformations both in CC and cerebellum advances with the disease progression.

Neurochemical-structural changes evaluation of brain in patients with obstructive sleep apnea syndrome.

PURPOSE: To evaluate neurochemical and structural changes in the patients with newly diagnosed obstructive sleep apnea syndrome (OSAS) by MR spectroscopy (MRS), T2 relaxometry, and diffusion weighted imaging (DWI). MATERIAL AND METHODS: Following the acquisition of routine cranial MR, MRS, T2 relaxometry, and DWI images; spectroscopic metabolite ratios and DWI-T2 relaxometry findings of the thalami, hippocampi, frontal white matter (FWM) and frontal cortex of 24 OSAS patients and 9 controls were statistically compared. The relationship between two groups was evaluated with Mann-Whitney test. RESULTS: Spectroscopic measurements in the frontal cortex and frontal white matter of the OSAS patients revealed significantly lower NAA/Cr ratios than those of the control group (P=0.004 and P=0.006, respectively). The measurements in the frontal white matter of the OSAS patients exhibited significantly lower NAA/Cho ratios compared with those of the control group (P=0.005). Thalamic Cho/Cr ratios of the patient group were significantly higher than those of the control group (P=0.002). In terms of the ADC-T2 relaxometry values, there was no significant relationship between the patient and the control groups (P>0.05). CONCLUSION: MRS is a useful and non-invasive modality in showing neurochemical changes in various regions of the brain but our data does not show any change on diffusion weighting or T2 quantification in the OSAS group. DWI and T2 relaxometry appear to be not effective techniques to evaluate the brain structural changes of the patients with newly diagnosed OSAS.

Sociodemographics, clinical features, and psychiatric comorbidities of patients with psychogenic nonepileptic seizures: experience at a specialized epilepsy center in Turkey.

Patients with psychogenic nonepileptic seizures (PNESs) or pseudoseizures are known to have psychiatric comorbidities. In the present retrospective analysis, we examined the sociodemographics, clinical characteristics, and psychiatric diagnoses of patients with PNESs. Our aim is to demonstrate the contribution of the consulting psychiatrists to the presumed psychiatric diagnoses of the neurologists. We used data from long-term video EEG monitoring (LVEM) performed at a specialized epilepsy center in Turkey. The study group comprised 67 patients (mean age: 30 years, 75% female) diagnosed with PNESs following LVEM of approximately 5 days' duration. Two hundred thirty-three episodes were recorded. Most of the patients experienced a PNES on the first day. All of the patients were taking antiepileptic drugs (AEDs) at the time of admission; 56.7% were taking antidepressant (AD) drugs. All of the PNES patients were diagnosed with conversion disorder by both the neurologists and the psychiatrists. Most of the PNES patients were using multiple AEDs. Cooperation between neurologists and psychiatrists and ongoing education for both neurologists and psychiatrists about PNES are needed in appropriate diagnosing and management of patients with PNES.

Detection of CSF leaks with magnetic resonance imaging in intracranial hypotension syndrome.

Intracranial hypotension syndrome (IHS) is a rare disorder characterized by postural headache, low cerebrospinal fluid (CSF) pressure, dural thickening and pachymeningeal contrast enhancement as a consequence of decreased CSF volume. The present report is a case of spontaneous IHS due to dural leak at the level of T12-L1. The site of CSF leakage was not detectable on either conventional magnetic resonance imaging (MRI) or T2-weighted MR myelography. However, it was evident on contrast-enhanced MR myelography (CE-MRM). The present report discusses the efficacy of CE-MRM in the detection of CSF leaks according to the literature so far.

Structural and neurochemical evaluation of the brain and pons in patients with Wilson's disease.

PURPOSE: The aim of this study was to examine the structural-neurochemical abnormalities of the frontal white matter (FWM), deep gray matter nuclei, and pons in patients with Wilson's disease (WD) using proton magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Nine patients with WD and 14 age-matched controls were examined with MRS. N-Acetylaspartate (NAA), choline (Cho), and creatine (Cr) peaks were calculated. DWI scans from six WD patients and six controls were also obtained. The relative metabolite ratios and apparent diffusion coefficient (ADC) values of the WD patients were compared to those of the control subjects by using statistical measures. RESULTS: Measurements in the thalamus and pons showed significantly lower NAA/Cho and NAA/Cr ratios in the WD group than in the control group (P < 0.05). Thalamic and pontine Cho/Cr ratios in the patient group were significantly higher than those of the control group (P < 0.05). No statistically significant relation was found between the patient and control groups as a result of the MRS examinations of FWM and all ADC measurements (P > 0.05). CONCLUSION: MRS is a noninvasive, valuable modality for detecting structural-neurochemical changes of the brain stem and deep gray matter in patients with WD. The contribution of DWI in these patients is limited.

Imaging of active multiple sclerosis plaques: efficiency of contrast-enhanced magnetization transfer subtraction technique.

PURPOSE: T1-weighted (T1W) magnetic resonance images with magnetization transfer (MT) are widely used in the evaluation of multiple sclerosis (MS) plaques. We aimed to evaluate the contribution of the subtraction technique with MT in the detection of acute MS plaques. MATERIALS AND METHODS: Sixty-four patients during an MS attack were enrolled in the study. Axial T1W spin echo (SE) with MT, axial-sagittal T2W fast SE, axial FLAIR and postcontrast axial T1W SE magnetic resonance imaging sequence with MT were acquired from all patients. The subtraction (postcontrast-precontrast) images were obtained on the workstation. FLAIR and T2W images were used as reference for plaque imaging. Contrast material enhanced plaques were considered as acute plaques. Qualitatively, both subtracted and contrast-enhanced with MT images were evaluated visually. Quantitatively, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. RESULTS: A total of 464 plaques were detected on T2W and FLAIR images. Thirty-five acute plaques were detected on both postcontrast MT and subtracted images. Additionally, 66 acute plaques were only detected on subtracted images visually. CNR and SNR values of acute MS plaques were significantly higher on subtracted MT images than on postcontrast MT images (P < 0.001). CONCLUSION: The subtraction technique seems to facilitate the detection of acute MS plaques by intensifying the visibility of poorly enhanced plaques without use of high dose contrast medium. We suggest the use of subtraction technique in routine imaging work-up of MS patients with acute attacks.