Lack of Association between Common LAG3/CD4 Variants and Risk of Migraine.

Several papers have been published suggesting a probable role of inflammatory factors in the etiopathogenesis of migraine. In this study, we investigated the possible association between common variants in the LAG3/CD4 genes (both genes, which are closely related, encode proteins involved in inflammatory and autoimmune responses) in the risk of migraine in a cohort of Caucasian Spanish participants. For this purpose, the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants, using a specific TaqMan-based qPCR assay, were assessed in 290 patients diagnosed with migraine and in 300 healthy controls. The relationship of these variables with several clinical features of migraine was also analyzed. The frequencies of the analyzed LAG3/CD4 genotypes did not differ significantly between the two study groups and were not related to the sex, age at onset of migraine, family history of migraine, presence or absence of aura, or the triggering effect of ethanol on migraine episodes. These results suggest a lack of association between common variants in the LAG3/CD4 genes and the risk of developing migraine in the Caucasian Spanish population.

Increased serum diamine oxidase activity in nonallergic patients with migraine.

BACKGROUND/OBJECTIVES: Histamine has shown a possible role in the etiopathogenesis of migraine. It has been reported an association between some polymorphisms in the diamine oxidase (DAO) gene and migraine, especially in women. Two studies addressing DAO activity in migraine patients showed conflicting results. We investigated the possible relationship of serum DAO activity and histamine levels and 3 polymorphisms in the DAO gene with the risk for migraine. METHODS: We studied the frequencies of DAO rs10156191, rs1049742 and rs1049793 genotypes and allelic variants in 298 migraine patients and 360 healthy controls (using a TaqMan-based qPCR assay), and serum DAO activity and histamine levels in a subset of 99 migraine patients and 115 controls with strict exclusion criteria, and analysed the relationship of these variables with several clinical features of migraine. RESULTS: The frequencies of the DAO genotypes and allelic variants analysed were similar in migraine patients and controls. Serum DAO activity was significantly higher in migraine patients (Vmax/Km 4.24 ± 2.93 vs. 3.60 ± 7.64, p < 0.001), especially in females (Vmax/Km 4.63 ± 2.96 vs. 3.18 ± 2.32, p < 0.0001), while serum histamine was similar in both study groups. CONCLUSION: Serum DAO activity was increased in patients with migraine, especially in females, while serum histamine levels were normal. None of the studied polymorphisms was associated with the risk for migraine.

LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome.

According to several studies, inflammatory factors could be related to the pathogenesis of idiopathic restless legs syndrome (RLS). In addition, RLS and Parkinson's disease (PD) have shown a possible relationship, and recent studies have shown an association between CD4 rs1922452 and CD4 rs951818 single nucleotide variants (SNVs) and the risk for PD. For these reasons, we investigated the possible association between common variants in the LAG3/CD4 genes (which encoded proteins involved in inflammatory and autoimmune responses) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants in 285 patients with idiopathic RLS and 350 healthy controls using a specific TaqMan-based qPCR assay. We also analyzed the possible influence of the genotypes' frequencies on several variables, including age at onset of RLS, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS. We found a lack of association between the frequencies of genotypes and allelic variants of the 3 SNVs studied and the risk of RLS, and a weak though significant association between the CD4 rs1922452 GG genotype and an older age at onset of RLS. With the exception of this association, our findings suggest that common SNVs in the CD4/LAG3 genes are not associated with the risk of developing idiopathic RLS in Caucasian Spanish people.

Association between endothelial nitric oxide synthase (NOS3) rs2070744 and the risk for migraine.

Because nitric oxide could play an important role in the pathogenesis of migraine (suggested by experimental, neuropathological, biochemical, and pharmacological data), and a recent meta-analysis showed an association between the single-nucleotide polymorphism (SNP) rs2070744 in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) and the risk for migraine in Caucasians, we attempted to replicate the possible association between this SNP and the and the risk for migraine in the Caucasian Spanish population. The frequencies for the NOS3 rs2070744 genotypes and allelic variants were assessed in 283 migraine patients and 287 healthy controls with a TaqMan-based qPCR Assay. The putative influence on genotype frequency of age at onset of migraine attacks, gender, family history of migraine, absence or presence of aura, and triggering of migraine attacks by ethanol, were also analyzed. The frequencies of NOS3 rs2070744 genotypes and allelic variants were not associated with the risk for migraine (OR [95%] CI for the minor allele = 0.91 [0.72-1.15]) and were not influenced by age at onset of migraine, gender, presence of aura, or triggering of migraine attacks by ethanol. NOS3 rs2070744CC genotypes were significantly more frequent in patients with a family history of migraine. NOS3 rs2070744 SNP is not associated with the risk for migraine in Caucasian Spanish people although it might be related to family history.

Response to Symptoms and Prehospital Delay in Stroke Patients. Is It Time to Reconsider Stroke Awareness Campaigns?

BACKGROUND: Despite recent advances in acute stroke care, reperfusion therapies are given to only 1%-8% of patients. Previous studies have focused on prehospital or decision delay. We aim to give a more comprehensive view by addressing different time delays and decisions. METHODS: A total of 382 patients with either acute stroke or transient ischemic attack were prospectively included. Sociodemographic and clinical parameters and data on decision delay, prehospital delay, and first medical contact were recorded. Multivariate logistic regression analyses were conducted to identify factors related to decision delay of 15 minutes or shorter, calling the Extrahospital Emergency Services, and prehospital delay of 60 minutes or shorter and 180 minutes or shorter. RESULTS: Prehospital delay was 60 minutes or shorter in 11.3% of our patients and 180 minutes or shorter in 48.7%. Major vascular risk factors were present in 89.8% of patients. Severity was associated with decision delay of 15 minutes or shorter (odds ratio [OR] 1.08; confidence interval [CI] 1.04-1.13), calling the Extrahospital Emergency Services (OR 1.17; CI 1.12-1.23), and prehospital delay of 180 minutes or shorter (OR 1.08; CI 1.01-1.15). Adult children as witnesses favored a decision delay of 15 minutes or shorter (OR 3.44; CI 95% 1.88-6.27; P < .001) and calling the Extrahospital Emergency Services (OR 2.24; IC 95% 1.20-4.22; P = .012). Calling the Extrahospital Emergency Services favored prehospital delay of 60 minutes or shorter (OR 5.69; CI 95% 2.41-13.45; P < .001) and prehospital delay of 180 minutes or shorter (OR 3.86; CI 95% 1.47-10.11; P = .006). CONCLUSIONS: Severity and the bystander play a critical role in the response to stroke. Calling the Extrahospital Emergency Services promotes shorter delays. Future interventions should encourage immediately calling the Extrahospital Emergency Services, but the target should be redirected to those with known risk factors and their caregivers.

Vitamin D receptor and binding protein genes variants in patients with migraine.

BACKGROUND/OBJECTIVES: Several studies have shown a relationship between vitamin D and migraine, including the association between decreased serum 25-hydroxyvitamin D in patients with migraine and the positive effects of vitamin D supplementations in the therapy of this disease. Two single-nucleotide variants (SNVs) vitamin D receptor (VDR) gene, VDR rs2228570, and VDR rs731236 have shown an association with migraine risk in a previous case-control association study, while an exome sequencing study identified a rare variant in GC vitamin D binding protein gene. This study aims to look for the association between several common variants in these two genes and the risk for migraine. METHODS: We genotyped 290 patients diagnosed with migraine and 300 age-matched controls using specific TaqMan assays for VDR rs2228570, VDR rs731236, VDR rs7975232, VDR rs739837, VDR rs78783628, GC rs7041, and GC rs4588 SNVs. RESULTS: We did not find an association between these SNVs and the risk for migraine. None of these SNVs were related to the positivity of a family history of migraine or with the presence of aura. The VDR rs731236A allele showed a significant association with the triggering of migraine attacks by ethanol (Pc = 0.007). CONCLUSIONS: In summary, the results of the current study suggest a lack of association between common SNVs in the VDR and GC gene and the risk of developing migraine. The possible relationship between VDR rs731236 and the triggering of migraine episodes with ethanol deserves future studies.

Serum Trace Elements Concentrations in Patients with Restless Legs Syndrome.

Increased brain and serum zinc levels in patients with idiopathic restless legs syndrome (idiopathic RLS or iRLS) were described when compared with controls, suggesting a possible role of zinc in the pathogenesis of this disease. However, serum magnesium, calcium, manganese, iron, and copper levels of RLS patients were similar to controls, suggesting a specific impairment of zinc-dependent metabolism in RLS. The aim of this study is to assess the serum concentrations of trace elements involved in oxidative stress or causing peripheral nerve toxicity in a large series of patients with iRLS and controls. We determined serum levels of iron, copper, manganese, zinc, magnesium, selenium, calcium, aluminium, lead, cadmium, arsenic and mercury in 100 patients diagnosed with iRLS and in 110 age- and sex-matched controls using Inductively Coupled Plasma Mass Spectrometry. Serum copper, magnesium, selenium, and calcium concentrations were significantly higher in RLS patients than in controls. These differences were observed both in men and women. There were no major correlations between serum trace metal concentrations and age at onset of RLS or RLS severity, nor was there any association with a family history of RLS or drug response. This study shows an association between increased serum concentrations of copper, magnesium, selenium, and calcium with RLS in a Spanish Caucasian population and does not confirm the previously reported increase in serum zinc concentrations in patients suffering from this disease, suggesting that the different accuracy of the analytical methods used could have influenced the inconsistent results found in the literature.

Increasing the confidence of 18F-Florbetaben PET interpretations: Machine learning quantitative approximation.

AIM: To assess the added value of semiquantitative parameters on the visual assessment and to study the patterns of 18F-Florbetaben brain deposition. MATERIALS AND METHODS: Retrospective analysis of multicenter study performed in patients with mild cognitive impairment or dementia of uncertain origin. 18F-Florbetaben PET scans were visually interpreted by two experienced observers, analyzing target regions in order to calculate the interobserver agreement. Semiquantification of all cortical regions with respect to three reference regions was performed to obtain standardized uptake value ratios (SUVRs). The ability of SUVRs to predict the visual evaluation, the possibility of preferential radiotracer deposition in some target regions and interhemisphere differences were analyzed. RESULTS: 135 patients were evaluated. In the visual assessment, 72 were classified as positive. Interobserver agreement was excellent. All SUVRs were significantly higher in positive PET scans than in negative ones. Prefrontal area and posterior cingulate were the cortical regions with the best correlations with the visual evaluation, followed by the composite region. Using ROC analysis, the SUVRs obtained in same target locations showed the best diagnostic performance. CONCLUSIONS: The derived information from target regions seems to help the visual classification, based on a preferential amyloid ß deposit, allowing machine learning. The amyloid ß deposit, although diffuse in all cortical regions, seems not to be uniform and symmetric.

Correlation of Global and Regional Amyloid Burden by 18 F-Florbetaben PET/CT With Cognitive Impairment Profile and Severity.

PURPOSE: To assess the correlation between profile and severity deterioration in the neuropsychological assessment and the most affected regions in amyloid PET semiquantification. The influence of vascular risk and other potential confounding factors was also evaluated. METHODS: A retrospective, observational, and multicenter study including all patients referred for amyloid PET in daily practice was conducted. Patients underwent neuropsychological assessment, and cognitive decline severity and domain(s) affected were recorded. The patients were grouped according to cognitive impairment (CI) profile and severity: (A) no CI, single-domain amnestic CI, multiple-domain amnestic CI, and nonamnestic CI; and (B) mild CI, moderate and severe dementia. An adapted Framingham Stroke Risk Profile was calculated for each individual. Depression and parkinsonism were also recorded. Standardized quantitative analysis software was used to obtain standardized uptake value ratio (SUVR) values from PET/CT images. The corresponding associations were assessed with the most appropriate statistical tests. RESULTS: One hundred twenty-nine patients were included (62 men, 67 women; 64.67 ± 7.47 years old). Significant differences in global and regional amyloid load were exclusively found in women between non-CI and moderate dementia ( P = 0.006, for total-cerebellum SUVR). Posterior and anterior cingulates and prefrontal cortex best represented CI severity ( P = 0.003, 0.006, and 0.006, respectively). No relationship between the CI profile and the regional amyloid load was shown. A significantly high positive correlation was found between age and vascular risk and between these variables and amyloid load in nearly all regions, especially in women with moderate dementia. CONCLUSION: Semiquantitative analysis of amyloid PET by SUVR values revealed a significant correlation between amyloid burden and CI severity, although only in women.

Common Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphisms are not Related With the Risk for Restless Legs Syndrome.

Because nitric oxide and endothelial dysfunction could play a role in the pathogenesis of idiopathic restless legs syndrome (RLS), as was suggested by some preliminary data, we investigated the possible association between the rs2070744 variants in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of NOS3 single nucleotide polymorphisms (SNPs) rs2070744, rs1799983, and rs79467411 genotypes and allelic variants in 273 patients with idiopathic RLS and 325 healthy controls using a TaqMan-based qPCR assay. We also analyzed the possible influence of genotype frequency on age at onset of RLS symptoms, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS such as dopaminergic drugs, clonazepam, and GABAergic drugs. The frequencies of genotypes and allelic variants were not associated with the risk for RLS and were not influenced by gender, age, and positive family history of RLS. We identified weak statistical associations of the SNP rs1799983 with the response to dopamine agonists (Pc = 0.018 for the rs1799983 G/T genotype) and of the SNP rs79467411 with the response to clonazepam (Pc = 0.018 for the rs79467411 G allele), although these findings should be cautiously interpreted and require further confirmation. These associations aside, our findings suggest that common NOS3 SNPs are not associated with the risk for idiopathic RLS in Caucasian Spanish people.

Serum vitamin D, vitamin D receptor and binding protein genes polymorphisms in restless legs syndrome.

BACKGROUND/OBJECTIVES: Several studies showed lower serum 25-hydroxyvitamin D levels in patients with idiopathic restless legs syndrome (RLS) compared with matched controls, and a single study showed an association between the rs731236 single nucleotide polymorphism (SNP) in the vitamin D receptor (VDR) gene and the risk for RLS. We aimed to study the relationship between the serum 25-hydroxyvitamin D levels and to confirm previous findings related to SNPs in the VDR and the GC vitamin D binding protein (GC) gene, with the risk for RLS in the Spanish Caucasian population. METHODS: We genotyped 285 idiopathic RLS patients and 325 age and sex-matched controls for VDRrs2228750, VDRrs7975232, VDRrs739837, VDRrs78783628, GCrs7041 and GCrs4588 SNPs using TaqMan assays, and determined serum 25-hydroxyvitamin D levels in 111 idiopathic RLS patients and 167 controls using an ELISA commercial kit. RESULTS: Serum 25-hydroxyvitamin D levels were significantly higher in RLS patients than in controls but were unrelated with the 7 SNPs studied. None of the 7 SNPs analyzed was associated with the risk for idiopathic RLS or with a positive family history of RLS. However, RLS patients carrying the rs7975232CC genotype or the rs7975232C allele, had a higher frequency of response to GABAergic drugs. Associations between the age at onset and the severity of RLS with SNPs were inconsistent. CONCLUSIONS: This study shows an association between increased serum concentrations of 25-hydroxyvitamin D and a lack of association between 7 SNPs in the VDR and in the GC genes with RLS in the Spanish Caucasian population.

Psoriasis during natalizumab treatment for multiple sclerosis.

Beta-interferon therapy is known to trigger psoriasis, but this effect has not been previously reported for other multiple sclerosis treatments, such as natalizumab. The following is a case report. A 31-year-old woman affected by psoriasis and relapsing-remitting multiple sclerosis suffered a severe worsening of psoriasis symptoms during natalizumab treatment and acquired a drug-resistant course. This case suggests that aggravation of psoriasis might be a rare side effect of natalizumab, and that clinicians should be aware of the possibility of paradoxical activation of autoimmune diseases during its treatment.

[The use of oral lacosamide in a patient with refractory partial epileptic status]. / Uso de lacosamida oral en un paciente con estado epiléptico parcial refractario.

INTRODUCTION: Generalised epileptic status is a medical emergency with a well-defined therapeutic algorithm. Nevertheless, in the partial status, treatment must be tailored to each patient and the risk of intensive treatment has to be assessed. Unlike generalised epileptic status, partial status is not considered a medical emergency, which means that when it comes to choosing a type of treatment the risk-benefit ratio must be carefully evaluated bearing in mind the characteristics of each particular case. CASE REPORT: A 72-year-old male with partial status secondary to an ischaemic lesion which was refractory to conventional treatment; treatment was established with lacosamide and his condition was rapidly inverted. This is the third case that has been reported of epileptic status being treated with this drug and the second in which it is employed orally. CONCLUSIONS: Although further research is required, lacosamide could be a good therapeutic option with few interactions and side effects.

Oftalmoplejía dolorosa recurrente secundaria a displasia fibrosa poliostótica del seno maxilar con afectación de la hendidura esfenoidal / Recurrent painful ophthalmoplegia secondary to polyostotic fibrous dysplasia of the maxillary sinuses with involvement of the superior orbital fissure

Introducción. La displasia fibrosa es una enfermedad ósea benigna que suele cursar con lesiones asintomáticas pero que en ocasiones puede dar manifestaciones neurológicas por afectación de los huesos craneofaciales. Caso clínico. Mujer de 25 años, con antecedentes de migraña, que consultó a los 18 años por un cuadro de dolor en la región maxilar y retrocular derecha de características diferentes de las de su migraña habitual y que asocia oftalmoparesia ipsolateral; presenta un curso autolimitado con buena respuesta a corticoides, aunque recidivante. La exploración puso de manifiesto un intenso dolor a la palpación en el seno maxilar derecho y parálisis incompleta del III par craneal ipsolateral con ptosis palpebral. Los estudios complementarios fueron normales, salvo la resonancia magnética craneal y la tomografía axial computarizada facial, donde se evidenció una lesión expansiva con afectación del seno maxilar superior derecho y el ala mayor del esfenoides, con probable afectación de la hendidura esfenoidal, compatible con el diagnóstico de displasia fibrosa, que fue confirmado mediante estudio anatomopatológico. Conclusiones. La displasia fibrosa es un trastorno óseo benigno cuya etiología se desconoce y que consiste en la sustitución del tejido óseo normal por tejido conjuntivo amorfo. En ocasiones, existe afectación craneofacial y se forma una masa ósea hipertrófica que puede ocupar los senos paranasales y la órbita, y dar lugar a exoftalmos y alteraciones visuales. Hasta el momento, no se ha descrito en la bibliografía científica la manifestación de esta enfermedad en forma de brotes de oftalmoparesia dolorosa recurrente con respuesta a corticoides, como ocurre en nuestra paciente (AU)

Introduction. Fibrous dysplasia is a bone disease that is usually accompanied by asymptomatic lesions but which may sometimes display neurological manifestations due to the involvement of the craniofacial bones. Case report. A 25-year-old female, with a history of migraines, who visited at the age of 18 due to pain in the right retro-ocular and maxillary region, although with characteristics that were unlike those of her usual migraines, and which was associated with ipsilateral ophthalmoparesis. The condition had a self-limiting course and responded well to corticoids, although it was recurring. Examination revealed intense pain on palpation of the right-hand maxillary sinus and incomplete paralysis of the ipsilateral oculomotor nerve with palpebral ptosis. Results of complementary studies were normal, except for magnetic resonance imaging of the head and computerised axial tomography of the face, which revealed an expansive lesion with involvement of the right superior maxillary sinus and the greater wing of the sphenoid bone, with probable compromise of the superior orbital fissure, consistent with the diagnosis of fibrous dysplasia, which was confirmed by means of a pathology study. Conclusions. Fibrous dysplasia is a benign bone disorder, of unknown causation, in which normal bone tissue is replaced by amorphous conjunctive tissue. There is sometimes craniofacial involvement and a hypertrophic bone mass is formed which can fill the paranasal sinuses and the orbit, resulting in exophthalmus and visual disorders. To date the scientific literature does not include any reports of this disease manifesting as bouts of recurrent painful ophthalmoparesis which responds to corticoids, as happened in the case of our patient (AU)

Uso de lacosamida oral en un paciente con estado epiléptico parcial refractario / The use of oral lacosamide in a patient with refractory partial epileptic status

Introducción. El estado epiléptico generalizado es una urgencia médica con un algoritmo terapéutico bien definido. Sin embargo, en el estado parcial, el tratamiento debe individualizarse y valorar el riesgo del tratamiento intensivo. A diferencia del estado epiléptico generalizado, el estado parcial no se considera una emergencia médica, por lo que en la elección de su tratamiento debe valorarse cuidadosamente y de modo individualizado la relación riesgo-beneficio.Caso clínico. Varón de 72 años con estado parcial secundario a lesión isquémica y refractario a tratamiento convencional, en el que se inicia tratamiento con lacosamida y se consigue su rápida reversión. Se trata del tercer caso de estado epiléptico publicado con este fármaco y del segundo en el que se emplea vía oral. Conclusión. Aunque se requieren más estudios la lacosamida podría representar una buena opción terapéutica con escasas interacciones y efectos secundarios (AU)

Introduction. Generalised epileptic status is a medical emergency with a well-defined therapeutic algorithm. Nevertheless, in the partial status, treatment must be tailored to each patient and the risk of intensive treatment has to be assessed. Unlike generalised epileptic status, partial status is not considered a medical emergency, which means that when it comes to choosing a type of treatment the risk-benefit ratio must be carefully evaluated bearing in mind the characteristics of each particular case. Case report. A 72-year-old male with partial status secondary to an ischaemic lesion which was refractory to conventional treatment; treatment was established with lacosamide and his condition was rapidly inverted. This is the third case that has been reported of epileptic status being treated with this drug and the second in which it is employed orally. Conclusions. Although further research is required, lacosamide could be a good therapeutic option with few interactions and side effects (AU)