Neurofibromatosis type 1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis: what should be offered?

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in NF1 Recently, NF1 testing has been included as a clinical criterion for NF1 diagnosis. Additionally, preconception genetic counselling in patients with NF1 focuses on a 50% risk of transmitting the familial variant as the risk of having a sporadic NF1 is considered the same as the general population. METHODS: 829 individuals, 583 NF1 sporadic cases and 246 patients with NF1 with documented family history, underwent genetic testing for NF1. Genotyping and segregation analysis of NF1 familial variants was determined by microsatellite analysis and NF1 sequencing. RESULTS: The mutational analysis of NF1 in 154 families with two or more affected cases studied showed the co-occurrence of two different NF1 germline pathogenic variants in four families. The estimated mutation rate in those families was 3.89×10-3, 20 times higher than the NF1 mutation rate (~2×10-4) (p=0.0008). Furthermore, the co-occurrence of two different NF1 germline pathogenic variants in these families was 1:39, 60 times the frequency of sporadic NF1 (1:2500) (p=0.003). In all cases, the de novo NF1 pathogenic variant was present in a descendant of an affected male. In two cases, variants were detected in the inherited paternal wild-type allele. CONCLUSIONS: Our results, together with previous cases reported, suggest that the offspring of male patients with NF1 could have an increased risk of experiencing de novo NF1 pathogenic variants. This observation, if confirmed in additional cohorts, could have relevant implications for NF1 genetic counselling, family planning and NF1 genetic testing.

Revisiting the UK Genetic Severity Score for NF2: a proposal for the addition of a functional genetic component.

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by the development of multiple schwannomas, especially on vestibular nerves, and meningiomas. The UK NF2 Genetic Severity Score (GSS) is useful to predict the progression of the disease from germline NF2 pathogenic variants, which allows the clinical follow-up and the genetic counselling offered to affected families to be optimised. METHODS: 52 Spanish patients were classified using the GSS, and patients' clinical severity was measured and compared between GSS groups. The GSS was reviewed with the addition of phenotype quantification, genetic variant classification and functional assays of Merlin and its downstream pathways. Principal component analysis and regression models were used to evaluate the differences between severity and the effect of NF2 germline variants. RESULTS: The GSS was validated in the Spanish NF2 cohort. However, for 25% of mosaic patients and patients harbouring variants associated with mild and moderate phenotypes, it did not perform as well for predicting clinical outcomes as it did for pathogenic variants associated with severe phenotypes. We studied the possibility of modifying the mutation classification in the GSS by adding the impact of pathogenic variants on the function of Merlin in 27 cases. This revision helped to reduce variability within NF2 mutation classes and moderately enhanced the correlation between patient phenotype and the different prognosis parameters analysed (R2=0.38 vs R2=0.32, p>0001). CONCLUSIONS: We validated the UK NF2 GSS in a Spanish NF2 cohort, despite the significant phenotypic variability identified within it. The revision of the GSS, named Functional Genetic Severity Score, could add value for the classification of mosaic patients and patients showing mild and moderate phenotypes once it has been validated in other cohorts.

Psychogenic nonepileptic seizures: The effect of accurate diagnosis on cognition.

OBJECTIVE: Much remains to be elucidated about the cognitive profile of patients with psychogenic nonepileptic seizures (PNES) and about how this changes over time and compares to that of patients with epilepsy. The aim of this study was to study the neuropsychological profile of patients with PNES and an age-matched group of patients with temporal lobe epilepsy (TLE) during admission to a video electroencephalography monitoring unit (VEMU) and 1 year after discharge. METHODS: Patients diagnosed with PNES or TLE at a VEMU were prospectively recruited. Neuropsychological, demographic, clinical, and treatment variables were collected at baseline and 1 year. To minimize multiple comparisons, scores from different cognitive tests were computed for attention and psychomotor speed, verbal memory, visual memory, language, and executive function. A global cognitive impairment index (GCII) was also created. Post hoc analyses were conducted to identify clinical variables that might mediate the differences observed in cognition over time between the groups. These included seizure frequency, number of antiseizure medication (ASM), number of psychotropic drugs, depression, and quality of life. RESULTS: We studied 24 patients with PNES and 24 patients with TLE. The groups performed similarly in the baseline neuropsychological tests. There was a significant time (baseline to 1-year follow-up) by group (PNES vs TLE) interaction for the GCII (p = 0.006), language (p = 0.04), and executive function (p = 0.013), with PNES patients showing improvement and TLE patients remaining stable. The time by group interaction for attention and psychomotor speed showed a trend toward significance (p = 0.056), Reduction in number of ASM was associated with improved cognition in PNES patients at 1 year. CONCLUSION: PNES patients showed improved cognition at 1 year of follow-up, particularly in language and executive functions. This finding shows the potential benefits of an early, accurate diagnosis, which range from improved cognition to better management.

Correlation of blood biomarkers with early-onset seizures after an acute stroke event.

INTRODUCTION: Blood biomarkers have not been widely studied in stroke-related seizures. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and to analyze their association with early-onset seizures. METHODS: We retrospectively evaluated a panel of 14 blood biomarkers in 1115 patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z scores. We also recorded stroke and epilepsy-related variables, including stroke severity (National Institute of Health Stroke Scale [NIHSS] scores), type, and causes, time from onset of stroke to occurrence of early seizures, and type of seizure. Adjusted logistic regression models were built to identify clinical variables and biomarkers independently associated with early seizures. RESULTS: Mean ±â€¯standard deviation (SD) age was 72.3 ±â€¯13.2 years, and 56.8% of the patients were men. Thirty-eight patients (3.9%) developed early seizures with a median time to onset of 1 day (interquartile range (IQR), 0-4). A higher NIHSS score (odds ratio [OR] = 1.046; 95% confidence interval (CI): 1.001-1.094; p = 0.044) and hemorrhagic stroke (OR = 2.133; 95% CI: 1.010-4.504; p = 0.047) were independently associated with a greater risk of early seizures. Independent blood biomarkers predictive of early seizures were lower levels of tumor necrosis factor receptor 1 (TNF-R1) (<0.013) (p = 0.006; OR = 3.334; 95% CI: 1.414-7.864) and higher levels of neural cell adhesion molecule (NCAM) (>0.326) (p = 0.009; OR = 2.625; 95% CI: 1.271-5.420). The predictive power of the regression model was greater when clinical variables were combined with blood biomarkers (73.5%; 95% CI: 65.1%-81.9%) than when used alone (64%; 95% CI: 55%-72.9%). CONCLUSION: Higher NCAM and lower TNF-R1 levels may help predict the occurrence of early seizures. The combined use of these biomarkers and clinical variables could be useful for identifying patients at risk of seizures. This article is part of the Special Issue "Seizures & Stroke".

The prevalence of narcolepsy in Catalunya (Spain).

Previous studies have estimated an overall prevalence for narcolepsy between 15 and 70 cases per 100 000 inhabitants. We aimed to estimate the prevalence of narcolepsy in Catalunya (Catalonia), a north-east region of Spain (7 424 754 inhabitants), on 31 December 2014 by identifying all living subjects diagnosed with narcolepsy. First, we identified patients diagnosed by one of the 13 sleep, paediatric or neurological departments that perform tests regularly to diagnose narcolepsy. In a second phase, we searched for additional patients with narcolepsy in a clinical database of the primary health-care system. Clinical files were reviewed and narcolepsy diagnosis validated according to the Brighton Collaboration case definitions. Three hundred and twenty-five patients had a validated diagnosis of narcolepsy in the specialized centres (mean age: 44.6 years, range: 6-89; male: 60.3%; 85% with narcolepsy type 1), including 17.8% cases in Brighton, definition level 1, 62.5% in level 2, 15.4% in level 3 and 4.3% in level 4a. The overall prevalence for narcolepsy was 4.4; 3.7 for narcolepsy type 1 and 0.7 cases per 100 000 inhabitants for narcolepsy type 2. Fifty-six additional narcoleptic patients were identified in the primary health-care system, increasing the overall prevalence to 5.2 cases per 100 000 inhabitants. Prevalence rates for narcolepsy type 1 increased from childhood to adulthood, but in subjects aged more than 50 years there was a substantial drop in prevalence rates, suggesting the presence of a significant pool of undiagnosed cases in this population. Narcolepsy can be considered a rare neurological disorder in Catalunya.

Effect of lacosamide on depression and anxiety symptoms in patients with focal refractory epilepsy: A prospective multicenter study.

INTRODUCTION: Depression is the main psychiatric comorbidity in epilepsy with an estimated prevalence between 20% and 55% and one of the main determinants of quality of life. The aim of this study was to investigate the effect of lacosamide (LCM) on mood and anxiety symptoms in patients with focal onset seizures (FOS). The secondary objective was to evaluate if the potential modifications in variables were related to seizure control or to the intrinsic effect of LCM. MATERIAL AND METHODS: We performed a prospective multicenter study in 8 tertiary epilepsy centers in adults with FOS in which LCM was initiated as add-on therapy. Patients' mood and quality of life were evaluated through questionnaires and scales such as the Beck Depression Inventory-II (BDI-II), the State-Trait Anxiety Inventory (STAI-S/T), the Hospital Anxiety and Depression Scale (HADS), and the Quality of Life in Epilepsy-10 (QOLIE-10). Initiation of psychotropic medication was not allowed during the observation period. Patients with diagnosis of major depression or bipolar disorder were excluded. Evaluations were scheduled before LCM treatment, at 3 and 6months. RESULTS: Forty-nine patients were included (51% female) with an average age of 39.5years (range 18-65). At the start of treatment with LCM, 65.3% of the patients were on treatment with one antiepileptic drug (AED). Based on BDI-II, 38.8% of patients had depressive symptoms and 46.9% according to HADS Depression (HADS-D), 63.3% of patients presented pathological levels of anxiety (STAI-S/T), and 44.9% according to HADS Anxiety (HADS-A). Quality of Life in Epilepsy-10 showed that 57.1% of patients had a relevant reduction in their quality of life. After LCM, the score on the BDI-II depression scale decreased significantly (p<0.001). Based on the STAI and HADS-anxiety scales, patients who had a pathological anxiety at baseline, significantly improved. The QOLIE-10 improved significantly over the observation period (p<0.001). At 6months, 28.3% of patients were seizure-free (67.4% were responders). The improvements on depression and anxiety scores were not statistically related to seizure control. CONCLUSION: Lacosamide seems to have a positive effect on depressive and anxiety symptoms. Although the efficacy of LCM in seizure control was demonstrated, the antidepressant and anxiolytic effect on mood and anxiety seems to be an independent factor.

Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacy.

BACKGROUND: Some studies suggest higher efficacy of lacosamide (LCM) in status epilepticus (SE) with higher loading doses; however, this weight-adjusted dose has not been evaluated. OBJECTIVE: The objective was to evaluate the relationship between loading weight-adjusted dose and efficacy of LCM in SE. METHODS: A group of patients with SE treated with LCM from Spanish hospitals was examined retrospectively. Demographic data, type of SE, etiology, response rate, last antiepileptic drug (AED) used, treatment line in which LCM was used, total loading dose, and weight-adjusted dose were collected. RESULTS: One hundred sixty-five cases of SE were collected; 87 (52.7%) patients had nonconvulsive SE. Mean age was 64.2 ±â€¯17.2 and 60.6% (n = 100) were men. Regarding etiology, SE was considered as acute symptomatic in 85 (51.5%), remote symptomatic in 51 (30.9%), progressive symptomatic in 10 (6.1%), and cryptogenic in 19 (11.5%). Lacosamide was used as the third drug in 46.1%, and as a second option in 28%. In 115 patients, clonazepam had been used as the first option, and no benzodiazepines had been administered in the remaining 50. The median loading dose was 400 mg (100-600 mg), and the weight-adjusted dose was 5 mg/kg (3-6 mg/kg). The response rate was 63.3%, and 55.1% responded within the first 12 h. Efficacy was significantly higher in patients who had taken benzodiazepines at LCM loading doses >5.3 mg/kg (p = 0.006). This relationship was maintained independent of using other concomitant AEDs. However, if benzodiazepines were not taken, this relationship was not found. CONCLUSIONS: In adults with benzodiazepine-resistant SE, the response rate to LCM was higher, with weight-adjusted doses above 5.3 mg/kg.

Importance of neuropsychological and clinical features to predict seizure control in medically treated patients with mesial temporal epilepsy and hippocampal sclerosis.

OBJECTIVE: It is not yet understood why seizures in certain patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) develop resistance to antiepileptic drugs (AEDs) while others achieve good seizure control with this treatment. We analyzed clinical and neuropsychological features associated with seizure control in patients with MTLE-HS who had not undergone resective surgery. METHODS: We enrolled 40 patients with medically treated MTLE-HS and retrospectively collected the following data from prospective databases: sex, febrile seizures, central nervous system infection, history of head trauma, cognitive impairment, psychiatric disturbances, history of status epilepticus, age at onset of epilepsy, aura, seizure type and frequency, electroencephalography abnormalities, HS side, AEDs, global cognitive status, and neuropsychological functions such as cognitive processing speed, attention and executive functions, verbal and visual memory, language, and visuospatial ability. These factors were compared between patients who achieved seizure control (no seizures or a >50% reduction in seizure frequency) with AED treatment and those who continued with poor seizure control (increase or no change in frequency or <50% reduction) after starting treatment. RESULTS: The factors associated with poor seizure control in the multivariate analysis were >2seizures per month before treatment (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.2-4.8, p=0.04), moderate or severe cognitive impairment (OR 2.1, 95% CI 1.8-7.6, p=0.02), and impairment of >2 neuropsychological functions (OR 2.88, 95% CI 2-6.6, p=0.04). No associations were observed between poor seizure control and specific neuropsychological function impairment. CONCLUSIONS: Poor seizure control in MTLE-HS is associated with moderate-severe cognitive impairment but not with a specific profile of impairment. Recognizing poor prognostic features such as a high frequency of monthly seizures prior to starting AED treatment could help to identify patients with medically intractable MTLE-HS who may be good candidates for early epilepsy surgery.

Epileptiform electroencephalogram discharges increase seizure recurrence risk in patients with acute symptomatic seizure due to a structural brain lesion.

OBJECTIVE: The risk factors for seizure recurrence after acute symptomatic seizure due to a structural brain lesion are not well established. The aim of this study was to analyze possible associations between demographic, clinical, and electroencephalographic variables and epilepsy development in patients with acute symptomatic seizure due to an acute structural brain lesion. METHODS: We designed an observational prospective study of patients with acute symptomatic seizure due to an acute structural brain lesion (hemorrhagic stroke, ischemic stroke, traumatic brain injury, or meningoencephalitis) who underwent EEG during their initial admission between January 2015 and January 2020. We analyzed prospectively recorded demographic, clinical, electroencephalographic (EEG), and treatment-related variables. All variables were compared between patients with and without seizure recurrence during 2 years of follow up. RESULTS: We included 194 patients (41.2 % women; mean [SD] age, 57.3 [15.8] years) with acute symptomatic seizure due to an acute structural brain lesion. They all underwent EEG during admission and were followed for at least 2 years. The identifiable causes were hemorrhagic stroke (44.8 %), ischemic stroke (19.5 %), traumatic brain injury (18.5 %), and meningoencephalitis (17 %). Fifty-six patients (29 %) experienced a second seizure during follow-up. Seizure recurrence was associated with epileptiform discharges on EEG (52% vs 32 %; OR 2.3 [95 % CI, 1.2-4.3], p = 0.008) and onset with status epilepticus (17% vs 0.05 %, OR 4.03 [95 % CI 1.45-11.2], p = 0.009). CONCLUSIONS: Epileptiform discharges on EEG and status epilepticus in patients with acute symptomatic seizure due to an acute structural brain lesion are associated with a higher risk of epilepsy development.

Identifying risk for status epilepticus with the ADAN scale: a prospective multicenter validation study. / Escala ADAN para la identificación del estado epiléptico: estudio de validación prospectivo y multicéntrico.

OBJECTIVES: Status epilepticus (SE) is a serious event associated with high mortality. This study aims to validate the recently developed ADAN (Abnormal speech, ocular Deviation, Automatisms, and Number of motor epileptic seizures) scale for detecting high risk for SE. MATERIAL AND METHODS: Prospective, multicenter, observational study in adults with suspected epileptic seizures. Consecutive recruitment took place over a 27-month period in 4 hospital emergency departments (EDs). The main endpoint was the proportion of patients with criteria for SE based on the collection and analysis of clinical characteristics and the ADAN scale criteria on arrival at the ED. RESULTS: Of the 527 patients recruited, 203 (38.5%) fulfilled the criteria that predicted SE. Multiple regression analysis demonstrated that the 4 ADAN criteria were the only variables independently associated with a final diagnosis of SE (P .001). The predictive power of the scale was 90.9% (95% CI, 88.4%-93.4%) for a final SE diagnosis. We established 3 risk groups based on ADAN scores: low (score, 0-1: 8.7%), moderate (2, 46.6%), and high (> 2, 92.6%). A cut point of more than 1 had a sensitivity of 88.2% for predicting SE, specificity of 77.8%, positive predictive value of 71.3%, and negative predictive value of 91.3%. CONCLUSION: The ADAN scale is a prospectively validated, simple clinical tool for identifying patients in the ED who are at high risk for SE.

OBJETIVO: El estado epiléptico (EE) es una enfermedad grave con elevada mortalidad. Este estudio tiene como objetivo validar la escala ADAN, propuesta recientemente para identificar pacientes con alto riesgo de desarrollar un EE. METODO: Se realizó un estudio prospectivo, multicéntrico y observacional que incluyó a pacientes adultos con sospecha de crisis epilépticas. Se llevó a cabo un reclutamiento consecutivo durante 27 meses en los servicios de urgencias (SU) de cuatro hospitales. La variable principal fue la proporción de pacientes que cumplían criterios para EE. Se han recopilado y analizado las características clínicas y la puntuación en la escala ADAN a su llegada al SU. RESULTADOS: Se reclutaron 527 pacientes, de los cuales 203 (38,5%) cumplieron criterios de EE. En el análisis de regresión múltiple, se demostró que el habla anormal, la desviación ocular, los automatismos y el número de crisis epilépticas motoras fueron las únicas variables independientemente asociadas con un diagnóstico final de EE (p 0,001). La capacidad predictiva de la escala fue del 90,9% (intervalo de confianza del 95%, 88,4-93,4) para identificar el EE como diagnóstico final. Se establecieron tres grupos de riesgo: bajo (0 1 puntos: 8,7%), moderado (2: 46,6%) y alto (> 2: 92,6%). Una puntuación de corte > 1 punto proporcionó una sensibilidad del 88,2%, especificidad del 77,8%, valor predictivo positivo del 71,3% y valor predictivo negativo del 91,3% para predecir el EE. CONCLUSIONES: La escala ADAN es una herramienta clínica simple y validada de manera prospectiva para identificar, en los SU, a los pacientes con elevado riesgo de EE.

Exploratory study of blood biomarkers in patients with post-stroke epilepsy.

INTRODUCTION: In addition to clinical factors, blood-based biomarkers can provide useful information on the risk of developing post-stroke epilepsy (PSE). Our aim was to identify serum biomarkers at stroke onset that could contribute to predicting patients at higher risk of PSE. PATIENTS AND METHODS: From a previous study in which 895 acute stroke patients were followed-up, 51 patients developed PSE. We selected 15 patients with PSE and 15 controls without epilepsy. In a biomarker discovery setting, 5 Olink panels of 96 proteins each, were used to determine protein levels. Biomarkers that were down-regulated and overexpressed in PSE patients, and those that showed the strongest interactions with other proteins were validated using an enzyme-linked immunosorbent assay in samples from 50 PSE patients and 50 controls. A ROC curve analysis was used to evaluate the predictive ability of significant biomarkers to develop PSE. RESULTS: Mean age of the PSE discovery cohort was 68.56 ± 15.1, 40% women and baseline NIHSS 12 [IQR 1-25]. Nine proteins were down-expressed: CASP-8, TNFSF-14, STAMBP, ENRAGE, EDA2R, SIRT2, TGF-alpha, OSM and CLEC1B. VEGFa, CD40 and CCL4 showed greatest interactions with the remaining proteins. In the validation analysis, TNFSF-14 was the single biomarker showing statistically significant downregulated levels in PSE patients (p = 0.006) and it showed a good predictive capability to develop PSE (AUC 0.733, 95% CI 0.601-0.865). DISCUSSION AND CONCLUSION: Protein expression in PSE patients differs from that of non-epileptic stroke patients, suggesting the involvement of several different proteins in post-stroke epileptogenesis. TNFSF-14 emerges as a potential biomarker for predicting PSE.

Anakinra and tocilizumab in the chronic phase of febrile infection-related epilepsy syndrome (FIRES): Effectiveness and safety from a case-series.

PURPOSE: There is scarce evidence of effective treatments for the chronic phase of Febrile infection-related epilepsy syndrome (FIRES). This study aimed to analyze the outcomes of treatment with anakinra and tocilizumab. METHODS: Retrospective study including patients receiving either anti-interleukin-1 (anti-IL-1, anakinra) or anti-IL-6 (tocilizumab) during the chronic phase of FIRES. We evaluated seizure outcomes, non-seizure comorbidities, and adverse events. Additionally, an indirect control group including patients during the chronic phase of FIRES non-treated with-IL therapies was evaluated. RESULTS: Five patients were included; three females. Median age at FIRES: 8 years (IQR: 6-10). Five patients received anakinra; one patient switched to tocilizumab after ineffectiveness. Median treatment duration was 9months (IQR: 7-20). While no patients became seizure-free, 20-50% reduction in seizure frequency was reported in 3/5 patients after 6 months with anakinra. Retention rate was 100% at 6 months and 40% at 12months. Three patients reported reduced seizure intensity and rescue medication needed, and better behavior/communication. Similar improvement was reported for the patient switching to tocilizumab. Patients with the best response received anti-IL a median of 9 years after acute phase. All discontinuations were due to ineffectiveness. There were none relevant adverse events apart from one patient presenting transient seizure aggravation. Nine patients were included in the control group; none of them showed relevant improvement in seizure outcomes or cognitive/behavioral comorbidities. Only one presented mild improvement in seizure frequency during the 6-months follow-up. CONCLUSION: This study provides promising data on effectiveness/safety of anakinra and tocilizumab in the chronic phase of FIRES. These findings warrant prospective/larger studies.

ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis.

A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1/LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70-85% of familial schwannomatosis and 30-40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12-14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients' psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.

Clinical predictors of adverse events during continuous video-EEG monitoring in an epilepsy unit.

Patients admitted to epilepsy monitoring units (EMUs) for diagnostic and presurgical evaluation have an increased risk of seizure-related injury, particularly in the many cases in which medication is withdrawn. The purpose of this study was to assess the prevalence of adverse events (AEs) in this setting and to analyse associated clinical factors and costs. We evaluated consecutive patients admitted to an EMU at a tertiary care hospital over a 10-year period based on a descriptive, longitudinal study. We analysed the occurrence of AEs (traumatic injury, psychiatric complications, status epilepticus, cardiorespiratory disturbances, and death), investigated potential risk factors using univariate and multivariate logistic regression analysis, and compared admission costs between patients with and without AEs. In total, 411 EMU admissions were studied corresponding to 352 patients (55% women; mean [SD] age: 41.7 [12.1] years). Twenty-five patients (6%) experienced an AE. The most common event was traumatic injury (n=9), followed by status epilepticus (n=8), psychiatric complications (n=7), and cardiorespiratory disturbances (n=1). On comparing patients with and without AEs, we observed that the former were more likely to experience generalized seizures (OR: 7.81; 95% CI: 3.51-12.23; p<0.001) or have more seizures overall during admission (OR: 3.2; 95% CI: 1.42-6.8; p=0.002). Patients with AEs also had longer EMU stays (6.91 [2.64] vs 5.08 [1.1]; p=0.004), longer hospital stays (8.45 [3.6] vs 5.18 [1.2]; p<0.001), and higher costs (€7277.71 [€2743.9] vs €5175.7 [€1182.5]; p<0.001). Patients with generalized seizures and more seizures during admission were at greater risk of AEs, which were associated with higher admission costs.

Refractory status epilepticus: Impact of baseline comorbidity and usefulness of STESS and EMSE scoring systems in predicting mortality and functional outcome.

PURPOSE: Little has been published on the prognostic value of the Status Epilepticus Severity Score (STESS) or the Epidemiology-based Mortality score in Status Epilepticus (EMSE) in refractory status epilepticus (RSE). We sought to analyze the prognostic value of STESS and EMSE and the impact of baseline comorbidities in mortality and functional outcome in RSE. METHODS: We designed an observational retrospective study of patients diagnosed with RSE between August 2013 and September 2017. For each patient, we analyzed prospectively recorded demographic, clinical, comorbidity, electroencephalographic, treatment, and hospital stay-related data and calculated STESS and EMSE. All variables were compared statistically between patients with good and poor functional outcome at discharge and between patients who died in hospital and those who were alive at discharge. RESULTS: Fourty-nine patients had RSE; 35.4% died in hospital and 88% showed functional decline at discharge. Mortality was associated with baseline chronic kidney disease (CKD) (OR 19.25, p = 0.006), baseline modified Rankin scale score (mRS) (OR 3.38, p = 0.005), non-convulsive status epilepticus (NCSE) with coma (OR 11.9, p = 0.04), STESS (OR 2, p = 0.04), and EMSE (OR 1.3, p = 0.02). Functional outcome was associated with baseline mRS (OR 13.9, p = 0.02), and EMSE (OR 1.3, p = 0.02). The optimal cutoff scores for predicting mortality were 4 for STESS and 60 for EMSE. EMSE predicted functional outcome with an optimal cutoff of 40. CONCLUSIONS: CKD, NCSE with coma and STESS were associated with mortality. mRS and EMSE were associated with mortality and functional outcome. EMSE was useful for predicting functional outcome, while EMSE and STESS were useful for predicting in-hospital mortality.

Early Genetic Diagnosis of Neurofibromatosis Type 2 From Skin Plaque Plexiform Schwannomas in Childhood.

Importance: Neurofibromatosis type 2 (NF2) is a devastating genetic condition characterized by the development of multiple tumors of the nervous system. An early diagnosis of individuals with NF2 would facilitate treatment and reduction of disease impact because most severe effects of the disease do not usually develop before adolescence. Little attention has traditionally been paid to dermatological signs in NF2. However, skin plaques are commonly seen in patients with NF2, normally appearing either at birth or early childhood, providing an opportunity for early NF2 detection and testing. Objective: To determine the clinical utility of skin plaque identification and characterization in children for reaching an early diagnosis of patients with NF2 and to evaluate their molecular pathogenesis and their use in the genetic diagnostics of NF2. Design, Setting, and Participants: Diagnostic test study by the histological and genetic characterization of skin plaques from patients with NF2. Patients were 7 individuals with NF2 or clinical suspicion of NF2 treated at the Spanish Reference Center on Phakomatoses. Main Outcomes and Measures: Histological evaluation of all skin plaques was performed. Fresh skin plaques were cultured to obtain Schwann cells and the NF2 gene was genetically analyzed. For all 7 patients, NF2 clinical history was reviewed. Results: In all 7 patients (4 male and 3 female), all skin plaques analyzed were histologically characterized as plexiform schwannomas. Genetic analysis of primary Schwann cell cultures derived from them allowed the identification of a constitutional and a somatic NF2 mutation. Genetic testing allowed the early diagnosis of NF2 in a child only exhibiting the presence of skin plaques. Most of the patients with NF2 analyzed had an early presentation of skin plaques and a severe NF2 phenotype. Conclusions and Relevance: This work emphasizes the clinical utility of a careful dermatological inspection and the correct identification of skin plaques in children for an early diagnosis of NF2. We show for the first time that Schwann cells derived from skin plaque plexiform schwannomas bear the double inactivation of the NF2 gene and thus constitute an excellent source of tissue for genetic testing, especially in the context of mosaicism.

Pregabalin as add-on therapy for refractory partial seizures in every day clinical practice.

We retrospectively reviewed our clinical experience with PGB when used as add-on therapy in 101 patients (56 women and 45 men) with refractory partial epilepsy, who have been followed up for at least 1 year. Mean age was 40 years (16-64); mean number of concomitant AEDs was 2.8. Most patients (43) had temporal lobe epilepsy. Median number of seizures per month was 16 (3-240). Mean PGB dose used was 412.5 mg. Responder rate (percentage of patients with >or=50% seizure reduction) at 6 and 12 months was 52% and 39.6%, respectively. Seizure freedom for at least 6 and 12 months has been achieved by 12 patients (11.8%) and 6 patients (5.9%) respectively. At 1 year, 61 patients (60.4%) are still taking PGB. Forty patients have discontinued PGB, because of inefficacy (16 patients, 15.8%), adverse effects (15 patients, 14.8%) or both (9 patients, 8.9%). Sixty per cent of patients reported adverse events, being weight gain (>10% body weight) the most frequent, seen in 26 patients (25.7%). Dizziness/ataxia was seen in 20 (19.8%). Adverse effects were generally mild to moderate.

Hypoglycemic seizures and epilepsy in type I diabetes mellitus.

PURPOSE: (1) To determine the characteristics of seizures and/or epilepsy among patients with adult onset type 1 diabetes mellitus (T1DM), and (2) to determine glutamic acid decarboxylase antibody (antiGADab) titres and other autoimmune characteristics of T1DM patients with seizure and/or epilepsy. METHODS: Patients were recruited after reviewing the databases of one Diabetes Unit and two Epilepsy Units. Prevalence of suffering epilepsy and/or seizures was calculated in the group of adult onset T1DM patients seen consecutively in the Diabetes Unit. Serum antiGADab titres were determined in all patients. RESULTS: Among the 229 T1DM patients, two had suffered hypoglycemic seizures (0.87%) and two unprovoked seizures (0.87%). We recruited 11 of these T1DM patients. Five reported only hypoglycemic seizures, and 6 temporal lobe epilepsy (TLE). Mean antiGADab titres in patients with T1DM and hypoglycemic seizures were lower (18.42 IU) than in those with T1DM and TLE (29.200 IU), p: 0.006. Patients with T1DM and TLE suffered more other autoimmune diseases than those with T1DM and hypoglycemic seizures, p: 0.015. CONCLUSIONS: Hypoglycemic seizures are rare in T1DM patients. AntiGADab titres do not differ from the general diabetic population. Patients with high titres of antiGADab are more likely to develop TLE.

Review of therapeutic options for adjuvant treatment of focal seizures in epilepsy: focus on lacosamide.

Epilepsy is one of the most common serious neurological conditions worldwide, with an age-adjusted incidence of approximately 50 per 100,000 persons per year in developed countries. Antiepileptic therapy can result in long-term remission in 60-70% of patients, but many patients will require combination treatment to achieve optimal seizure control, as monotherapy is ineffective at controlling seizures in 30-53% of patients. Despite the increase in available treatment options, patient outcomes have not improved significantly and there is still a need for more effective therapies. Drugs used in the treatment of focal-onset seizures are a diverse range of compounds, and in most cases their mechanism of action is unknown or poorly defined. This review discusses the efficacy and safety of the newer adjuvant antiepileptic therapies that may improve outcomes in patients unresponsive to monotherapy, including clobazam, vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam, oxcarbazepine, pregabalin, zonisamide and eslicarbazepine, with focus on lacosamide. Lacosamide has been shown to exert its anticonvulsant effects predominantly by enhancement of the slow inactivation of voltage-gated sodium channels. Lacosamide is indicated for use as adjuvant treatment of focal-onset seizures in patients with epilepsy, and there is some evidence that it may also be of use in patients with status epilepticus and cancer patients with epilepsy. The efficacy of lacosamide has been assessed in three randomized, double-blind, placebo-controlled clinical trials, all of which have shown lacosamide to be effective at reducing seizure frequency and increasing 50% responder rates in patients with focal-onset seizures. Long-term lacosamide treatment is generally well tolerated and is not associated with significant drug interactions; the availability of an intravenous form of the drug also makes it particularly useful for a broad range of patients.