VEMPs and Dysautonomia Assessment in Definite Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS): a Case Series Study.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described slowly progressive ataxia with severe imbalance due to the compromise of three of the four sensory inputs for balance, leaving only vision unaffected. Bilateral vestibulopathy is present but saccular and utricular function, measured by vestibular evoked myogenic potentials (VEMPs), has not been widely studied in these patients. Dysautonomia has been reported but is not among the diagnostic criteria. We performed a database analysis to identify patients evaluated between 2003 and 2019 with probable diagnosis of CANVAS by using key words "bilateral vestibulopathy and/or cerebellar ataxia and/or sensory polyneuropathy." Five out of 842 met all conditions. Patients underwent neurological/neurootological exam, brain MRI, visually enhanced vestibulo-ocular reflex (VVOR) exam by high-speed video-oculography using video-Head Impulse Test (vHIT), VEMPs, neurophysiological studies, and genetic tests to exclude other causes of ataxia. Dysautonomia was addressed by the standardized survey of autonomic symptoms. All patients had clinically definite CANVAS as brain MRI showed vermal cerebellar atrophy, neurophysiological studies showed a sensory neuronopathy pattern (absent sensory action potentials), VVOR was abnormal bilaterally, and genetic tests ruled out other causes of ataxia including SCA 3 and Friedreich ataxia. Patients had at least 3 dysautonomic symptoms, including xerostomia/xerophthalmia (5/5). VEMP results varied among patients, ranging from normal to completely abnormal. We found inconsistent results with VEMPs. The utilization of VEMPs in more CANVAS cases will determine its utility in this syndrome. Dysautonomia may be included in the diagnostic criteria.

Interictal amylin levels in chronic migraine patients: A case-control study.

BACKGROUND: Recently, amylin and its receptors were found in different structures involved in migraine pathophysiology. Here, we evaluate interictal concentrations of amylin and calcitonin gene-related peptide in peripheral blood as biomarkers for chronic migraine. METHODS: We prospectively recruited patients with episodic migraine, chronic migraine and healthy controls. Interictal amylin and calcitonin gene-related peptide levels were assessed in blood samples using enzyme linked immunosorbent assay. RESULTS: We assessed plasma samples from 58 patients with episodic migraine (mean age 37.71 ± 10.47, 87.9% female), 191 with chronic migraine (mean age 46.03 ± 11.93, 95% female), and on 68 healthy controls (mean age 43.58 ± 11.08 years, 86% female). Body mass index was 25.94 ± 4.53 kg/m2 for migraine patients and 25.13 ± 4.92 kg/m2 for healthy controls (p = 0.0683). Interictal plasma amylin levels were higher in chronic migraine patients (47.1 pg/mL) than in the episodic migraine patients (28.84 pg/mL, p < 0.0001) and healthy controls (24.74 pg/mL, p < 0.0001). Plasma calcitonin gene-related peptide levels were increased (20.01 pg/mL) in chronic migraine patients when compared to healthy controls (11.37 pg/mL, p = 0.0016), but not to episodic migraine patients (18.89 pg/mL, p = 0.4369). Applying a cut-off concentration of 39.68 pg/mL plasma amylin, the sensitivity to differentiate chronic migraine from healthy controls was 57.6% and the specificity was 88.2%. Variables such as age, analgesic overuse, depression, allodynia, use of preventive medication or a history of aura did not influence the plasma concentrations of amylin or calcitonin gene-related peptide. CONCLUSION: Interictal plasma amylin levels are higher in patients with chronic migraine and may serve as a diagnostic biomarker for chronic migraine.

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. METHODS: We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. RESULTS: Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with non-neoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575). CONCLUSIONS: Our data suggest that the expression of RNU6-1 in circulating exosomes could be useful for the differentiation of GBM from non-neoplastic brain lesions and PCNSL, but not from brain metastases.

Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study.

BACKGROUND: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. METHODS: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDG-PET/CT focusing on several territories' vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. RESULTS: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. CONCLUSIONS: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory.

Excess abdominal fat is associated with cutaneous allodynia in individuals with migraine: a prospective cohort study.

OBJECTIVE: To investigate the specific relationship between cutaneous allodynia (CA) and the percentages of body fat (BF) and abdominal fat in migraineurs. Additionally, we compared serum levels of inflammatory biomarkers in patients with and without CA. BACKGROUND: Excess abdominal fat might facilitate progressive changes in nociceptive thresholds causing central sensitization, clinically reflected as CA, which could drive migraine progression. METHODS: This prospective cohort study included 80 patients with migraine (mean age 39 years, 81.2% female) and 39 non-migraine controls. We analysed each participant's height, body weight, and body mass index (BMI). The amount and distribution of BF was also assessed by air displacement plethysmography (ADP) and ViScan, respectively. We analysed serum levels of markers of inflammation, during interictal periods. RESULTS: We studied 52 patients with episodic migraine (EM) and 28 with chronic migraine (CM). Of the 80 patients, 53 (53.8%) had CA. Migraineurs with CA had a higher proportion of abdominal fat values than patients without CA (p = 0.04). The independent risk factors for CA were the use of migraine prophylaxis (OR 3.26, 95% CI [1.14 to 9.32]; p = 0.03), proportion of abdominal fat (OR 1.13, 95% CI [1.01 to 1.27]; p = 0.04), and presence of sleep disorders (OR 1.13, 95% CI [00.01 to 1.27]; p = 0.04). The concordance correlation coefficient between the ADP and BMI measurements was 0.51 (0.3681 to 0.6247). CA was not correlated with the mean plasma levels of inflammatory biomarkers. CONCLUSIONS: There is a relation between excess abdominal fat and CA. Abdominal obesity might contribute to the development of central sensitization in migraineurs, leading to migraine chronification.

Amylin as a potential link between type 2 diabetes and alzheimer disease.

OBJECTIVE: Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and ß-amyloid (Aß) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. METHODS: We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined Aß and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or Aß interact with amylin in either the pancreas or brain of these subjects. RESULTS: Cytoplasmic tau and Aß protein deposits were detected in pancreatic ß cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with Aß and tau in both the pancreas and hippocampus. INTERPRETATION: The presence of both tau and Aß inclusions in pancreatic ß cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019;86:539-551.

Epicardial Adipose Tissue in the General Middle-aged Population and Its Association With Metabolic Syndrome.

INTRODUCTION AND OBJECTIVES: There is currently increasing interest in epicardial adipose tissue (EAT) as a marker of cardiovascular disease. Our purpose was to describe EAT, measured by transthoracic echocardiography, and to assess its association with metabolic syndrome (MS) in the RIVANA population-based study. METHODS: Physical examination was performed in 880 participants aged 45 to 74 years (492 of them with MS according to the harmonized definition). Fasting glucose, high-density lipoprotein cholesterol, triglyceride, and C-reactive protein concentrations were determined in a blood sample. In all participants, EAT thickness was measured with transthoracic echocardiography at end-systole. RESULTS: Among participants without MS, the prevalence of EAT ≥ 5mm significantly increased with age (OR > 65 years vs 45-54 years=8.22; 95%CI, 3.90-17.35; P for trend<.001). Increasing EAT quintiles were significantly associated with MS (OR fifth quintile vs first quintile=3.26; 95%CI, 1.59-6.71; P for trend=.001). Considering the different MS criteria, increasing quintiles of EAT were independently associated with low high-density lipoprotein cholesterol (OR fifth quintile vs first quintile=2.65; 95%CI, 1.16-6.05; P for trend=.028), high triglycerides (OR fifth quintile vs first quintile=2.22; 95%CI, 1.26-3.90; P for trend=.003), and elevated waist circumference (OR fifth quintile vs first quintile=6.85; 95%CI, 2.91-16.11; P for trend<.001). CONCLUSIONS: In a subsample of the general population, EAT measured by echocardiography increased significantly and independently with age. Increased EAT thickness was independently associated with MS and with low high-density lipoprotein cholesterol, high triglycerides, and elevated waist circumference as individual criteria.

Citicoline for Acute Ischemic Stroke: A Systematic Review and Formal Meta-analysis of Randomized, Double-Blind, and Placebo-Controlled Trials.

BACKGROUND: Citicoline is a drug approved for the treatment of acute ischemic stroke. Although evidence of its efficacy has been reported, recently published results of a large placebo-controlled clinical trial did not show differences. This study aims to assess whether starting citicoline treatment within 14 days after stroke onset improves the outcome in patients with acute ischemic stroke, as compared with placebo. METHODS: A systematic search was performed to identify all published, unconfounded, randomized, double-blind, and placebo-controlled clinical trials of citicoline in acute ischemic stroke. RESULTS: Ten randomized clinical trials met our inclusion criteria. The administration of citicoline was associated with a significant higher rate of independence, independently of the method of evaluation used (odds ratio [OR] 1.56, 95% confidence interval [CI] = 1.12-2.16 under random effects; OR 1.20, 95% CI = 1.06-1.36 under fixed effects). After studying the cumulative meta-analysis, and with the results obtained with the subgroup of patients who were not treated with recombinant tissue plasminogen activator (rtPA) (OR 1.63, 95% CI = 1.18-2.24 under random effects; OR 1.42, 95% CI = 1.22-1.66 under fixed effects), our hypothesis of dilution of the effect of citicoline was confirmed. When we analyzed the effect of citicoline in patients who were not treated with rtPA and were receiving the highest dose of citicoline started in the first 24 hours after onset, based on more recent trials, there was no heterogeneity, and the size of the effect has an OR of 1.27 (95% CI = 1.05-1.53). CONCLUSIONS: This systematic review supports some benefits of citicoline in the treatment of acute ischemic stroke. But, on top of the best treatment available (rtPA), citicoline offers a limited benefit.

[ASSOCIATION BETWEEN DIETARY GLYCEMIC INDEX AND GLYCEMIC LOAD AND INTIMA MEDIA THICKNESS IN A POPULATION AT HIGH CARDIOVASCULAR RISK: A SUBGROUP ANALYSIS IN THE PREDIMED TRIAL]. / ASOCIACIÓN ENTRE EL ÍNDICE GLUCÉMICO O LA CARGA GLUCÉMICA Y EL GROSOR DE LA ÍNTIMA MEDIA EN PACIENTES CON ALTO RIESGO CARDIOVASCULAR: ANÁLISIS DE UNA SUBMUESTRA DEL ENSAYO PREDIMED.

BACKGROUND: increased carotid íntima-media thickness (IMT) is a marker of atherosclerosis and a predictor of future cardiovascular events. Although a beneficial effect of Mediterranean diets, in particular, enhanced with virgin olive oil and nuts, on longitudinal changes in IMT has been reported, the association between carbohydrates and the development of atherosclerosis is still unclear. OBJECTIVE: to assess the association between glycemic index (IG) and glycemic load (CG) of the diet and intima media thickness (GIMC) in a population at high cardiovascular risk with no clinical symptoms. METHODS: one hundred eighty seven participants of the PREDIMED-NAVARRA center (PREDIMED means in Spanish "PREvención con DIeta MEDiterránea") were randomly selected to undergo baseline and 1-year measurement of GIMC. Dietary information was collected at baseline and yearly using a validated 137-item food frequency questionnaire. Participants were categorized into four groups of energy-adjusted IG and CG intake. Multivariate analysis models (ANCOVA) were used to study the association between dietary IG and CG and GIMC and its changes. RESULTS: in our study we found no significant association between IG or CG and GIMC at baseline or after one year.

Introducción: el grosor de la íntima media carotídea (GIMC) es un conocido marcador de arteriosclerosis precoz y un buen predictor de eventos cardiovasculares futuros. Aunque se ha demostrado que la adhesión a la dieta mediterránea, especialmente si está enriquecida con aceite de oliva virgen extra o frutos secos, tiene efectos beneficiosos sobre los cambios en el GIMC, el papel de los carbohidratos en el desarrollo de la arterioesclerosis sigue siendo controvertido. Objetivo: valorar la relación entre el índice glucémico (IG) o la carga glucémica (CG) de la dieta y el GIMC en una población asintomática con alto riesgo cardiovascular. Métodos: en el marco del estudio PREDIMED (PREvención con Dieta MEDiterránea), se seleccionaron de manera aleatorizada 187 sujetos del centro PREDIMED- NAVARRA. A estos pacientes asintomáticos, pero con alto riesgo cardiovascular, se les realizó una ecografía carotídea basal para determinar su GIMC, y tras un año en el estudio se les repitió la misma medición. Se usó un cuestionario validado de frecuencia de consumo de alimentos (137 ítems) tanto basal como anualmente para obtener el IG y la CG, que fueron categorizados en cuartiles, tras ser ajustados por energía. Mediante modelos multivariables (ANCOVA) se estudió la posible asociación entre el IG o la CG de la dieta y el GIMC o su cambio al año. Resultados: en la población estudiada no se observó una asociación estadísticamente significativa entre el IG o la CG y el GIMC, ni al inicio ni tras un año de seguimiento.

Monitoring the Effect of Immunotherapy in Autoimmune Limbic Encephalitis Using 18F-FDG PET.

A 70-year-old woman with a history of autoimmune hepatitis and renal cell carcinoma presented with subacute cognitive impairment. A brain MRI revealed mild leukoaraiosis, whereas brain F-FDG PET/CT showed diffuse cerebral hypometabolism that resembled some of the patterns described in limbic encephalitis and neurodegenerative diseases. With the suspicion of autoimmune encephalitis, the patient received immunotherapy with dramatic improvement of cognitive function and metabolic normalization at the 2-month follow-up on brain F-FDG PET/CT. Our results demonstrate that brain F-FDG PET/CT might be a useful tool in the assessment of patients with autoimmune encephalitis.

[What is the optimal dose for the prophylactic treatment of chronic migraine patients?]. / Realmente es beneficioso usar las dosis de OnabotulinumtoxinA del estudio PREEMPT?

INTRODUCTION: OnabotulinumtoxinA (OnabotA) is indicated for headache prophylaxis in patients with chronic migraine. However, there is some controversy about what is the minimum effective dose for treating chronic migraine patients. AIM: To determine the optimal dose of OnabotA for the prophylactic treatment of patients with chronic migraine. DEVELOPMENT: We performed a literature review of the randomized, double blind, placebo-controlled studies that have evaluated the safety and efficacy of OnabotA as headache prophylactic treatment in migraine patients. In the studies conducted before the PREEMPT clinical programme, a variety of dose ranges and infiltration paradigms were used. Initial phase II studies of OnabotA in chronic daily headache showed that those patients treated with 150 U had significant mean reductions from baseline in headache frequency compared with placebo, and this benefit was not observed for patients treated with 75 U. The experience from previous studies allowed to define an injection paradigm and dose range (155-195 U) that was used in the PREEMPT clinical trials. PREEMPT studies demonstrate that OnabotA is a safe an effective prophylactic treatment for chronic migraine. CONCLUSIONS: Available evidence to date supports that the optimal dose for the treatment of chronic migraine patients is the use of at least 150 U of OnabotA, that should be administered according to the PREEMPT injection paradigm.

TITLE: Realmente es beneficioso usar las dosis de OnabotulinumtoxinA del estudio PREEMPT?Introduccion. La OnabotulinumtoxinA (OnabotA) esta indicada para el tratamiento preventivo de los pacientes con diagnostico de migraña cronica. Existe cierta controversia acerca de cual es la dosis minima eficaz de OnabotA. Objetivo. Determinar cual es la dosis mas adecuada de OnabotA para el tratamiento de la migraña cronica. Desarrollo. Se revisan los estudios controlados frente a placebo, que han evaluado la eficacia y seguridad de OnabotA para el tratamiento de la migraña, prestando especial atencion a las dosis de toxina utilizadas. En los diferentes ensayos clinicos llevados a cabo antes del año 2010 se utilizaron distintos protocolos de infiltracion. La experiencia obtenida de los estudios previos permitio definir un protocolo de infiltracion que se utilizo en el programa PREEMPT, y que demostro que el tratamiento con OnabotA es seguro y eficaz en pacientes con migraña cronica. La dosis elegida en los ensayos PREEMPT 1 y 2 fue de 155-195 U, al observarse en los estudios en fase II que la dosis de 75 U no era eficaz y que la utilizacion de 150-200 U aumentaba la eficacia sin incrementar los efectos adversos. Ademas de la dosis, el paradigma de inyeccion PREEMPT tambien establece de manera detallada los puntos de inyeccion y la metodologia de infiltracion. Conclusiones. La evidencia cientifica disponible hasta la fecha sustenta que la dosis mas adecuada para el tratamiento de la migraña cronica es la utilizacion de al menos 150 U de OnabotA, y que la infiltracion debe realizarse con la metodologia definida en el paradigma de inyeccion PREEMPT.

[Predictive factors of the response to treatment with onabotulinumtoxinA in refractory migraine]. / Factores predictores de respuesta al tratamiento con onabotulinumtoxina A en la migraña refractaria.

AIM: To identify the clinical features that predict a favourable response to onabotulinumtoxinA (OnabotA) treatment in patients with refractory migraine. PATIENTS AND METHODS: Retrospective analysis of patients with refractory migraine who underwent at least two pericranial injections of OnabotA between 2008 and 2012. Patients were divided into responders and non-responders. Some clinical features including unilateral location of headache, presence of pericranial muscle tension, type of pain (imploding or exploding), duration of migraine (less than or greater than 10 years) and medication overuse were compared between the two groups. RESULTS: 39 patients were included (35 women) with a mean age of 46 years. 18 patients (46.2%) showed a greater than 50% reduction in the number of headache days/month (responders). When analyzing the different features of migraine, we observed that all were equally prevalent in responders and non-responders (p > 0.05): unilateral location (66.7% vs 66.6% respectively), implosive pain (27.8% vs 38.1%), presence of pericranial muscle tension (33.3% vs 38.1%), duration of migraine more than 10 years (77.8% vs 69.2%) and presence of medication overuse (50% vs 81%). CONCLUSION: We failed to identify any clinical feature in our patients with refractory migraine that predicts a favourable response to OnabotA treatment.

TITLE: Factores predictores de respuesta al tratamiento con onabotulinumtoxina A en la migraña refractaria.Objetivo. Identificar las caracteristicas clinicas que predicen una respuesta favorable al tratamiento con onabotulinumtoxina A (OnabotA) en pacientes con migraña refractaria. Pacientes y metodos. Estudio retrospectivo de pacientes con migraña refractaria que recibieron al menos dos infiltraciones de OnabotA entre los años 2008 y 2012. Los pacientes fueron divididos en respondedores y no respondedores a OnabotA y se compararon entre ambos grupos, y de forma retrospectiva, una serie de caracteristicas clinicas consideradas predictoras de respuesta en estudios previos: localizacion unilateral de la cefalea, presencia de tension muscular pericraneal, tipo de dolor (implosivo, explosivo u ocular), tiempo de evolucion de la migraña (menor o mayor de 10 años) y abuso de medicacion analgesica. Resultados. Se incluyeron 39 pacientes (35 mujeres) con una edad media de 46 años. En 18 pacientes (46,2%) se observo una reduccion mayor del 50% en el numero de dias de cefalea/mes (pacientes respondedores). Al analizar las diferentes caracteristicas de la migraña, se observo que todas ellas fueron igualmente prevalentes en los pacientes respondedores y en los no respondedores (p > 0,05): localizacion unilateral (66,7% frente a 66,6%, respectivamente), dolor implosivo (27,8% frente a 38,1%), presencia de tension muscular pericraneal (33,3% frente a 38,1%), tiempo de evolucion de la migraña mayor de 10 años (77,8% frente a 69,2%) y presencia de abuso de medicacion analgesica (50% frente a 81%). Conclusion. En esta serie de pacientes no se ha identificado ningun rasgo clinico que permita predecir en pacientes con migraña refractaria una respuesta favorable al tratamiento con OnabotA.

The neuroprotection exerted by memantine, minocycline and lithium, against neurotoxicity of CSF from patients with amyotrophic lateral sclerosis, is antagonized by riluzole.

In a recent study we found that cerebrospinal fluids (CSFs) from amyotrophic lateral sclerosis (ALS) patients caused 20-30% loss of cell viability in primary cultures of rat embryo motor cortex neurons. We also found that the antioxidant resveratrol protected against such damaging effects and that, surprisingly, riluzole antagonized its protecting effects. Here we have extended this study to the interactions of riluzole with 3 other recognized neuroprotective agents, namely memantine, minocycline and lithium. We found: (1) by itself riluzole exerted neurotoxic effects at concentrations of 3-30 µM; this cell damage was similar to that elicited by 30 µM glutamate and a 10% dilution of ALS/CSF; (2) memantine (0.1-30 µM), minocycline (0.03-1 µM) and lithium (1-80 µg/ml) afforded 10-30% protection against ALS/CSF-elicited neurotoxicity, and (3) at 1-10 µM, riluzole antagonized the protection afforded by the 3 agents. These results strongly support the view that at the riluzole concentrations reached in the brain of patients, the neurotoxic effects of this drug could be masking the potential neuroprotective actions of new compounds being tested in clinical trials. Therefore, in the light of the present results, the inclusion of a group of patients free of riluzole treatment may be mandatory in future clinical trials performed in ALS patients with novel neuroprotective compounds.

Cephalalgia alopecia or nummular headache with trophic changes? A new case with prolonged follow-up.

Cephalalgia alopecia is a rare and recently described headache syndrome in which recurrent, burning head and neck pain is associated with hair loss from areas of scalp affected by the pain. We here report the case of a 33-year-old woman with continuous unilateral occipital pain and colocalized alopecia, only responsive to onabotulinumtoxin A injections. We hypothesize whether this clinical phenotype may correspond to either cephalalgia alopecia or nummular headache with trophic changes, conditions that might represent 2 manifestations of the same spectrum of disorders.

Leptomeningeal carcinomatosis: prognostic value of clinical, cerebrospinal fluid, and neuroimaging features.

INTRODUCTION: Leptomeningeal carcinomatosis (LC) is a devastating complication occurring in 5% of all patients with cancer. To date there are no well-established prognostic markers in patients with LC, except for the presence of cerebrospinal fluid (CSF) blocks and the Karnofsky performance status scale (KPS). We aimed to identify clinical, neuroradiologic and CSF prognostic factors related to LC survival and to develop an easy-to-use Prognostic Scoring Scale (PSS) to identify patients who are more likely to benefit from receiving treatment. METHODS: Single-center retrospective study evaluating patients who had a diagnosis of LC during a 10-year period. Diagnosis was made by malignant cytology or imaging; suspicious cases treated as LC were also included. RESULTS: Fifty patients with LC were analyzed (58% women). Median age was 54.4 years, and KPS was 60%. The most common types of tumor were breast (35%), lung (24%), and hematologic malignancies (16%). Thirty-two percent of patients were diagnosed by imaging, 22% by cytology, and 40% by both. Median overall survival (OS) was 10 weeks (95% confidence interval 5.1-14.9). Median OS for patients who received specific treatment was 21.2 weeks vs. 6.38 weeks for patients receiving supportive care only (p<0.001). In multivariate analysis, initial KPS, initial CSF protein level (<112 mg/dL) and time from diagnosis of primary tumor to diagnosis of LC (>67 weeks) were significant and independent predictors of increased survival. CONCLUSIONS: Prognosis remains poor in LC. The predictive factors for patients with LC here identified could help to improve the selection of patients who are more likely to benefit from receiving treatment.

Chronic migraine: a therapeutic challenge for clinicians.

Chronic migraine is a common disabling condition. Severe migraine attacks should be treated with triptans, but these agents are contraindicated in patients with vascular problems and may not be effective or tolerated in around one third of the patients. New acute migraine therapies without vasoconstrictive activity and triptan-specific side effects are emerging. For the prophylaxis of chronic migraine, only topiramate and OnabotulinumtoxinA have been shown to be effective in placebo-controlled randomized trials, so novel therapeutic strategies are needed. The growing understanding of the pathophysiology of chronic migraine will contribute to the identification of new treatment targets.

[Clinical experience of treatment with onabotulinumtoxin A in patients with refractory migraine]. / Experiencia clinica del tratamiento con onabotulinumtoxin A en pacientes con migrana refractaria.

AIM: To analyse our experience in the treatment of refractory chronic migraine, episodic frequent refractory migraine (≥10 days/month), with onabotulinumtoxin A (OnabotA). PATIENTS AND METHODS: Retrospective analysis of patients with refractory migraine who underwent, at least two sessions of OnabotA pericranial injections following the PREEMPT protocol between 2008 and 2012. The efficacy of OnabotA was evaluated comparing the basal situation with 12-16 weeks after the second session. We analysed the subjective improvement of the patients, number of days with headache, preventive and abortive drugs consumption, and adverse effects. RESULTS: Forty-one patients (37 women, 4 male) were identified. 65.8% patients experienced subjective improvement after OnabotA treatment. 36.58% responded (reduction of > 50% in headache days). Differences between days with headache before the first session (24.5 ± 7.3), and 12-16 weeks after the second session (17.4 ± 11.6), as well as the differences between the number of abortive drugs taken before the first session (26.8 ± 23.1) and 12-16 weeks after the second session (16.7 ± 19.3), were statistically significant (p < 0.001). Subgroups analysis showed that all differences were significant, except for the reduction of the number of days with headache in patients with episodic frequent refractory migraine. CONCLUSION: Our work shows that treatment with OnabotA is safe and useful in patients with episodic and chronic refractory migraine, including those patients with medication overuse headache.

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial).

BACKGROUND: Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. METHODS: We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. RESULTS: 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. INTERPRETATION: Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. FUNDING: Ferrer Grupo.

Reversible cerebral vasoconstriction syndrome induced by adrenaline.

INTRODUCTION: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by acute severe thunderclap headaches and evidence of multifocal, segmental, reversible vasoconstrictions of the cerebral arteries. Several precipitating factors have been identified and reported, including the use of recreational substances or sympathomimetic drugs and the postpartum state. CASE DESCRIPTION: Here we present the case of a woman who developed RCVS after the administration of adrenaline (epinephrine) in the setting of an anaphylactic reaction during antibiotic allergy testing. DISCUSSION: To our knowledge, this is the first reported case of RCVS following the administration of exogenous adrenaline. This case contributes to the understanding of the physiopathological mechanisms underlying reversible cerebral vasoconstriction.