The impact of genetic factors on the response to migraine therapy.

Migraine is a multidimensional disease affecting a large portion of the human population presenting with a variety of symptoms. In the era of personalized medicine, successful migraine treatment presents a challenge, as several studies have shown the impact of a patient's genetic profile on therapy response. However, with the emergence of contemporary treatment options, there is promise for improved outcomes. A literature search was conducted in PubMed and Scopus, in order to obtain studies investigating the impact of genetic factors on migraine therapy outcome. Overall, 23 studies were included in the current review, exhibiting diversity in the treatments used and the genetic variants investigated. Divergent genes were assessed for each category of migraine treatment. Several genetic factors were identified to contribute to the heterogeneous response to treatment. SNPs related to pharmacodynamic receptors, pharmacogenetics and migraine susceptibility loci were the most investigated variants, revealing some interesting significant results. To date, various associations have been recorded correlating the impact of genetic factors on migraine treatment responses. More extensive research needs to take place with the aim of shedding light on the labyrinthine effects of genetic variations on migraine treatment, and, consequently, these findings can promptly affect migraine treatment and improve migraine patients' life quality in the vision of precise medicine.

Pesticides and tremor: An overview of association, mechanisms and confounders.

Pesticides are a heterogeneous class of chemicals mainly used for the protection of crops from pests. Because of their very widespread use, acute or/and chronic exposure to these chemicals can lead to a plethora of sequelae inflicting diseases, many of which involve the nervous system. Tremor has been associated with pesticide exposure in human and animal studies. This review is aimed at assessing the studies currently available on the association between the various types of pesticides/insecticides and tremor, while also accounting for potential confounding factors. To our knowledge, this is the first coherent review on the subject. After appraising the available evidence, we call for more intensive research on this topic, as well as intonate the need of implementing future preventive measures to protect the exposed populations and to reduce potential disabilities and social drawbacks.

Migraine in transient global amnesia: a meta-analysis of observational studies.

BACKGROUND: PURPOSE: Although many studies have investigated the relationship between transient global amnesia (TGA) and migraine, to date, no meta-analysis has confirmed the existence and size of their association. METHODOLOGY: Literature search involved MEDLINE, EMBASE, CENTRAL and PsycINFO. Observational controlled studies including TGA patients (Caplan, Hodges and Warlow) were retrieved. Quality evaluation was based on the Newcastle-Ottawa scale. The prevalence of migraine was compared in TGA patients vs. healthy controls (HC), as well as in TGA against TIA individuals. Data from case-control, cross-sectional and cohort studies were pooled separately. RESULTS: Literature search yielded 1178 articles, 12 of which were included in the present meta-analysis. Results from case-control (ten), cohort (one) and cross-sectional (one) studies were compatible with an association between TGA and migraine. The nationwide inpatient cross-sectional study was of lesser value due to its inpatient orientation. The high-quality, population-based, retrospective cohort (158,301 participants per group) determined a higher relative-risk (RR) of TGA for migraine vs. non-migraine individuals [RR = 2.48, 95%confidence-interval (95% CI) = (1.32, 4.87)]. Sensitivity testing based on stricter diagnostic criteria strengthened the estimated association [RR = 3.84, 95% CI = (1.57, 9.38)]. Additionally, pooled data from eight case-control studies (700 TGA, 746 HC) yielded similar results [Odds-Ratio, OR = 2.51, 95% CI = (1.85, 3.41)], with the association mainly driven by the three high-quality studies, rather than the five articles of moderate quality. Finally, pooled findings from four case-control studies of moderate-quality revealed a higher prevalence of migraine among TGA compared to TIA patients [OR = 1.82, 95% CI = (1.22, 2.73)]. CONCLUSIONS: A significant association between TGA and migraine was established. The underlying connecting mechanism remains undetermined, yet.

Factors associated with recurrent transient global amnesia: systematic review and pathophysiological insights.

The examination of the risk factors that affect the recurrence of transient global amnesia (TGA) may shed light on the pathophysiological substrate of the disease. A systematic review was performed to identify the factors associated with the recurrence of TGA. MEDLINE, EMBASE, CENTRAL and PsycINFO were meticulously searched. Observational controlled studies involving patients with single (s-TGA) and recurrent TGA (r-TGA) according to Hodges and Warlow's criteria were retrieved. Differences in the demographic characteristics, personal and family medical history, previous exposure to precipitating events and laboratory findings were examined. Retrieved evidence was assessed in the context of the individual article validity, based on the numerical power and methodological quality of each study. Nine cohort studies with retrospective, prospective or mixed design were retrieved. In total, 1989 patients with TGA were included, 269 of whom suffered from r-TGA (13.5%). R-TGA presented an earlier age of onset. Evidence was suggestive of a relationship between recurrence and a family or personal history of migraine, as well as a personal history of depression. There was weaker evidence that associated recurrence with a positive family history of dementia, a personal history of head injury and hippocampal lesions in diffusion-weighted MRI. On the other hand, no connection was found between recurrence and electroencephalographic abnormalities, impaired jugular venous drainage, cardiovascular risk factors, atrial fibrillation, previous cerebrovascular events, exposure to precipitating events, a positive family history of TGA and hypothyroidism. Important pathophysiological insights that arised from these findings were discussed.

Conventional cardiovascular risk factors in Transient Global Amnesia: Systematic review and proposition of a novel hypothesis.

Transient Global Amnesia (TGA) is an enigmatic amnestic syndrome. We conducted a systematic review to investigate the relationship between the conventional cardiovascular risk factors and TGA. MEDLINE, CENTRAL, EMBASE and PsycINFO were comprehensively searched and 23 controlled observational studies were retrieved. The prevalence of hypertension, diabetes mellitus, dyslipidemia and smoking was lower among patients with TGA compared to Transient Ischemic Attack. Regarding the comparison of TGA with healthy individuals, there was strong evidence suggesting a protective effect of diabetes mellitus on TGA and weaker evidence for a protective effect of smoking. Hypertension was associated with TGA only in more severe stages, while dyslipidemia was not related. In view of these findings, a novel pathophysiological hypothesis is proposed, in which the functional interactions of Angiotensin-II type-1 and N-methyl-D-aspartate receptors are of pivotal importance. The whole body of clinical evidence (nature of precipitating events, associations with migraine, gender-based association patterns) was integrated.

The long-term prognosis of Transient Global Amnesia: a systematic review.

Transient Global Amnesia (TGA) constitutes an enigmatic amnestic condition. In view of the admittedly limited knowledge regarding the nature of TGA, we decided to systematically review existing evidence for the generally regarded benign course of the disease. MEDLINE, EMBASE, CENTRAL and PsycINFO were searched for relevant articles. Observational (case-control, cross-sectional and cohort) controlled studies were retrieved. TGA diagnosis was made according to the diagnostic criteria of Caplan, validated by Hodges and Warlow. The TGA group was compared with either healthy controls (HC) or/and individuals with transient ischaemic attacks (TIA). The long-term risks of dementia, epilepsy, psychological-emotional disturbances, as well as long-term vascular and (vascular or nonvascular) mortality risks, were evaluated. Quality assessment was based on the Newcastle-Ottawa Scale. Literature search provided 12 eligible articles. Retrospective, prospective or mixed cohort designs were implemented in every study. Five articles registered a high quality, five registered a moderate quality, while two articles were assessed as part of the grey literature (conference abstract, abstract in English-article in Spanish). Overall, retrieved evidence was suggestive of similar vascular and mortality risks in TGA patients and HC, while TIA individuals exhibited elevated risks. Moreover, psychological disturbances were comparable between TGA and healthy individuals. On the other hand, studies for dementia and epilepsy obtained contradictory results, indicating both a similar and an increased risk in the TGA group compared to the HC group. Therefore, additional high-quality studies are warranted for the acquisition of more determining conclusions regarding the long-term risk of dementia and epilepsy in TGA.

Serum lipid abnormalities in migraine: A meta-analysis of observational studies.

BACKGROUND: The association of migraine with vascular comorbidities is long-established. The contribution of the "traditional" cardiovascular risk factors to this connection remains unclear. OBJECTIVE: To determine-quantify the differences in the serum lipid concentrations between lipid-lowering agents-naïve individuals with migraine and healthy controls (HC). METHODS: The study protocol was not preregistered with an online systematic review-protocol registry. A literature search involving MEDLINE, EMBASE, CENTRAL, Google Scholar, and the OpenGrey database was performed. Case-control, cross-sectional, or cohort studies involving HC and participants with migraine (with and without aura regardless of the use of prophylactic treatment) that quantitatively assessed serum low-density lipoprotein cholesterol (LDL-C) (primary index) and/or total cholesterol (TC) and/or high-density lipoprotein cholesterol (HDL-C) and/or triglycerides (TG) (secondary indices) were retrieved. Articles including participants with known dyslipidemia (or under lipid-lowering medications) or with secondary causes of dyslipidemia (aside from the subjectively assessed lifestyle parameters) were excluded. Studies with abstracts and full texts not published in English and articles reporting the implementation of other study designs (reviews, meta-analyses, commentaries, case reports, etc.) were excluded as well. Conference abstracts and English abstracts from studies with full texts not published in English were evaluated as part of the gray literature. Each step of the review process was performed by two investigators independently, and relevant data were abstracted based on standardized extraction forms. Any discrepancies were resolved by a third investigator. RESULTS: Seventeen studies (16 case-control and 1 cross-sectional) fulfilled the eligibility criteria. Retrieved articles involved adult participants, principally during the fourth decade of life. Results were compatible with higher LDL-C levels in migraine individuals (1370) than in HC (1215) [12 studies, mean difference (MD) = 10.4 mg/dl, 95% confidence interval (CI) = (1.6, 19.2)]. Similarly, higher TC levels were determined in migraine patients [14 studies, migraine = 1325, HC = 1213, MD = 10.6 mg/dl, 95% CI = (1.8, 19.3)], as were TG levels [15 studies, migraine = 1526, HC = 1262, MD = 11.8 mg/dl, 95% CI = (3.6, 20.0)]. HDL-C concentrations were not different between the two groups [14 studies, migraine = 1488, HC = 1328, MD = -0.4 mg/dl, 95% CI = (-2.2, 1.5)]. Prespecified sensitivity analysis following the exclusion of studies not presenting comparable body mass index values between the groups nullified the significant difference regarding LDL-C levels [MD = 5.3 mg/dl, 95% CI = (-0.1, 10.8)]. Subgroup analyses as well as the direct comparison of migraine with aura and migraine without aura individuals were compatible with no difference regarding lipid concentrations, but only a small fraction of the retrieved studies presented relevant figures. CONCLUSIONS: Although our results are of limited generalizability, since most retrieved studies were performed in Turkey (nine studies), TC abnormalities may provide part of the explanation for the unfavorable cardiovascular profile of migraine patients. Lifestyle may be partly or entirely accountable for the determined increased serum TC. Additional studies that will completely address the effect that lifestyle parameters exert on lipid concentrations are required to better capture existing abnormalities.

Recurrent episodes of syncope requiring pacemaker implantation as an initial presentation of neuromyelitis optica spectrum disorder.

Neuromyelitis Optica Spectrum Disorders (NMOSD) can manifest with a variety of heterogeneous symptoms, mainly encompassing optic neuritis, acute myelitis and area postrema syndrome (hiccups, nausea, and vomiting). Syncopal episodes have rarely been described as an initial manifestation of NMOSD. Here, we report a case of a 42-year-old male who was diagnosed with NMOSD after initially presenting with intractable hiccups and recurrent episodes of syncope. This report is of particular interest, as it suggests that NMOSD should be included in the differential diagnosis of patients with intractable hiccups and heart rhythm disorders.

Genetic Risk Factors for Essential Tremor: A Review.

Highlights: In the current review, we thoroughly reviewed 74 identified articles regarding genes and genetic loci that confer susceptibility to ET. Over 50 genes/genetic loci have been examined for possible association with ET, but consistent results failed to be reported raising the need for collaborative multiethnic studies. Background: Essential tremor (ET) is a common movement disorder, which is mainly characterized by bilateral tremor (postural and/or kinetic) in the upper limbs, with other parts of the body possibly involved. While the pathophysiology of ET is still unclear, there is accumulating evidence indicating that genetic variability may be heavily involved in ET pathogenesis. This review focuses on the role of genetic risk factors in ET susceptibility. Methods: The PubMed database was searched for articles written in English, for studies with humans with ET, controls without ET, and genetic variants. The terms "essential tremor" and "polymorphism" (as free words) were used during search. We also performed meta-analyses for the most examined genetic variants. Results: Seventy four articles concerning LINGO1, LINGO2, LINGO4, SLC1A2, STK32B, PPARGC1A, CTNNA3, DRD3, ALAD, VDR, HMOX1, HMOX2, LRRK1,LRRK2, GBA, SNCA, MAPT, FUS, CYPsIL17A, IL1B, NOS1, ADH1B, TREM2, RIT2, HNMT, MTHFR, PPP2R2B, GSTP1, PON1, GABA receptors and GABA transporter, HS1BP3, ADH2, hSKCa3 and CACNL1A4 genes, and ETM genetic loci were included in the current review. Results from meta-analyses revealed a marginal association for the STK32B rs10937625 and a marginal trend for association (in sensitivity analysis) for the LINGO1 rs9652490, with ET. Discussion: Quite a few variants have been examined for their possible association with ET. LINGO1 rs9652490 and STK32B rs10937625 appear to influence, to some extent, ET susceptibility. However, the conflicting results and the lack of replication for many candidate genes raise the need for collaborative multiethnic studies.

SLC2A3 rs12842 polymorphism and risk for Alzheimer's disease.

BACKGROUND: Many studies support the hypothesis that brain glucose dysregulation contributes to neurodegeneration and disease progression. The SLC2A3 gene encodes the Neuronal Glucose Transporter 3 (GLUT3), a critical molecule for glucose transport into the neuron. The GLUT3 rs12842 polymorphism has been associated with an increased risk for attention-deficit/hyperactivity disorder (ADHD). Epidemiological and genetic studies have reported a link between antecedent ADHD and Alzheimer's disease (AD), as both share a dysregulation of brain glucose. AIM: This study aimed to explore the possible correlation of the SLC2A3 rs12842 polymorphism with susceptibility towards AD. METHODS: We genotyped 327 patients with AD and 327 controls for the GLUT3 rs12842. Results: Rs12842 was associated with a decreased risk of developing AD in the co-dominant [Odds Ratio (OR) (95% confidence interval (CI) = 0.67 (0.45-0.99)), p = 0.039], dominant [OR (95% CI) = 0.64 (0.44-0.93), p = 0.019] and log-additive modes [OR (95% CI) = 0.65 (0.46-0.91), p = 0.012]. CONCLUSIONS: Our results suggest a significant, inverse association between SLC2A3 rs12842 and the risk of AD.

Serum Homocysteine, Pyridoxine, Folate, and Vitamin B12 Levels in Migraine: Systematic Review and Meta-Analysis.

BACKGROUND: Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies. OBJECTIVE: The present study aims to review and meta-analyze data from studies investigating the difference of serum Hcy and Hcy lowering vitamins between migraine patients and healthy controls (HC), as well as between patients with MA and migraine without aura (MO). METHODS: Literature search involved MEDLINE, Embase, CENTRAL, Google Scholar, and trial registries. The Newcastle-Ottawa Scale was used to evaluate the quality of the retrieved studies. Standardized mean differences (SMDs) and 95% confidence intervals (95%CIs) were calculated. Funnel-plots were utilized for the evaluation of publication bias. RESULTS: Overall, 29 (28 case-control and 1 cross-sectional) studies were retrieved. Meta-analysis was indicative of higher Hcy concentration in migraine patients vs HC overall [adults and children: 16 studies, I2  = 81%, SMD = 0.41, 95%CI = (0.20, 0.61)]. Hcy was consistently elevated in adults with migraine [adults: 12 studies, I2  = 76%, SMD = 0.35, 95%CI = (0.15, 0.54); children: 1 study, SMD = 0.37, 95%CI = (-0.05, 0.79)]. Subgroup analyses reproduced the results for both adults with MA [7 studies, I2  = 83%, SMD = 0.37, 95%CI = (0.03, 0.71)] and MO [5 studies, I2  = 84%, SMD = 0.46, 95%CI = (0.03, 0.89)]. Figures for serum folate were lower in the overall comparison of migraine patients with HC [adults and children: 11 studies, I2  = 87%, SMD = -0.36, 95%CI = (-0.68, -0.05); adults: 8 studies, I2  = 6%, SMD = -0.11, 95%CI = (-0.22, 0.01); children: 1 study, SMD = -0.71, 95%CI = (-1.14, -0.29); MA adults: 4 studies, I2  = 44%, SMD = -0.16, 95%CI = (-0.35, 0.04); MO adults: 4 studies, I2  = 47%, SMD = -0.17, 95%CI = (-0.44, 0.10)]. Serum vitamin B12 levels were not different between migraine patients and HC [adults and children: 11 studies, I2  = 88%, SMD = -0.24, 95%CI = (-0.57, 0.09); adults: 8 studies, I2  = 57%, SMD = -0.10, 95%CI = (-0.28, 0.08); children: 1 study, SMD = 0.29, 95%CI = (-0.13, 0.71); MA adults: 4 studies, I2  = 63%, SMD = -0.14, 95%CI = (-0.48, 0.20); MO adults: 4 studies, I2  = 59%, SMD = -0.15, 95%CI = (-0.45, 0.15)]. Serum Hcy was lower in MO than MA [adults and children: 10 studies, I2  = 39%, SMD = 0.30, 95%CI = (0.14, 0.46), adults: 6 studies, I2  = 29%, SMD = 0.21, 95%CI = (0.09, 0.36), children: 1 study, SMD = 0.51, 95%CI = (0.22, 0.80)]. Serum folate and vitamin B12 did not differ between MA and MO. CONCLUSIONS: Our results suggest that there is a possible link between migraine, mainly MA, and elevated serum Hcy.

Pyridoxine, folate and cobalamin for migraine: A systematic review.

There is a possible relationship between migraine and hypercoagulability inducing factors, such as hyperhomocysteinemia. In this context, homocysteine (Hcy)-lowering vitamins (B6-folate-B12) may prove beneficial in the management-prophylaxis of migraine. We performed a systematic literature search in order to retrieve studies assessing the supplementation of B6, folate and B12 (alone or as adjunctive therapies) to migraine patients, as well as patients suffering from other primary headache disorders. MEDLINE, EMBASE, CENTRAL, Google Scholar, trial registries and OpenGrey were searched. Twelve relevant articles were retrieved. The management of acute migraine attacks with Hcy-lowering vitamins has not provided promising results (one randomized controlled trial-RCT-and one prospective uncontrolled trial). On the contrary, significant benefits were registered for the use of B6 alone, in combination with folate and in combination with folate and B12 in the prophylaxis of migraine with aura (MA) in adults compared to placebo (five RCTs, only one did not obtain significant results). Folate supplementation alone was not more efficacious than placebo (one RCT). Limited data for the prophylaxis of migraine without aura (MO) in children (two prospective uncontrolled trials) and adults (two prospective uncontrolled trials involving both MA and MO participants) impede the extraction of safe conclusions. An overall attractive safety profile was exhibited with gastrointestinal adverse events being the most common. Overall, a potential beneficial effect regarding the administration of B6, folate and/or B12 in the prophylaxis of MA in adults was indicated. Additional high-quality RCTs that will investigate MO in adults as well as MO and MA in children are warranted.

Body mass index and survival from amyotrophic lateral sclerosis: A meta-analysis.

BACKGROUND: Several studies have examined the relationship between body mass index (BMI) and survival from amyotrophic lateral sclerosis (ALS). Many indicate that low BMI at diagnosis or during follow-up may be associated with accelerated progression and shortened survival. This study systematically evaluated the relationship between BMI and survival in patients with ALS. METHODS: The PubMed database was searched to identify all available studies reporting time-to-event data. Eight studies with 6,098 patients fulfilled the eligibility criteria. BMI was considered a continuous and ordered variable. Interstudy heterogeneity was assessed by the Cochran Q test and quantified by the I2 metric. Fixed- or random-effects odds ratios summarized pooled effects after taking interstudy variability into account. Significance was set at p < 0.05. RESULTS: The ALS survival hazard ratio (HR) decreased approximately by 3% (95% confidence interval [CI]: 2%-5%) for each additional BMI unit when BMI was considered a continuous variable. When BMI was considered a categorical variable, the HRs for "normal" BMI vs "overweight" BMI and "obese" BMI were estimated to be as high as 0.91 (95% CI: 0.79-1.04) and 0.78 (95% CI: 0.60-1.01), respectively. The HR for the comparison of the "normal" BMI vs "underweight" BMI was estimated to be as high as 1.94 (95% CI: 1.42-2.65). CONCLUSIONS: BMI is significantly and inversely associated with ALS survival.

H. pylori and Parkinson's disease: Meta-analyses including clinical severity.

The exact etiology of Parkinson's disease (PD) remains unclear. Some evidence supports Helicobacter pylori infection as a trigger or driving event, but detection and eradication of H. pylori are not part of PD management. The aims of this case-control study and meta-analysis were to determine (i) the prevalence of H. pylori infection in PD patients, (ii) associations between H. pylori infection and clinical status, and (iii) differences in motor status in PD patients before and after H. pylori eradication. A literature search was performed using the PubMed database. The prevalence of H. pylori infection in PD, its association with the unified Parkinson's disease rating scale (UPDRS), and the association of H. pylori eradication therapy with the UPDRS-III score were determined by calculating the odds ratios (OR) and the standardized mean differences (SMD) with 95% confidence intervals (CI). Fixed- and random-effects models were applied. Ten studies were included in the first meta-analysis (5043 PD patients, 23,449 HCs); H. pylori infection prevalence was higher in PD patients than in HCs [OR (95% CI): 1.47 (1.27, 1.70), Pz<0.00001]. In seven studies reporting UPDRS scores (150 H. pylori infected, 228 non-infected PD patients), there was a significant association between H. pylori infection and mean UPDRS scores [SMD (95% CI): 0.33 (0.12, 0.54), Pz = 0.003]. Regarding H. pylori eradication, in five studies (90 PD patients), there was a significant reduction in UPDRS-III scores after treatment [SMD (95% CI): 6.83 (2.29, 11.38), Pz = 0.003]. In conclusion, the present meta-analysis revealed a higher prevalence of H. pylori infection in PD patients suggesting that H. pylori may contribute to PD pathophysiology. In addition, the significantly lower UPDRS scores in non-infected PD patients and in patients after H. pylori eradication therapy demonstrate that the infection may deteriorate the clinical severity of the disease.

Vitamin B12, folate, and homocysteine levels and multiple sclerosis: A meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating and disabling inflammatory disease of the central nervous system. Several factors contribute to MS pathogenesis including genetic-environmental interactions. Case-control studies suggest that there might be associations between MS and homocysteine (Hcy), vitamin B12, and folate blood levels. AIM: To meta-analyze all available data describing associations between MS and serum or plasma Hcy, vitamin B12, and folate levels. METHODS: The PubMed, MEDLINE, and EMBASE databases were searched for eligible case-control studies published until June 2017. After data extraction, separate analyses using mainly random-effects models were conducted to test for associations between MS and vitamin B12, Hcy, or folate blood levels. RESULTS: Twelve, 12, and 9 studies met the inclusion criteria for meta-analysis of MS and Hcy, vitamin B12, and folate levels, respectively. The standardized mean difference (SMD) between MS patients and controls was statistically significant for Hcy (SMD: 0.70, 95% CI: 0.06, 1.34). Stratification according to clinical pattern did not reveal significant differences between relapsing-remitting MS patients and controls (SMD: 0.30, 95% CI: -0.93, 1.54) or between secondary progressive MS patients and controls (SMD: 0.12, 95% CI: -1.65, 1.90). There were no significant differences in SMD between MS patients and healthy individuals for vitamin B12 (SMD: -0.09, 95% CI: -0.29, 0.10) or folate (SMD: -0.06, 95% CI: -0.17, 0.05). CONCLUSION: MS patients tend to have elevated Hcy blood levels compared to healthy controls. Hcy may contribute to the pathogenesis of the disease.