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Thunderclap headache is a medical emergency presented as the worst headache ever, is characterised by an abrupt onset and maximal intensity within seconds to minutes. However, cerebrovascular causes are among the most common causes of thunderclap headache, and other non-vascular life-threatening aetiologies should be considered in evaluating a patient. We describe a 23-year-old previously healthy Latino woman who presented to our hospital after a month of repetitive severe, abrupt-onset headaches. Her prior medical history was unremarkable. After a normal brain MRI with angio-MRI, a lumbar puncture was performed with normal opening pressure, hypoglycorrhachia, increased proteins and a leucocyte; India ink staining was positive for encapsulated yeast, cultures were positive for

It is recognized that the country to the north of ours is the result of migration. It seems to be the conjunction of multiple cultures and dreams of people who came searching for opportunities. The desire of those dreamers to make a better society resulted in changes in infrastructure, education, science, and culture that made this nation a robust community.

Background: There are >70 million forcibly displaced people worldwide, including refugees, internally displaced persons, and asylum seekers. While the health needs of forcibly displaced people have been characterized in the literature, more still needs to be done globally to translate this knowledge into effective policies and actions, particularly in neurology. Methods: In 2020, a global network of published experts on neurological disease and refugees was convened. Nine physician experts from nine countries (2 low, 1 lower-middle income, 5 upper-middle, 1 high income) with experience treating displaced people originating from 18 countries participated in three survey and two discussion rounds in accordance with the Delphi method. Results: A consensus list of priority interventions for treating neurological conditions in displaced people was created, agnostic to cost considerations, with the ten highest ranking tests or treatments ranked as: computerized tomography scans, magnetic resonance imaging scans, levetiracetam, acetylsalicylic acid, carbamazepine, paracetamol, sodium valproate, basic blood tests, steroids and anti-tuberculous medication. The most important contextual considerations (100% consensus) were all economic and political, including the economic status of the displaced person’s country of origin, the host country, and the stage in the asylum seeking process. The annual cost to purchase the ten priority neurological interventions for the entire displaced population was estimated to be 220 million USD for medications and 4.2 billion USD for imaging and tests. Conclusions: A need for neuroimaging and anti-seizure medications for forcibly displaced people was emphasized. These recommendations could guide future research and investment in neurological care for forcibly displaced people.

Neuromyelitis optica is an autoimmune demyelinating astrocytopathy of the central nervous system that primarily affects the optic nerve and spinal cord. It is considered a multifactorial disease associated with antibodies against aquaporin 4, with complement cascade activation and lymphocytic infiltration leading to axonal loss and causing significant morbidity and disability. In addition, cases of inflammatory diseases of the central nervous system have been described after vaccination against SARS-CoV-2, mainly acute disseminated encephalomyelitis. Also, a few cases of neuromyelitis optica spectrum disorder, mostly aquaporin 4+, have been reported. We describe a patient who developed symptoms suggestive of acute disseminated encephalomyelitis the next day after vaccination against SARS-CoV-2. Three months later, a longitudinally extensive transverse myelitis compatible with aquaporin 4+ neuromyelitis optica was successfully treated with an interleukin 6 inhibitor. There is no proven association and research is needed to establish whether optic neuromyelitis is related to vaccination; this is a single case report from which no conclusion can be drawn.

We present a woman in her 40s who arrived at the emergency room with hypertension and optic ataxia. Her medical history is only relevant for obesity. Her lumbar puncture revealed high intracranial pressure and lymphocytic pleocytosis, and her neuroimaging tests, including angiography and venography, were normal. The patient improved after a cerebrospinal fluid drainage with a lumbar puncture, and her clinical manifestations resolved in parallel to the lymphocytic pleocytosis.The patient was diagnosed with a syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis and fully recovered 21 days after her discharge.

Introduction: Migraine is a polygenic multifactorial disorder with a neuronal initiation of a cascade of neurochemical processes leading to incapacitating headaches. Headaches are generally unilateral, throbbing, 4–72 h in duration, and associated with nausea, vomiting, photophobia, and sonophobia. Chronic migraine (CM) is the presence of a headache at least 15 days per month for ≥3 months and has a high global impact on health and economy, and therapeutic guidelines are lacking. Methods: Using the Grading of Recommendations, Assessment, Development, and Evaluations system, we conducted a search in MEDLINE and Cochrane to investigate the current evidence and generate recommendations of clinical practice on the identification of risk factors and treatment of CM in adults. Results: We recommend avoiding overmedication of non-steroidal anti-inflammatory drugs (NSAIDs); ergotamine; caffeine; opioids; barbiturates; and initiating individualized prophylactic treatment with topiramate eptinezumab, galcanezumab, erenumab, fremanezumab, or botulinum toxin. We highlight the necessity of managing comorbidities initially. In the acute management, we recommend NSAIDs, triptans, lasmiditan, and gepants alone or with metoclopramide if nausea or vomiting. Non-pharmacological measures include neurostimulation. Conclusions: We have identified the risk factors and treatments available for the management of CM based on a grading system, which facilitates selection for individualized management.

Dementia is a public health problem with an extraordinary increase in recent years. Alzheimer’s disease (AD) is the most common cause of dementia. This disease has been considered a consequence of cytoplasmic and extracellular accumulations of Tau protein and β- amyloid, respectively. Nevertheless, a nuclear origin of AD has recently emerged. Both Tau protein and the nuclear lamin protect the nuclear and chromatin organization for proper gene expression throughout neuronal life. Accumulation of DNA damage, mainly as a result of aging, drives post-mitotic neurons to initiate DNA repair by entering the cell cycle. The complexity of the nucleus-cytoskeleton prevents neurons from dividing and condemns them to a state of hyperdiploidy ending in neuronal death, after transiently prolonging their life. In AD, hippocampal neurons survive their fatal fate by triggering an aberrant structural and functional transformation of the nucleus. Lamin A expression and Tau protein transfer to the cytoplasm results in loss of the protector role of nuclear Tau and the subsequent global chromatin disorganization. Therefore, the cytoplasmic Tau protein accumulations that characterize AD are consequence of the attempted neuronal repair. Alzheimer’s neurons with unstructured nuclei and aberrant cytoskeletons manage to survive by sacrificing their plasticity, which inexorably leads to dementia. La demencia es un problema de salud pública que se ha incrementado a un ritmo desmedido. La enfermedad de Alzheimer (EA) es la causa más frecuente de demencia, considerada como consecuencia de acúmulos citoplasmáticos y extracelulares de proteína Tau y βamiloide, respectivamente. Sin embargo, recientemente ha emergido un origen nuclear . La proteína Tau y la lámina nuclear resguardan la organización nuclear y de la cromatina necesarias para la correcta expresión génica. El daño al DNA asociado al envejecimiento orilla a las neuronas posmitóticas a iniciar su reparación entrando en ciclo celular. La complejidad del núcleo-citoesqueleto impide su división y permanecen en estado de hiperdiploidía que, aun alargando la vida neuronal, culmina en su muerte. No obstante, en EA las neuronas del hipocampo sobreviven desencadenando una aberrante transformación estructural y funcional del núcleo a través de la expresión de lámina A y el trasvase al citoplasma de la proteína Tau, lo que conlleva la pérdida del rol protector de Tau nuclear y la desorganización cromatínica global. Así, los agregados de proteína Tau citoplasmática característicos de EA son consecuencia del intento de reparación neuronal. Estas neuronas con núcleos desestructurados y citoesqueletos aberrantes sobreviven sacrificando su plasticidad, lo que conduce inexorablemente a la demencia.

Neurocysticercosis (NCC) is a common disease produced by helminths (larval form of Taenia Solium) in the Central Nervous System (CNS). It is one of the common causes of epilepsy in the world. Without aggressive treatment, it continues to be associated with high mortality, with intracranial hypertension, and a lack of seizure control. This chapter reviews several cases of patients with secondary epilepsy who meet the diagnostic criteria for NCC and compares 2001 and 2016 diagnostic criteria: one of the cases with a definitive diagnosis, and the rest with a probable diagnosis. This problem is common for residents of regions where cysticercosis is an endemic zone, like in Mexico. Most patients presented clinical courses and image studies highly suggestive of NCC and positive ELISA testing for cysticerci in CSF. We emphasize the importance of ruling out the differential diagnosis, especially in endemic areas, questioning the use of ELISA in the CSF testing for cysticerci antibodies seems to be not enough, and advise caution when interpreting cystic lesions as having a discernible scolex because potential mimics are not infrequent.

Klüver-Bucy syndrome is a rare neurobehavioral disorder caused by a bilateral temporal lobe lesion affecting the hippocampus and amygdala; clinically characterised by hyperorality, hypermetamorphosis, placidity, altered sexual behaviour, eating, disorders and visual impairment, agnosia and amnesia. However, the complete syndrome is rarely seen, and diagnosis does not require all the symptoms to be manifested simultaneously.We describe a patient who developed a complete Klüver-Bucy syndrome secondary to bilateral temporal involvement due to herpetic encephalitis.

As in many parts of the world, lack of education, poverty and insufficient public health resources in Mexico result in the inability to make early and timely diagnoses. The new public health system (INSABI) offers free and universal support, but much work is needed to achieve this goal and ensure that patients with ALS have quality care. In private hospitals, care for patients with ALS, especially for those with resources, is possibly as good as in the best places in the first world. Neurology programs in Mexico are not sufficient to meet the country’s needs. Palliative measures, ventilation and nutrition support must be improved, and thanatology services in the country should be increased. Mexico continues as a place of opportunities where there is much to be done.

Multiple Sclerosis (MS) is the most common neurodegenerative disease among young adults. Diagnosis and progress monitoring of MS is performed by the aid of T2-weighted or T2 FLAIR magnetic resonance imaging, where MS lesions appear as hyperintense spots in the white matter. In recent years, multiple algorithms have been proposed to detect these lesions with varying results. In this work, a fully automatic method that does not rely on a priori anatomical information is proposed and evaluated. The proposed algorithm is based on an over-segmentation in superpixels and their classification by means of Gauss-Markov Measure Fields (GMMF). The main advantage of the over-segmentation is that it preserves the borders between tissues and may also reduce the execution time, while the GMMF classifier is robust to noise and also computationally efficient. The proposed segmentation is then applied in two stages: first to segment the brain region and then to detect hyperintense spots within the brain. The proposed method is evaluated with synthetic images from BrainWeb, as well as real images from MS patients. The proposed method produces competitive results without requiring user assistance nor anatomical prior information.

The protein alpha-synuclein (α-Syn) has been linked to neuroinflammatory conditions. We investigated whether the presence of α-Syn in peripheral tissues is a surrogate of brain inflammatory status in a small group of relapsing-remitting multiple sclerosis (RRMS) patients in a pilot cross-sectional study. Skin biopsies and peripheral blood were sampled from 34 healthy controls and 23 MS patients for measurement of α-Syn levels. Within the RRMS group 15 patients were in remission, and 8 patients were in the relapsing phase. The protein α-Syn was evaluated by means of immunohistochemistry and flow cytometry in skin and nucleated blood cells, respectively. In the skin, α-Syn levels were lower in relapsing MS than in the other groups, both in positive area (p = .021) and staining intensity (p = .004). In blood, the percentage of α-Syn-positive lymphocytes and monocytes were not statistically different between study groups. Moreover, the use of systemic steroids did not affect α-Syn positivity in MS-relapse patients. Finally, epidermic Langerhans cells did not stain positively for α-Syn. Overall, the levels of α-Syn positivity were lower in inflammatory relapse of RRMS patients when measured in peripheral tissues. We discuss the role of α-Syn levels in inflammation according to the obtained results.

Our objective is to review the initial presentation, evolution, progression, final stage, and images in the follow up of an adult patient who presented an uncommon peroxisomal disease (1/20,000 males) that occurred by ABCD1 gene mutation in the Xq28 chromosome; to bring forward the imaging features (which nowadays is the most useful and accessible diagnostic tool) and clinical presentation of adrenoleukodystrophy in adulthood; to propose a differential diagnosis in aid of a prompt recognition of the disease hereafter from a neurologist approach. In relation of a clinical case we reviewed the literature to correlate the principal findings and evolution of the disease. This thrilling but at the same time unfortunate disease is not only a diagnostic problem is also a therapeutic quest besides all the related familial, labor, and social related problems. The very-long chain fatty acids (VLCFA) accumulation leads to a not completely understood mechanisms that precipitate the specific malfunction of the nervous system and adrenal gland. The initial corticospinal bilateral involvement provokes a spastic paraparesis but with the affection of others pathways multiple manifestations appears, with dementia and finally loss of the most of cortical functions secondary to the white matter affection. Since the hematopoietic stem cell transplantation can be treated with variable results, other treatments, as the Lorenzo's oil, have not been consistent with a substantial improvement of the affected individual. The genetic advice and support to the patient and the family are essentials as well as the screening in individuals at risk before the onset of the disease., Highlights • Being more common in the pediatric population adrenoleukodystrophy is not well understood if it presents in adulthood. • The imaging features are almost unequivocal and should be helpful to differentiate from clinically similar diseases. • The disease onset with predominant affection of upper motor neuron is a diagnosis challenging. • The screening is a promising approach before the onset of the disease for counseling and therapeutic consideration. • Stem cell transplant, Lorenzo’s oil, and diet modifications are still insufficient to stop the progression of the disease. • The pathogenesis should be understood to search new and sufficient therapeutic approaches.

Dose individualization is essential in epilepsy treatment, especially in antiepileptic drugs that present high interindividual variability such as lamotrigine. We aimed an observational study to develop a population pharmacokinetic model for quantitative evaluation of the factors that influence lamotrigine pharmacokinetics in Mexican adults with epilepsy. Patients on stable treatment with lamotrigine therapy were included, plasma concentrations were analyzed by a high-performance liquid chromatography method and UGT2B7–161C > T polymorphism was determined. The data were analyzed by NONMEM® 7.3, model validation was performed using bootstrap approach and visual predictive check. Finally, stochastic simulations were carried out to propose dosage regimens. A total of 73 lamotrigine plasma concentrations from 2 h after last dose and up to 0.5 h prior to next administration were fitted to a one-compartment open model. The final population pharmacokinetic model for lamotrigine indicates that concomitant treatment with valproic acid and carbamazepine should be considered to individualize epilepsy treatment with this drug. Based on this model, we proposed dosage regimens to achieve trough lamotrigine concentrations within reference interval (2.5–15 mg/L). These results provide clinical useful data to give more rational anticonvulsant therapy in our population.

Thunderclap headache is a medical emergency presented as the worst headache ever, is characterised by an abrupt onset and maximal intensity within seconds to minutes. However, cerebrovascular causes are among the most common causes of thunderclap headache, and other non-vascular life-threatening aetiologies should be considered in evaluating a patient. We describe a 23-year-old previously healthy Latino woman who presented to our hospital after a month of repetitive severe, abrupt-onset headaches. Her prior medical history was unremarkable. After a normal brain MRI with angio-MRI, a lumbar puncture was performed with normal opening pressure, hypoglycorrhachia, increased proteins and a leucocyte; India ink staining was positive for encapsulated yeast, cultures were positive forCryptococcus gattii. The patient received appropriate antifungal treatment with a good response. This case highlights the particular presentation of cryptococcal meningitis due toC. gattiiamong immunocompetent patients.

Objective The purpose of this study was to evaluate the relation between cognitive performance and white matter (WM) integrity in patients with temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS). Methods We included 26 patients with TLE (10 right, 16 left onset) as well as 24 healthy controls matched for age, gender, and years of education. In addition to quantitative hippocampal volume and transverse relaxation (T2) evaluation, whole-brain WM was analyzed using fractional anisotropy (FA) maps, derived from the diffusion tensor model. Average FA values were obtained from 38 regions of interest (ROI) of the main WM fascicles using an atlas-based approach. All subjects underwent extensive coFignitive assessments, Wechsler Adult Intelligence Scale (WAIS-IV) and Wechsler Memory Scale (WMS-IV). Fractional anisotropy was correlated with neuropsychological scores, and group effects were evaluated. Finally, patients were clustered based on their cognitive performance to evaluate if clinical and structural variables relate to specific cognitive profiles. Results Patients had differential alterations in the integrity of the WM dependent on seizure laterality and presence of hippocampal sclerosis. Patients with TLE showed, on average, lower scores in most of the cognitive assessments. Correlations between cognition and WM followed specific trajectories per group with TLE, particularly in Left-TLE, in which we found a marked association between cognitive abilities and WM abnormalities. Cluster analysis of cognitive performance revealed three cognitive profiles, which were associated with the degree and spread of WM abnormalities. Significance White matter diffusion characteristics differ between patients, particularly in relation to seizure laterality and hippocampal damage. Moreover, WM abnormalities are associated with cognitive performance. The extent of WM alterations leads to disrupted cerebral intercommunication and therefore negatively affects cognition.

Background: Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by deterioration of the substantia nigra, resulting in a deficiency of dopamine. PD is considered a movement disorder associated with numerous non-motor symptoms related to Autonomic Nervous System failures which can precede the motor ones. Therefore, their awareness could be helpful in the diagnosis of PD at an early stage. Methods: Heart Rate Variability (HRV) is assessed by time and frequency domain indices, and by nonlinear indices based on symbolic dynamics and multiscale symbolic entropy. The features obtained were used to classify between PD patients and control volunteers using a support vector machine. Volunteers performed cardiovascular autonomic reflex tests: active standing, post- hyperventilation and controlled breathing. Results: Temporal and frequency indices showed significantly lower values in PD patients compared to control volunteers. Symbolic dynamics and multiscale symbolic entropy results suggest a decrease in the complexity of the HRV signal in PD patients, in contrast with a more variable pattern of words for control volunteers. During controlled breathing differences between groups were found with most of the indices computed. Additionally, classification process achieves good separability during cardiorespiratory maneuvers (>95% of accuracy) and features based on symbolic dynamics showed high discrimination between groups. Conclusions: The results found in this work suggest that the proposed methodological approach can classify PD patients in an early disease stage from healthy controls and give additional information about the cardiorespiratory system, which could be useful for diagnosis and follow up of PD patients.

Measurement of intra-abdominal pressure (IAP) is realized with the Kron's method. However, this technique has drawbacks like an infusion of water into the bladder of the patient.The prove a new novel disposable sensor in the way to measure the IAP (DSIAP) this one addresses some limitations of the Kron method.The DSIAP was tested in vitro and clinical settings. The proposed technique was compared with Kron's method through Pearson correlation and Bland-Altman analysis. For in vitro tests, 159 measurements were taken performed by simulating the IAP in the bladder. For the clinical test, 20 pairs of measurements were made in patients with routine IAP monitoring in the intensive care unit.In vitro measurements showed a strong correlation between the DSIAP and the reference (r = 0.99, p-value2.2 × 10The results suggest that the proposed DSIAP showed a profile similar to pressure transducers already in clinical use while overcoming some limitations of the former.La medición de la presión intraabdominal (PIA) generalmente se realiza con el método de Kron, a pesar de presentar inconvenientes como la infusión de agua en la vejiga del paciente.Introducir un nuevo sensor desechable para medir la PIA (SDPIA) que aborda algunas limitaciones del método de Kron.Se probó el SDPIA en pruebas in vitro y clínicas. La técnica se contrastó con el método de Kron empleando la correlación de Pearson y el análisis de Bland-Altman. Para las pruebas in vitro se realizaron 159 mediciones simulando la PIA en la vejiga. Para las pruebas clínicas se realizaron 20 mediciones en pacientes con monitorización rutinaria de la PIA en la unidad de cuidados intensivos.En las mediciones in vitro se encontró una alta correlación (r = 0.99; p2.2 × 10Los resultados sugieren que el SDPIA propuesto muestra un desempeño similar al de los transductores de presión actualmente en uso clínico, mientras sobrelleva algunas limitaciones de estos últimos.

The objective was to develop and externally validate a population pharmacokinetic model of levetiracetam in adult and elderly patients with epilepsy, and to perform dosing simulations to propose individualized dosing regimens more likely to achieve therapeutic concentrations. This prospective study included 367 plasma samples from 107 patients receiving oral levetiracetam. Samples were analyzed by HPLC-UV. Pharmacokinetic data, as well as patient demographic, clinical characteristics, other drug therapy, and the use of innovator or generic products of levetiracetam, were collected. Population modeling was performed with NONMEM and included internal and external validations of the final model. Simulations were used to propose optimized dosing regimens. The pharmacokinetics of levetiracetam was described by a one-compartment model with first-order absorption and linear elimination. Body surface area had a significant effect on the apparent volume of distribution, as did creatinine clearance (CrCL) over the drug clearance (p < 0.01). The final model performed adequately during external validation testing. The final model showed a better predictive performance. Dosing simulations support 1000 mg 12-hourly dosing of levetiracetam for patients with CrCL ~60-75 mL/min with higher dose needed for higher values (1500 mg 12-hourly for CrCL ~93-111 mL/min). Dosing regimens should be personalized to the patient's CrCL to maximize the likelihood of therapeutic concentrations.

COVID-19 has shown different neurological manifestations even sometimes there are the initial or the main presentation.The following case report is about a middle-aged woman who, over 3 days, developed fever, clinical neurological alterations (stupor, muteness, fixed gaze and catatonia), cerebrospinal fluid (16 lymphocytes) and an electroencephalogram (EEG) (4–6 Hz generalised activity) with characteristics of encephalitis. A serum IgG, IgM, nasopharyngeal swab PCR for SARS-CoV-2. The patient responded positively to support measures, symptomatic and corticosteroid treatment. At discharge, the patient was independent and improved considerably.We report the presence of catatonia as a possible and atypical manifestation of encephalitis in association with COVID-19.

Objective This study characterizes the expression of tau (p‐tau) and α‐synuclein (α‐syn) by immunohistochemistry in the skin of three different populations: healthy control (HC), Parkinson disease (PD), and progressive supranuclear paralysis (PSP) subjects, with the purpose of finding a biomarker that could differentiate between subjects with PD and PSP. Material and Methods We evaluated the presence of p‐tau and α‐syn in a pilot study in the skin of three distinct groups of patients: 17 healthy subjects, 17 patients with PD, and 10 patients with PSP. Four millimeters punch biopsies were obtained from the occipital area and analyzed by immunohistochemistry using antibodies against α‐syn and phosphorylated species of tau. PHF (paired helical filaments) antibody identifies p‐tau in both normal and pathological conditions and AT8 recognizes p‐tau characteristic of pathological conditions. Differences between the three groups were assessed by quantification of immunopositive areas in the epidermis. Results The immunopositivity pattern of p‐tau and α‐syn was significantly different among the three groups. Healthy subjects showed minimal staining using AT8 and α‐syn. The PD group showed significantly higher α‐syn and AT8 immunopositivity, while the PSP group only expressed higher AT8 immunopositivity than HCs. Conclusion These data suggest that the skin reflects brain pathology. Therefore, immunohistochemical analysis of p‐tau and α‐syn in the skin can be useful for further characterization of PD and PSP.

Objective The presence in the brain of α-synuclein containing Lewy neurites, or bodies, is the histological hallmark of Parkinson's disease (PD). The discovery of α-synuclein aggregates in nerve endings of the heart, digestive tract, and skin has lent support to the concept of PD as a systemic disease. Our goals were, first, to demonstrate the presence of α-synuclein inclusions in the skin and, second, to detect quantitative differences between patients with PD and atypical parkinsonism (AP). Methods Skin biopsies were taken from 67 patients and 20 controls. The biopsies underwent immunohistochemistry (IHC) and immunofluorescence (IF) testing for α-synuclein, whereupon its presence was quantified as the percentage of positive cells. Patients were divided into those with PD and those with AP. AP patients included AP with neurodegenerative disease (proteinopathies) and secondary AP. Results Sixty-seven patients (34 with PD) and 20 controls were recruited. In the PD group, α-synuclein was detected in 58% of the cells in the spinous cell layer (SCL), 62% in the pilosebaceous unit (PSU), and 58% in the eccrine glands (EG). The AP-proteinopathies group showed 7%, 7%, and 0% expression of α-synuclein, respectively. No expression was found in the skin of the control group. Conclusions The expression of α-synuclein in the skin was relatively high in the PD group, scarce in AP, and null for the individuals in the control group. While these findings require further confirmation, this minimally invasive technique may aid in the improvement of the accuracy of PD diagnoses.

TM ) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial. Acta Neurol Scand 2014: 129: 143‐153. © 2013 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objective – To evaluate the efficacy, tolerability, and safety of oncedaily 1200 mg and 2400 mg SPN-804 (Oxtellar XR TM , Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization. Methods – The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intentto-treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with ≥ 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration. Results – Median percent reduction was -28.7% for placebo, 38.2% (P = 0.08 vs placebo) for once-daily SPN-804 1200 mg, and 42.9% (P = 0.003) for SPN-804 2400 mg. Responder rates were 28.1%, 36.1% (P = 0.08), and 40.7% (P = 0.02); 16-week seizure-free rates in a pragmatic ITT analysis were 3.3%, 4.9% (P = 0.59), and 11.4% (P = 0.008), respectively. When data were analyzed separately for study site clusters, a post hoc analysis demonstrated that both SPN-804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: 13.3%; 1200 mg: 34.5%, P = 0.02; 2400 mg: 52.7%, P = 0.006) in the North American study site cluster. A concentration–response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug’s established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN-804 produces lower peak plasma concentrations vs immediate-release OXC. Once-daily dosing was not associated with any new safety signals. Conclusions – Adjunctive once-daily SPN-804 improved seizure control in patients with inadequately controlled partial-onset seizures. Adverse event occurrence and discontinuations due to adverse events suggest improved tolerability vs previously published data with immediaterelease OXC.

Background The misfolding and prion-like propagation of the protein alpha-synuclein (α-syn) is the leading molecular signature in Parkinson's disease (PD). There is a significant co-incidence of PD and melanoma which may suggest a shared pathophysiology. This study compared the presence of α-syn in neural crest-derived tissues, such as nevi, melanoma, skin tags and skin biopsies from PD cases and controls. Methods Biopsies from PD participants were obtained from patients of a tertiary referral center for dermatology and neurology in Mexico and a dermatopathology private center in Florida, USA, between January 2015 and March 2016. Biopsies from 7 patients with melanoma, 15 with nevi, 9 with skin tags, 8 with PD, and 9 skin biopsies from healthy volunteers were analyzed for immunohistochemical determination of α-syn and tyrosinase. All analyses were performed by pathologists blinded with respect to the clinical diagnosis. Results In healthy controls, α-syn immunopositivity was restricted to scattered cells in the basal layer of the epidermis and accounted for 1± 0.8% of the analyzed area. In PD patients, there was increased staining for α-syn PD (3.3 ± 2.3%), with a higher percentage of positive cells in nevi (7.7 ± 5.5%) and melanoma (13.6 ± 3.5%). There was no increased staining in skin tags compared to healthy controls. Conclusions Patients with PD and melanoma have increased staining for α-syn in their skin. We propose that neurons and melanocytes, both derived from neuroectodermal cells, may share protein synthesis and regulation pathways that become dysfunctional in PD and melanoma. This article is protected by copyright. All rights reserved.

Raman spectroscopy of biological tissue presents fluorescence background, an undesirable effect that generates false Raman intensities. This paper proposes the application of the Empirical Mode Decomposition (EMD) method to baseline correction. EMD is a suitable approach since it is an adaptive signal processing method for nonlinear and non-stationary signal analysis that does not require parameters selection such as polynomial methods. EMD performance was assessed through synthetic Raman spectra with different signal to noise ratio (SNR). The correlation coefficient between synthetic Raman spectra and the recovered one after EMD denoising was higher than 0.92. Additionally, twenty Raman spectra from skin were used to evaluate EMD performance and the results were compared with Vancouver Raman algorithm (VRA). The comparison resulted in a mean square error (MSE) of 0.001554. High correlation coefficient using synthetic spectra and low MSE in the comparison between EMD and VRA suggest that EMD could be an effective method to remove fluorescence background in biological Raman spectra.

Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genome-wide significant result ( P = 1.84 × 10 −8 ) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder of upper and lower motor neurons. Genetic variants in the paraoxonase gene cluster have been associated with susceptibility to sporadic ALS. Because these studies have yielded conflicting results, we have further investigated this association in a larger data set. Twenty SNPs spanning the paraoxonase gene cluster were genotyped on a panel of 597 case and 692 control samples and tested for association with risk of sporadic ALS and with ALS sub-phenotypes. Our study revealed two SNPs, rs987539 and rs2074351, within the paraoxonase gene cluster that are associated with susceptibility to sporadic ALS (uncorrected p=6.47E-04 and 7.87E-04, respectively). None of the 20 SNPs displayed significant associations with age of onset, site of onset or disease survival. Using a sliding window approach, we have also identified a 5-SNP haplotype that is significantly associated with risk of sporadic ALS (p=2.75E-05). We conclude that a common haplotype within the PON1 promoter region is associated with susceptibility to sporadic ALS.

Summary Purpose To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response. Methods Design was an open-label, multicenter study. Twenty-one children (4–12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20mg/(kgday) and titrated at 2-week intervals to 40 and then 60mg/(kgday). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale. Results Levetiracetam was rapidly absorbed following oral dosing, with median t max of 0.5h. Dose proportional increases were observed for C max and AUC (0–12) over the dose range; t 1/2 was 4.9h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7–13% faster and AUC was decreased by only 15–24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population ( n =21) and in 56% of those with seizures at baseline ( n =16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated. Conclusion Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy.