Validation of the transcranial Doppler rescue criteria for mechanical thrombectomy.

BACKGROUND AND PURPOSE: Transcranial Doppler (TCD) identifies acute stroke patients with arterial occlusion where treatment may not effectively open the blocked vessel. This study aimed to examine the clinical utility and prognostic value of TCD flow findings in patients enrolled in a multicenter prospective study (CLOTBUST-PRO). METHODS: Patients enrolled with intracranial occlusion on computed tomography angiography (CTA) who underwent urgent TCD evaluation before intravenous thrombolysis was included in this analysis. TCD findings were assessed using the mean flow velocity (MFV) ratio, comparing the reciprocal ratios of the middle cerebral artery (MCA) depths bilaterally (affected MCA-to-contralateral MCA MFV [aMCA/cMCA MFV ratio]). RESULTS: A total of 222 patients with intracranial occlusion on CTA were included in the study (mean age: 64 ± 14 years, 62% men). Eighty-eight patients had M1 MCA occlusions; baseline mean National Institutes of Health Stroke Scale (NIHSS) score was 16, and a 24-hour mean NIHSS score was 10 points. An aMCA/cMCA MFV ratio of <.6 had a sensitivity of 99%, specificity of 16%, positive predictive value (PV) of 60%, and negative PV of 94% for identifying large vessel occlusion (LVO) including M1 MCA, terminal internal carotid artery, or tandem ICA/MCA. Thrombolysis in Brain Ischemia scale, with (grade ≥1) compared to without flow (grade 0), showed a sensitivity of 17.1%, specificity of 86.9%, positive PV of 62%, and negative PV of 46% for identifying LVO. CONCLUSIONS: TCD is a valuable modality for evaluating arterial circulation in acute ischemic stroke patients, demonstrating significant potential as a screening tool for intravenous/intra-arterial lysis protocols.

Cognitive, Functional, and Emotional Changes During the COVID-19 Pandemic in Greek Patients with Neurocognitive Disorders.

BACKGROUND: Prolonged periods of social deprivation, such as COVID-19-related lockdowns, are associated with deleterious effects on cognitive functions. OBJECTIVE: The aim of this study was to gauge the effect of prolonged social isolation on the cognitive function of older adults with neurocognitive disorders. METHODS: We recruited 125 older adults with minor or major neurocognitive disorders divided into two groups. The control group was tested at the first period of the study (October 2018-May 2019), whereas the experimental group was evaluated at the second chronological period of the study (October 2020-May 2021) during the second wave of COVID-19. Neuropsychological tests were performed at baseline and six months after baseline. RESULTS: In the control group, significant changes in the scores from the Montreal Cognitive Assessment (MoCA; p = 0.049) and the Functional Rating Scale for Symptoms of Dementia (FRSSD; p = 0.005) were found between baseline and follow-up assessments, whereas no changes were identified in Mini-Mental State Examination (MMSE; p = 0.229) and Geriatric Depression Scale (GDS; p = 0.619) scores. In the experimental group, the scores from all neuropsychological tests (MoCA, MMSE, GDS, and FRSSD; p < 0.001 for all) were significantly different at follow-up when compared with those at baseline measurements. Moreover, significant deterioration of specific functions assessed in MMSE and FRSSD was detected, especially in the experimental group. CONCLUSION: This study highlights cognitive functions directly affected by social deprivation of individuals with neurocognitive disorders. The findings can be used in the rehabilitation from confinement and its negative consequences.

Signaling through the S1P-S1PR Axis in the Gut, the Immune and the Central Nervous System in Multiple Sclerosis: Implication for Pathogenesis and Treatment.

Sphingosine 1-phosphate (S1P) is a signaling molecule with complex biological functions that are exerted through the activation of sphingosine 1-phosphate receptors 1-5 (S1PR1-5). S1PR expression is necessary for cell proliferation, angiogenesis, neurogenesis and, importantly, for the egress of lymphocytes from secondary lymphoid organs. Since the inflammatory process is a key element of immune-mediated diseases, including multiple sclerosis (MS), S1PR modulators are currently used to ameliorate systemic immune responses. The ubiquitous expression of S1PRs by immune, intestinal and neural cells has significant implications for the regulation of the gut-brain axis. The dysfunction of this bidirectional communication system may be a significant factor contributing to MS pathogenesis, since an impaired intestinal barrier could lead to interaction between immune cells and microbiota with a potential to initiate abnormal local and systemic immune responses towards the central nervous system (CNS). It appears that the secondary mechanisms of S1PR modulators affecting the gut immune system, the intestinal barrier and directly the CNS, are coordinated to promote therapeutic effects. The scope of this review is to focus on S1P-S1PR functions in the cells of the CNS, the gut and the immune system with particular emphasis on the immunologic effects of S1PR modulation and its implication in MS.

Influence of Social and Demographic Factors on the Montreal Cognitive Assessment (MoCA) Test in Rural Population of North-Eastern Greece.

The current study aims to investigate the influence of socio-demographic factors on the Montreal Cognitive Assessment (MoCA) test results in a Greek-speaking population consisting of a sample of healthy older adults, individuals with mild cognitive impairment (MCI), and dementia patients in rural areas. In addition, the current research focuses on determining optimal cut-off scores for the clinical diagnoses of MCI and dementia. The data originated from 283 participants in an ongoing registry of the Neurology Department of Alexandroupolis University Hospital, recruited in different rural districts of north-eastern Greece, across a broad range of educational and occupational categories. Total and sub-domain scores for the MoCA varied significantly, according to sex, age, and education, among the three study groups. The optimal cut-off points of 25/26 for the MoCA total score was determined to classify healthy subjects from individuals with MCI, 24 to discriminate healthy participants from demented, and 21/22 to discriminate subjects with MCI from dementia. Overall, the clinical use of the MoCA test can be supported by demographically adjusted standard scores in a Greek-speaking rural population. These findings serve to improve the diagnostic accuracy and utility of the MoCA test.

Vessel Density around Foveal Avascular Zone as a Potential Imaging Biomarker for Detecting Preclinical Diabetic Retinopathy: An Optical Coherence Tomography Angiography Study.

Purpose: The purpose of this study was to investigate the changes of optical coherence tomography angiography (OCTA) parameters in diabetic retinopathy (DR) using an updated software with 3D projection artifact removal. Methods: In this cross-sectional observational study, 192 eyes of 111 patients with diabetes mellitus (DM) and 55 eyes of 34 age-matched healthy subjects were included. Diabetic patients were divided into three subgroups: without DR, with mild non-proliferative DR, and with moderate-to-severe non-proliferative DR. All eyes underwent dilated fundoscopy along with 3x3mm and 6x6mm OCTA image acquisition. Vessel density (VD), retinal thickness and foveal avascular zone (FAZ) parameters were analyzed. Correlation analyses between OCTA parameters and DR severity were also performed. Results: There was a statistically significant difference in all OCTA parameters among groups, except for superficial foveal VD in 6x6mm scan and whole image retinal thickness in both 3x3mm and 6x6mm scans, while 3x3mm scan parameters were found to be diagnostically superior to the corresponding ones of 6x6mm scan. As the DR stage progressed, the mean VD values decreased. FD-300, which is the VD of a 300-µm width annulus surrounding FAZ, demonstrated the strongest inverse correlation with DR severity (r = -0.590/rs = -0.562, p < .001) and showed the highest area under the ROC curve (AUROC = 0.833 ± 0.030, p < .001) in scan 3 × 3. Conclusion: OCTA shows progressive decrease of VD parameters with increasing DR severity. Foveal VD, FAZ area, and perimeter are not very useful indexes due to the high interindividual variability of FAZ size. OCTA and specifically FD-300 may serve as a promising DR screening tool for detecting preclinical microvascular alterations.

Timing of Recanalization and Functional Recovery in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Although onset-to-treatment time is associated with early clinical recovery in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (tPA), the effect of the timing of tPA-induced recanalization on functional outcomes remains debatable. METHODS: We conducted a multicenter, prospective observational cohort study to determine whether early (within 1-hour from tPA-bolus) complete or partial recanalization assessed during 2-hour real-time transcranial Doppler monitoring is associated with improved outcomes in patients with proximal occlusions. Outcome events included dramatic clinical recovery (DCR) within 2 and 24-hours from tPA-bolus, 3-month mortality, favorable functional outcome (FFO) and functional independence (FI) defined as modified Rankin Scale (mRS) scores of 0-1 and 0-2 respectively. RESULTS: We enrolled 480 AIS patients (mean age 66±15 years, 60% men, baseline National Institutes of Health Stroke Scale score 15). Patients with early recanalization (53%) had significantly (P<0.001) higher rates of DCR at 2-hour (54% vs. 10%) and 24-hour (63% vs. 22%), 3-month FFO (67% vs. 28%) and FI (81% vs. 39%). Three-month mortality rates (6% vs. 17%) and distribution of 3-month mRS scores were significantly lower in the early recanalization group. After adjusting for potential confounders, early recanalization was independently associated with higher odds of 3-month FFO (odds ratio [OR], 6.19; 95% confidence interval [CI], 3.88 to 9.88) and lower likelihood of 3-month mortality (OR, 0.34; 95% CI, 0.17 to 0.67). Onset to treatment time correlated to the elapsed time between tPA-bolus and recanalization (unstandardized linear regression coefficient, 0.13; 95% CI, 0.06 to 0.19). CONCLUSIONS: Earlier tPA treatment after stroke onset is associated with faster tPA-induced recanalization. Earlier onset-to-recanalization time. RESULTS: in improved functional recovery and survival in AIS patients with proximal intracranial occlusions.

Factors defining occurrence of ischemic and hemorrhagic strokes during continuous flow left ventricular assist device support.

OBJECTIVE: LVAD-related strokes occur at a much higher rate compared to traditional open heart surgery. The pathophysiology of ischemic and hemorrhagic strokes after LVAD implantation is not well defined. The aim of this study was to better describe the etiopathogenesis of strokes during continuous flow LVAD support based on our institutional experience. METHODS: We performed a retrospective analysis of 200 patients, with and without stroke that underwent implantation of a continuous flow LVAD from 2011 to 2016. RESULTS: The incidences of stroke in our patient population were 13% (26/200), of which 50% (13/26) were ischemic and 50% hemorrhagic (13/26). Only 8% of strokes occurred within the first 48 h from LVAD implantation, all of which were ischemic. The median duration of support was 148 days for ischemic and 351 days (p = 0.012) for hemorrhagic strokes. The average mean arterial pressure measurements at the time of hospital discharge were 89 mmHg for patients who subsequently developed stroke and 72 mmHg (p = 0.03) for stroke-free patients. The average outpatient pressure measurements were 96 mmHg and 76 mmHg (p = 0.02) for the stroke and stroke-free patients, respectively. The mean velocity index showed the potential impairment of cerebral autoregulation. Multivariate analysis demonstrated that INR, COPD, aortic cross clamping, previous stroke, and device infections were statistically significant risk factors for stroke occurrence after LVAD implantation. CONCLUSIONS: In addition to LVAD-related thrombogenicity, the subsequent need for anticoagulation, and an acquired von Willebrand syndrome, several clinical factors, such as deviation from the anticoagulation regimen, hypertension, COPD, device infections, and aortic cross clamping, appear to have an influence on the extremely high rate of postoperative ischemic and hemorrhagic strokes.

Clinical and Neuroimaging Characteristics in Embolic Stroke of Undetermined versus Cardioembolic Origin: A Population-Based Study.

BACKGROUND AND PURPOSE: Evidence suggests that cardioembolism represents the underlying mechanism in the minority of embolic strokes of undetermined source (ESUS). In this population-based study, we sought to compare the clinical and imaging characteristics as well as outcomes in patients with ESUS and cardioembolic stroke (CE). METHODS: We included consecutive patients with first-ever ischemic stroke (IS) from the previously published population-based Evros-Stroke-Registry identified as ESUS or CE according to standardized criteria. Baseline characteristics, admission NIHSS scores, cerebral edema, hemorrhagic transformation, stroke recurrence, functional outcomes (determined by modified Rankin Scale [mRS] scores), and mortality rates were recorded during the 1-year follow-up period. RESULTS: We identified 21 ESUS (3.7% of IS) and 211 CE (37.1% of IS) cases. Patients with ESUS were younger (median age: 68 years [interquartile range [IQR]: 61-75] vs 80 years [IQR: 75-84]; P < .001), had lower median admission NIHSS scores (4 points [IQR: 2-8] vs 10 points [IQR: 5-17]; P < .001), and lower prevalence of cerebral edema on neuroimaging studies (0 vs. 33.3%, P = .002). Functional outcomes were more favorable in ESUS at 28 (median mRS score: 2 [IQR: 1-3] vs 4 [IQR: 4-5]; P < .001), 90 (median mRS score: 1 [IQR: 0-2] vs 4 [IQR: 3-5]; P < .001), and 365 days (median mRS score: 1 [IQR: 0-2] vs 4 [IQR: 2-4]; P < 0.001). At 1-year, the mortality rate was lower in ESUS (0% [95% confidence interval [CI]: 0-13.5%] vs 34.6% [95% CI: 28.2-41.0%]; P < .001); the 1-year recurrent rate was also lower numerically (0% [95% CI: 0-13.5%] vs 9.5% [95% CI: 5.5-13.4%]; P = .140) but this difference failed to reach statistical significance due to the small study population. CONCLUSIONS: The clinical and neuroimaging profiles as well as clinical outcomes vary substantially between ESUS and CE indicating different underlying mechanisms.

Stroke after implantation of continuous flow left ventricular assist devices.

OBJECTIVE: Stroke remains a frequent and devastating complication after left ventricular assist device (LVAD) implantation, despite recent advances in device technology. The aim of this study was to analyze risk factors and outcomes of stroke following implantation of 200 continuous-flow LVADs at our institution. METHODS: We retrospectively analyzed patients who underwent LVAD implantation from 2011-2016. Data were available for a total of 200 patients. RESULTS: Post-LVAD stroke occurred in 13% of patients (26 of 200). Ischemic stroke occurred in 50% of patients (13 of 26), and hemorrhagic stroke in 50% (13 of 26). The median duration of LVAD support at the time of stroke was 257.4 days. Baseline characteristics did not differ significantly between the stroke and stroke-free cohorts. The mean international normalized ratio (INR) at the time of embolic stroke was 1.86 (range, 1.23-3.25) and 4.62 (range, 1.4-21.4) in patients with hemorrhagic stroke (P = .014). Mortality within 30 days of stroke was 31% (8 of 26). Mortality for hemorrhagic stroke was 63% (5 of 8) and 37% (3 of 8) for ischemic stroke ( P = .03). Among the 18 patients that survived stroke, 28% (5 of 18) received a heart transplant, 39% (7 of 18) are receiving ongoing LVAD support, and 33% (6 of 18) have died from unrelated causes. Multivariate analysis showed that INR level, aortic cross-clamping, a history of previous stroke, and postoperative infection were significant predictors for post-LVAD stroke. CONCLUSION: The occurrence of stroke significantly increases morbidity and mortality after LVAD implantation. Despite an adverse impact on survival and quality of life, several patients who suffered stroke still received a heart transplant. Furthermore, none of our patients had recurrence of a neurological event. Strict implementation of anticoagulation protocols is likely the mainstay of preventing this devastating complication.

Incidence, characteristics and outcomes in patients with embolic stroke of undetermined source: A population-based study.

Embolic stroke of undetermined source (ESUS) represents a subgroup of cryptogenic ischemic stroke (CS) distinguished by high probability of an underlying embolic mechanism. There are scarce population-based data regarding the incidence, characteristics and outcomes of ESUS. Consecutive patients included with first-ever ischemic stroke of undetermined cause in the previously published population-based Evros Stroke Registry were further subdivided into ESUS and non-ESUS CS. Crude and adjusted [according to the European Standard Population (ESP), WHO and Segi population] incidence rates (IR) for ESUS and non-ESUS CS were calculated. Baseline characteristics, admission stroke severity (assessed using NIHSS-score), stroke recurrence and functional outcomes [determined by modified Rankin Scale (mRS) scores], were recorded during the 1-year follow-up period. We identified 21 and 242 cases with ESUS (8% of CS) and non-ESUS CS. The crude and ESP-adjusted IR for ESUS were 17.5 (95%CI: 10-25) and 16.6 (95%CI: 10-24) per 100,000 person-years. Patients with ESUS were younger (p < .001) and had lower median admission NIHSS-scores (p < .001). Functional outcomes were more favorable in ESUS at 28, 90 and 365 days. ESUS was independently (p = .033) associated with lower admission NIHSS-scores (unstandardized linear regression coefficient: -13.34;95%CI: -23.34, -3.35) on multiple linear regression models. ESUS was not related to 1-year stroke recurrence, mortality and functional improvement on multivariable analyses. In conclusion we found that ESUS cases represented 8% of CS patients in this population-based study. Despite the fact that ESUS was independently related to lower admission stroke severity, there was no association of ESUS with long-term outcomes.

Paraneoplastic autoimmunity and small-cell lung cancer: Neurological and serological accompaniments.

Paraneoplastic neurological autoimmunity is often associated with small-cell lung cancer (SCLC), a highly malignant neuroendocrine tumor. Paraneoplastic autoimmunity often correlates with longer survival. We describe the paraneoplastic neurological manifestations of patients with SCLC with and without SCLC-predictive autoantibodies and the correlation between autoimmunity and survival. We reviewed the records of 116 patients (51% male) from the Mayo Clinic with histopathologically confirmed SCLC for whom stored serum was available for neural autoantibody testing. Cancer was limited stage in 41%; the median age at diagnosis was 64 years. Paraneoplastic neurological manifestations were recorded in 61% (decreasing frequency: peripheral neuropathy, dysautonomia, cognitive decline, cerebellar ataxia, neuromuscular junction disorder, seizures, cranial neuropathy, movement disorder, brainstem disorder, or myelopathy). Neural autoantibodies, some with pathogenic potential, were detected in the sera of SCLC patients with and without neurological autoimmunity. The most frequent among patients with neurological manifestations were: anti-neuronal nuclear antibody-type 1, voltage-gated calcium channel (VGCC)-N-type, VGCC-P/Q-type, glutamic acid decarboxylase 65 (GAD65), SOX1, and muscle acetylcholine receptor (AChR); while the most common in patients without neurological manifestations were: GAD65, muscle-AChR, and VGCC-P/Q-type. Neither cancer stage at diagnosis nor survival correlated with neurological manifestations or autoantibody-positivity, except for shorter survival in patients with myelopathy. The only predictor of longer survival was limited-stage disease at diagnosis.

Stroke recurrence and mortality in northeastern Greece: the Evros Stroke Registry.

Up to date there is no population-based study from Greece providing long-term data on incidence of both all-cause mortality and stroke recurrence for patients with first ever stroke (FES). Adult patients with FES were registered during a 24-month period (2010-2012) and followed-up for 12 months. We calculated cumulative incidences of stroke mortality and recurrence. Univariable and multivariable Cox proportional hazards regression analyses were used to identify independent determinants of 1-year mortality and 1-year stroke recurrence. We prospectively documented 703 first ever stroke cases (mean age 75 ± 12 years; 52.8% males; ischemic stroke 80.8%, intracerebral hemorrhage 11.8%, subarachnoid hemorrhage 4.4%, undefined 3.0%) with a total follow-up time of 119,805 person-years. The cumulative incidence rates of mortality of all FES patients at 28 days, 3 months and 1 year were 21.3% (95% CI 18.5-24.5%), 26% (95% CI 22.9-29.4%) and 34.7% (95% CI 31.3-38.3%), respectively. The risk of 1-year mortality was independently (p < 0.05) associated with advancing age, history of hypertension, increased stroke severity on admission, and hemorrhagic FES type. Cumulative 1-year stroke mortality differed according to both index FES type (ischemic vs. hemorrhage; p < 0.001), but also across different ischemic stroke subtypes (p = 0.025). The cumulative incidence rates of recurrent stroke at 28 days, 3 months and 1 year were 2.0% (95% CI 1.2-3.6%), 4.2% (2.8-6.2%) and 6.7% (5.1-8.8%), respectively. Comparable to other population-based surveys, our study reports 1-year mortality and stroke recurrence rates in patients with FES. These findings highlight the need for effective secondary prevention strategies in a border region of southeastern Europe, which exhibits very high FES incidence rates.

Stroke Incidence and Outcomes in Northeastern Greece: The Evros Stroke Registry.

BACKGROUND AND PURPOSE: Data are scarce on both stroke incidence rates and outcomes in Greece and in rural areas in particular. We performed a prospective population-based study evaluating the incidence of first-ever stroke in the Evros prefecture, a region of a total 147 947 residents located in North Eastern Greece. METHODS: Adult patients with first-ever stroke were registered during a 24-month period (2010-2012) and followed up for 12 months. To compare our stroke incidence with that observed in other studies, we standardized our incidence rate data according to the European Standard Population, World Health Organization, and Segi population. We also applied criteria of data quality proposed by the Monitoring Trends and Determinants in Cardiovascular Disease project. Stroke diagnosis and classification were performed using World Health Organization criteria on the basis of neuroimaging and autopsy data. RESULTS: We prospectively documented 703 stroke cases (mean age: 75±12 years; 52.8% men; ischemic stroke: 80.8%; intracerebral hemorrhage: 11.8%; subarachnoid hemorrhage: 4.4%; undefined: 3.0%) with a total follow-up time of 119 805 person-years. The unadjusted and European Standard Population-adjusted incidences of all strokes were 586.8 (95% confidence interval [CI], 543.4-630.2) and 534.1 (95% CI, 494.6-573.6) per 100 000 person-years, respectively. The unadjusted incidence rates for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage were 474.1 (95% CI, 435-513), 69.3 (95% CI, 54-84), and 25.9 (95% CI, 17-35) per 100 000 person-years, respectively. The corresponding European Standard Population-adjusted incidence rates per 100 000 person-years were 425.9 (95% CI, 390.9-460.9), 63.3 (95% CI, 49.7-76.9), and 25.8 (95% CI, 16.7-34.9) for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, respectively. The overall 28-day case fatality rate was 21.3% (95% CI, 18.3%-24.4%) for all strokes and was higher in hemorrhagic strokes than ischemic stroke (40.4%, 95% CI, 31.3%-49.4% versus 16.2%, 95% CI, 13.2%-19.2%). CONCLUSIONS: This is the largest to date population-based study in Greece documenting one of the highest stroke incidences ever reported in South Europe, highlighting the need for efficient stroke prevention and treatment strategies in Northeastern Greece.

Therapeutic Monoclonal Antibodies and Multiple Sclerosis: The Essentials.

BACKGROUND: Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases. Two monoclonal antibodies are available for treatment and other antibodies are currently being tested in multiple sclerosis (MS) patients. OBJECTIVES: The purpose of the present review paper is to outline the antibody engineering technologies, the immunologic and pharmacologic concepts of mbs and the current status of treatment in MS with emphasis on clinical efficacy and safety. METHOD: We conducted a through review of the scientific literature published until 31 December 2014 (print and electronic publications) concerning the production, applications and side effects of the use of Mabs. Sixty five articles were used in total (both original research and review papers). CONCLUSION: With the introduction of mAbs the treatment of MS has entered a new era, both with respect to efficacy and target specificity. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness, infection and other autoimmune diseases. In addition, unexpected consequences arise from our incomplete knowledge of the immune system. For example, natalizumab, a monoclonal antibody targeting α4-integrin on leukocytes increases the risk of developing progressive multifocal leukoencephalopathy, without causing notable immunosuppression. Further study on the use of mabs is required, both in vitro and in the clinical field, in order to increase our knowledge upon these new revolutionary therapeutic agents.

Association of SCN1A gene polymorphism with antiepileptic drug responsiveness in the population of Thrace, Greece.

INTRODUCTION: The aim was to examine the influence of the SCN1A gene polymorphism IVS5-91 rs3812718 G>A on the response to antiepileptic drugs (AEDs) in monotherapy or polytherapy. MATERIAL AND METHODS: Two hundred epilepsy patients and 200 healthy subjects were genotyped for SCN1A IVS5-91 rs3812718 G>A polymorphism using TaqMan assay. Patients were divided into drug-responsive and drug-resistant patients. The drug-responsive group was further studied, comparing monotherapy in maximum and minimum doses and monotherapy-responsive and -resistant groups. RESULTS: There were no statistically significant differences in the allelic frequencies and genotype distributions between patients and controls (p = 0.178). The distribution of SCN1A IVS5-91 rs3812718 G>A genotypes was similar between drug-responsive and drug-resistant patients (p = 0.463). The differences in genotype distributions (A/A or A/G vs. G/G) between monotherapy-responsive and -resistant groups were statistically significant (p = 0.021). Within the monotherapy-responsive group, patients with the A/A or A/G genotype needed higher dose AEDs than patients with the G/G genotype (p = 0.032). The relative risk for generalized epilepsy due to A-containing genotypes was of marginal statistical significance when compared with the G/G genotype (p = 0.05). CONCLUSIONS: Overall, our findings demonstrate an association of SCN1A IVS5-91 rs3812718 G>A polymorphism with AED responsiveness in monotherapy without evidence of an effect on drug-resistant epilepsy.

The Efficacy of Natalizumab versus Fingolimod for Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review, Indirect Evidence from Randomized Placebo-Controlled Trials and Meta-Analysis of Observational Head-to-Head Trials.

BACKGROUND: Although Fingolimod (FGD) and Natalizumab (NTZ) appear to be effective in relapsing-remitting multiple sclerosis (RRMS), they have never been directly compared in a randomized clinical trial (RCT). METHODS AND FINDINGS: We evaluated the comparative efficacy of FGD vs. NTZ using a meta-analytical approach. Data from placebo-controlled RCTs was used for indirect comparisons and observational data was utilized for head-to-head comparisons. We identified 3 RCTs (2498 patients) and 5 observational studies (2576 patients). NTZ was associated with a greater reduction in the 2-year annualized relapse rate (ARR; SMDindirect = -0.24;95% CI: from -0.44 to -0.04; p = 0.005) and with the probability of no disease activity at 2 years (ORindirect:1.82, 95% CI: from 1.05 to 3.15) compared to FGD, while no differences between the two therapies were found in the proportion of patients who remained relapse-free (ORindirect = 1.20;95% CI: from 0.84 to 1.71) and those with disability progression (ORindirect = 0.76;95% CI: from 0.48 to 1.21) at 2 years. In the analysis of observational data, we found no significant differences between NTZ and FGD in the 2-year ARR (SMD = -0.05; 95% CI: from -0.26 to 0.16), and 2-year disability progression (OR:1.08;95% CI: from 0.77 to 1.52). However, NTZ-treated patients were more likely to remain relapse-free at 2-years compared to FGD (OR: 2.19;95% CI: from 1.15 to 4.18; p = z0.020). CONCLUSIONS: Indirect analyses of RCT data and head-to-head comparisons of observational findings indicate that NTZ may be more effective than FGD in terms of disease activity reduction in patients with RRMS. However, head-to-head RCTs are required to independently confirm this preliminary observation.

The Effect of Disease Modifying Therapies on Disease Progression in Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis.

IMPORTANCE: A number of officially approved disease-modifying drugs (DMD) are currently available for the early intervention in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to systematically evaluate the effect of DMDs on disability progression in RRMS. METHODS: We performed a systematic review on MEDLINE and SCOPUS databases to include all available placebo-controlled randomized clinical trials (RCTs) of RRMS patients that reported absolute numbers or percentages of disability progression during each study period. Observational studies, case series, case reports, RCTs without placebo subgroups and studies reporting the use of RRMS therapies that are not still officially approved were excluded. Risk ratios (RRs) were calculated in each study protocol to express the comparison of disability progression in RRMS patients treated with a DMD and those RRMS patients receiving placebo. The mixed-effects model was used to calculate both the pooled point estimate in each subgroup and the overall estimates. RESULTS: DMDs for RRMS were found to have a significantly lower risk of disability progression compared to placebo (RR = 0.72, 95%CI: 0.66-0.79; p<0.001), with no evidence of heterogeneity or publication bias. In subsequent subgroup analyses, neither dichotomization of DMDs as "first" and "second" line RRMS therapies [(RR = 0.72, 95% CI = 0.65-0.80) vs. (RR = 0.72, 95% = 0.57-0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64-0.87) vs. RR = 0.74 (95% CI = 0.66-0.83); p = 0.92] had a differential effect on the risk of disability progression. Either considerable (5-20%) or significant (>20%) rates of loss to follow-up were reported in many study protocols, while financial and/or other support from pharmaceutical industries with a clear conflict of interest on the study outcomes was documented in all included studies. CONCLUSIONS: Available DMD are effective in reducing disability progression in patients with RRMS, independently of the route of administration and their classification as "first" or "second" line therapies. Attrition bias needs to be taken into account in the interpretation of these findings.

The effect of disease-modifying therapies on brain atrophy in patients with clinically isolated syndrome: a systematic review and meta-analysis.

OBJECTIVES: Brain atrophy is associated with cognitive deficits in patients with clinically isolated syndrome (CIS) and can predict conversion to clinical definite multiple sclerosis. The aim of the present meta-analysis was to evaluate the effect of disease-modifying drugs (DMDs) on brain atrophy in patients with CIS. METHODS: Eligible placebo-control randomized clinical trials of patients with CIS that had reported changes in brain volume during the study period were identified by searching the MEDLINE, SCOPUS, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. This meta-analysis adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses. RESULTS: Three eligible studies were identified, comprising 1362 patients. The mean percentage change in brain volume was found to be significantly lower in DMD-treated patients versus placebo-treated subgroups (standardized mean difference [SMD]: = -0.13, 95% confidence interval [CI]: -0.25, 0.01; p = 0.04). In the subgroup analysis of the two studies that provided data on brain-volume changes for the first (0-12 months) and second (13-24 months) year of treatment, DMD attenuated brain-volume loss in comparison with placebo during the second year (SMD = -0.25; 95% CI: -0.43, -0.07; p < 0.001), but not during the first year of treatment (SMD = -0.01; 95% CI: -0.27, 0.24; p = 0.93). No evidence of heterogeneity was found between estimates, while funnel-plot inspection revealed no evidence of publication bias. CONCLUSIONS: DMDs appear to attenuate brain atrophy over time in patients with CIS. The effect of DMDs on brain-volume loss is evident after the first year of treatment.