Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence.

High-dose benzodiazepine (BZD) dependence represents an emerging and under-reported addiction phenomenon and is associated with reduced quality of life. To date there are no guidelines for the treatment of high-dose BZD withdrawal. Low-dose slow flumazenil infusion was reported to be effective for high-dose BZD detoxification, but there is concern about the risk of convulsions during this treatment. We evaluated the occurrence of seizures in 450 consecutive high-dose BZD dependence patients admitted to our unit from April 2012 to April 2016 for detoxification with low-dose slow subcutaneous infusion of flumazenil associated with routine anticonvulsant prophylaxis. In our sample, 22 patients (4.9%) reported history of convulsions when previously attempting BZD withdrawal. Only four patients (0.9%) had seizures during ( n = 2) or immediately after ( n = 2) flumazenil infusion. The two patients with seizures during flumazenil infusion were poly-drug misusers. The most common antiepileptic drugs (AEDs) used for anticonvulsant prophylaxis were either valproate 1000 mg or levetiracetam 1000 mg. Our data indicate that, when routinely associated with AEDs prophylaxis, low-dose slow subcutaneous flumazenil infusion represents a safe procedure, with low risk of seizure occurrence.

Terminology of psychogenic nonepileptic seizures.

Several different terms have been used to describe "psychogenic nonepileptic seizures" (PNES) in the literature. In this study, we evaluated the most common English terms used to describe PNES on Google and in PubMed using multiple search terms (https://www.google.com and http://www.ncbi.nlm.nih.gov/pubmed). The information prevalence of the five terms most frequently used to refer to PNES in PubMed were: psychogenic non(-)epileptic seizure(s), followed by pseudo(-)seizure(s), non(-)epileptic seizure(s), psychogenic seizure(s), and non(-)epileptic event(s). The five most frequently adopted terms to describe PNES in Google were: psychogenic non(-)epileptic seizure(s), followed by non(-)epileptic event(s), psychogenic attack(s), non(-)epileptic attack(s), and psychogenic non(-)epileptic attack(s). The broad spectrum of synonyms used to refer to PNES in the medical literature reflects a lack of internationally accepted, uniform terminology for PNES. In addition to "seizure(s)," lay people use the word "attack(s)" to describe PNES. Although considered obsolete, some terms, e.g., pseudoseizure(s), are still used in the recent medical literature. Adopting a uniform terminology to describe PNES could facilitate communication between epileptologists, physicians without specific expertise in epilepsy, and patients.

Postictal serum creatine kinase for the differential diagnosis of epileptic seizures and psychogenic non-epileptic seizures: a systematic review.

The aim of this review was to evaluate the sensitivity and specificity of postictal creatine kinase (CK) levels in the differential diagnosis of epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES). A systematic search was conducted for studies that evaluated postictal CK levels in patients with ES (all types) and PNES. Sensitivity and specificity with 95 % confidence intervals were determined for each study, taking into account: (a) the upper limits adopted; and (b) the 95.7th percentile values, which are recently proposed practical upper reference limits for CK activity. Four studies, comprising a total of 343 events (248 ES and 95 PNES), were available for analysis. Most patients (47/78, 60 %) with ES considered had primarily or secondarily generalized tonic-clonic seizures. The sensitivity of increased postictal CK levels for ES ranged from 14.6 to 87.5, whereas specificity ranged from 85.0 to 100.0. At the 95.7th percentile threshold, sensitivity ranged from 14.6 to 62.5 and specificity was 100.0. The limited number of studies available, their small sample size, and lack of individual event data prevented further stratification analysis by seizure type. Despite the clinical heterogeneity and the limitations of the included studies, increased postictal CK levels are highly specific for the diagnosis of ES, although no definite conclusion on its role in differentiating between convulsive and non-convulsive ES can be drawn. Postictal serum CK levels can provide valuable retrospective information at the later stages of the differential diagnosis of ES and PNES. Due to low sensitivity, normal postictal CK levels do not exclude ES.

EEG-fMRI evaluation of patients with mesial temporal lobe sclerosis.

This preliminary study sought more information on blood oxygen level dependent (BOLD) activation, especially contralateral temporal/extratemporal spread, during continuous EEG-fMRI recordings in four patients with mesial temporal sclerosis (MTS). In two patients, EEG showed unilateral focal activity during the EEG-fMRI session concordant with the interictal focus previously identified with standard and video-poly EEG. In the other two patients EEG demonstrated a contralateral diffusion of the irritative focus. In the third patient (with the most drug-resistant form and also extratemporal clinical signs), there was an extratemporal diffusion over frontal regions, ipsilateral to the irritative focus. fMRI analysis confirmed a single activation in the mesial temporal region in two patients whose EEG showed unilateral focal activity, while it demonstrated a bilateral activation in the mesial temporal regions in the other two patients. In the third patient, fMRI demonstrated an activation in the supplementary motxor area. This study confirms the most significant activation with a high firing rate of the irritative focus, but also suggests the importance of using new techniques (such as EEG-fMRI to examine cerebral blood flow) to identify the controlateral limbic activation, and any other extratemporal activations, possible causes of drug resistance in MTS that may require a more precise pre-surgical evaluation with invasive techniques.

Reproducibility of EEG-fMRI results in a patient with fixation-off sensitivity.

Blood oxygenation level-dependent (BOLD) activation associated with interictal epileptiform discharges in a patient with fixation-off sensitivity (FOS) was studied using a combined electroencephalography-functional magnetic resonance imaging (EEG-fMRI) technique. An automatic approach for combined EEG-fMRI analysis and a subject-specific hemodynamic response function was used to improve general linear model analysis of the fMRI data. The EEG showed the typical features of FOS, with continuous epileptiform discharges during elimination of central vision by eye opening and closing and fixation; modification of this pattern was clearly visible and recognizable. During all 3 recording sessions EEG-fMRI activations indicated a BOLD signal decrease related to epileptiform activity in the parietal areas. This study can further our understanding of this EEG phenomenon and can provide some insight into the reliability of the EEG-fMRI technique in localizing the irritative zone.

Why do people Google epilepsy? An infodemiological study of online behavior for epilepsy-related search terms.

Millions of people worldwide use the Internet daily as a source of health information. Google is the most popular search engine and is used by patients and physicians to search for online health-related information. This study aimed to evaluate changes in web search behavior occurring in English-speaking countries over time for terms related to epilepsy and epileptic seizures. Using Google Trends, data on global search queries for the terms "epilepsy", "seizure", and "seizures" between January 2004 and September 2013 were analyzed. The reduction over time in search queries for the term "epilepsy" (and, to a lesser extent, "seizures") was counterbalanced by an increased trend in searches for the term "seizure". Most terms associated with the search queries were related to symptoms of seizures, especially tonic-clonic seizures, and to seizures occurring in children. Three peaks in search volume over the period studied corresponded to news of celebrities having seizures. The volume of searches for the term "epilepsy SUDEP" was found to be enormously increased over time. Most people appear to use search engines to look for terms related to epilepsy to obtain information on seizure symptoms, possibly to aid initial self-diagnosis. Fears and worries about epileptic seizures and news on celebrities with epilepsy seem to be major factors that influence online search behavior.

A common reference-based indirect comparison meta-analysis of intravenous valproate versus intravenous phenobarbitone for convulsive status epilepticus.

OBJECTIVE: To compare intravenous valproate (IV-VPA) with intravenous phenobarbitone (IV-PB) in the treatment of established generalised convulsive status epilepticus (GCSE). Efficacy and safety were estimated using a common-reference based indirect comparison meta-analysis (CRBMA) methodology. METHODS: Randomised controlled trials (RCTs) investigating the use of IV-VPA or IV-PB versus intravenous phenytoin (IV-PHT) for GCSE were identified by a systematic search of the literature. A random effects model was used to estimate Mantel-Haenszel odds ratios (ORs) for efficacy and safety of IV-VPA or IV-PB versus IV-PHT in a standard meta-analysis. Adjusted indirect comparisons were then made between VPA and PB using the obtained results. RESULTS: CRBMA showed that VPA does not lead to significantly higher seizure cessation (OR 1.00; 95% CI: 0.36-2.76) compared to PB, although it exhibits fewer adverse effects (OR 0.17; 95% CI: 0.04-0.71). Results of this CRBMA are consistent with results of a recently published head-to-head comparison of IV-VPA and IV-PB. CONCLUSION: There is insufficient evidence to demonstrate superiority of IV-VPA over IV-PB for the treatment of GCSE in terms of efficacy. Some direct and indirect comparisons suggest that VPA has a better safety profile than PB. However, the limited numbers of underpowered RCTs included in this meta-analysis are not sufficient to justify a change in clinical practice. More rigorous and appropriately powered RCTs are therefore required to definitively determine the efficacy and tolerability of VPA for the treatment of GCSE.

Visual cortex hyperexcitability in idiopathic generalized epilepsies with photosensitivity: a TMS pilot study.

BACKGROUND: The current understanding of the mechanisms underlying photosensitivity is still limited, although most studies point to a hyperexcitability of the visual cortex. METHODS: Using transcranial magnetic stimulation, we determined the resting motor threshold (rMT) and the phosphene threshold (PT) in 33 patients with IGEs (8 with photosensitivity) compared with 12 healthy controls. RESULTS: Eleven controls (92%) reported phosphenes compared with fifteen (46%) patients with idiopathic generalized epilepsy (p=0.015). Phosphenes were reported more frequently among patients with epilepsy with photosensitivity (87.5%) than in patients with active epilepsy without photosensitivity (30.8%) (p=0.038) and patients with epilepsy in remission without photosensitivity (33.3%) (p=0.054); no differences were found between patients with epilepsy with photosensitivity and controls (p=0.648). Resting motor threshold and phosphene threshold were significantly higher among patients with epilepsy (active epilepsy or epilepsy in remission without photosensitivity) compared to healthy controls (p<0.01). Conversely, patients with active epilepsy and photosensitivity had significantly lower values than controls (p=0.03). CONCLUSIONS: The marked decrease in PT and the high phosphene prevalence in patients with IGE with photosensitivity indicate a regional hyperexcitability of the primary visual cortex. Results of this study also suggest that the PT may serve as a biomarker for excitability in patients with IGE and photosensitivity.

Subclinical rhythmic electroencephalogram discharge of adults occurring during sleep: a diagnostic challenge.

Subclinical rhythmic electroencephalogram discharge of adults (SREDA) is an electroencephalogram (EEG) pattern of uncertain significance, which occurs without any correlation with epilepsy. It resembles epileptiform activity, and is therefore likely to be misinterpreted as an authentic epileptiform pattern. We describe the occurrence of SREDA during stage II nonrapid eye movement (NREM) sleep and discuss the diagnostic difficulties that may arise when such a pattern is encountered during sleep EEG recordings. SREDA may occur during sleep, leading to difficulties in correct identification of this pattern, as the patient is unconscious and unable to report any symptoms. Although there are rather distinctive EEG features, the lack of changes in electrocardiogram rhythm and the absence of ocular/muscular artifacts suggest a nonepileptic phenomenon. The ultimate diagnosis, and the correct identification of SREDA, may be achieved by a comparison of EEG features between the pattern occurring during sleep and that recorded in the awake state.

Clinical utility of ictal eyes closure in the differential diagnosis between epileptic seizures and psychogenic events.

The presence of ictal eye closure (IEC) has been considered to represent an additional clinical sign supporting the diagnosis of psychogenic non-epileptic events (PNEEs). We undertook a systematic review to evaluate sensitivity, specificity and likelihood ratios (LR) of IEC in the differential diagnosis between PNEEs and epileptic seizures. Six studies (total of 1496 events; 1021 epileptic seizures and 475 PNEEs) were included. Pooled accuracy measures of IEC for the diagnosis of PNEE were: sensitivity 58% (0.579) (95% CI 0.534-0.623), specificity 80% (0.895) (95% 0.875-0.9131)%, pLR 5.524 (95% CI 4.546-6.714) and nLR 0.47 (95% CI 0.422-0.524). However, a sensitivity analysis including only the studies performing an IEC assessment blinded to the diagnoses yielded results indicative of a rather low diagnostic value of IEC (pLR 3.056) compared with the analysis including unblinded studies (pLR 12.754). Further studies evaluating the occurrence of IEC through direct observation by means of video-EEG recording and blind to both EEG tracings and patient diagnosis are therefore required to definitely estimate the diagnostic utility of this sign in the differential diagnosis between epileptic seizures and PNEEs.

The diagnostic value of urinary incontinence in the differential diagnosis of seizures.

PURPOSE: Urinary incontinence may occur both in epileptic seizures (ES) and in non-epileptic events (NEE) such as psychogenic nonepileptic events (PNEEs) and syncope. A comprehensive search of the literature to determine the accuracy of this physical finding and its prevalence in epileptic seizures and syncope is still lacking. To undertake a systematic review to determine sensitivity, specificity and likelihood ratios (LR) of urinary incontinence in the differential diagnosis between ES and NEEs (including syncope and PNEEs). METHODS: Studies evaluating the presence of urinary incontinence in ES and NEEs were systematically searched. Sensitivity, specificity, positive and negative likelihood ratio (pLR, nLR) of incontinence were determined for each study and for the pooled results. RESULTS: Five studies (221 epilepsy patients and 252 subjects with NEEs) were included. Pooled accuracy measures of urinary incontinence (ES versus NEEs) were: sensitivity 38%, specificity 57%, pLR 0.879 (95% CI 0.705-1.095) and nLR 1.092 (95% CI 0.941-1.268). For each comparison (epileptic seizures versus NEEs; ES versus syncope; ES versus PNEEs), pooled accuracy measures for urinary incontinence showed a statistically not significant pLR (the 95% CI of the pooled value included 1, and the LR value of 1 has no discriminatory value). CONCLUSIONS: A pooled analysis of data from the literature shows that urinary incontinence has no value either in the differential diagnostic between ES and syncope/PNEEs. Systematic reviews with pooled analyses of data from the literature allow an increase in statistical power and an improvement in precision, representing a useful tool to determine the accuracy of a certain physical finding in the differential diagnosis between ES and other paroxysmal events.

Tongue biting in epileptic seizures and psychogenic events: an evidence-based perspective.

Tongue biting (TB) may occur both in seizures and in psychogenic non-epileptic events (PNEEs). We undertook a systematic review to determine sensitivity, specificity, and likelihood ratios (LR) of TB. Five studies (222 epilepsy patients and 181 subjects with PNEEs) were included. There was a statistically significant higher prevalence of TB (both without further specifications on site of lesions and lateral TB) in patients with seizures. Pooled accuracy measures of TB (no further specifications) were sensitivity 38%, specificity 75%, pLR 1.479 (95% CI 1.117-1.957), and nLR 0.837 (95% CI 0.736-0.951). Pooled measures of lateral TB were sensitivity 22%, specificity 100%, pLR 21.386 (95% CI 1.325-345.169), and nLR 0.785 (95% CI 0.705-0.875). Only a pooled analysis of data demonstrated a statistically significant pLR for lateral TB. Lateral TB but not 'any' TB has diagnostic significance in distinguishing seizures from PNEEs, supporting the diagnosis of seizures. Tongue biting without further specifications has, therefore, no value in the differential diagnosis between seizures and PNEEs.

Value of tongue biting in the differential diagnosis between epileptic seizures and syncope.

BACKGROUND: Tongue biting (TB) may occur both in epileptic seizures and in syncope. A comprehensive search of the literature to determine the accuracy of this physical finding and its prevalence in epileptic seizures and syncope is still lacking. AIMS: To undertake a systematic review and a meta-analysis of studies evaluating the prevalence of TB in patients with epileptic seizures and syncope, and to determine sensitivity, specificity and likelihood ratios (LR) of this physical finding. METHOD: Studies comparing the prevalence of TB in epileptic seizures and syncope were systematically searched. Prevalence of TB was analyzed calculating odds ratio (OR) with 95% confidence intervals (CIs). Sensitivity, specificity, positive and negative likelihood ratio (pLR, nLR) of TB were determined for each study and for the pooled results. RESULTS: Two studies (75 epilepsy patients and 98 subjects with syncope) were included. There was a significantly higher prevalence of TB in patients with epileptic seizures (OR 12.26; 95% CI 3.99-37.69). Pooled accuracy measures of TB for the diagnosis of epileptic seizures were: sensitivity 33%, specificity 96%, pLR 8.167 (95% CI 2.969-22.461) and nLR 0.695 (95% CI 0.589-0.82). CONCLUSIONS: A pooled analysis of data from the literature shows that TB has great value in the differential diagnosis between epileptic seizures and syncope. Given a certain pre-test probability of seizures, the presence of TB greatly increases the chance that the patient had an epileptic seizure. Systematic reviews with pooled analyses (meta-analyses) of data from the literature allow an increase in statistical power and an improvement in precision, representing a useful tool to determine the accuracy of a certain physical finding in the differential diagnosis between seizures and other paroxysmal events.

Resting motor threshold in idiopathic generalized epilepsies: a systematic review with meta-analysis.

Resting motor threshold (rMT) assessed by means of Transcranial Magnetic Stimulation (TMS) is thought to reflect trans-synaptic excitability of cortico-spinal neurons. TMS studies reporting rMT in idiopathic generalized epilepsies (IGEs) yielded discrepant results, so that it is difficult to draw a definitive conclusion on cortico-spinal excitability in IGEs by simple summation of previous results regarding this measure. Our purpose was to carry out a systematic review and a meta-analysis of studies evaluating rMT values obtained during single-pulse TMS in patients with IGEs. Controlled studies measuring rMT by single-pulse TMS in drug-naive patients older than 12 years affected by IGEs were systematically reviewed. rMT values were assessed calculating mean difference and odds ratio with 95% confidence intervals (CI). Fourteen trials (265 epileptic patients and 424 controls) were included. Patients with juvenile myoclonic epilepsy (JME) have a statistically significant lower rMT compared with controls (mean difference: -6.78; 95% CI -10.55 to -3.00); when considering all subtypes of IGEs and IGEs other than JME no statistically significant differences were found. Overall considered, the results are indicative of a cortico-spinal hyper-excitability in JME, providing not enough evidence for motor hyper-excitability in other subtypes of IGE. The considerable variability across studies probably reflects the presence of relevant clinical and methodological heterogeneity, and higher temporal variability among rMT measurements over time, related to unstable cortical excitability in these patients.

Transcranial magnetic stimulation of visual cortex in migraine patients: a systematic review with meta-analysis.

We systematically reviewed the literature to evaluate the prevalence of phosphenes and the phosphene threshold (PT) values obtained during single-pulse transcranial magnetic stimulation (TMS) in adults with migraine. Controlled studies measuring PT by single-pulse TMS in adults with migraine with or without aura (MA, MwA) were systematically searched. Prevalence of phosphenes and PT values were assessed calculating mean difference (MD) and odds ratio (OR) with 95 % confidence intervals (CI). Ten trials (277 migraine patients and 193 controls) were included. Patients with MA had statistically significant lower PT compared with controls when a circular coil was used (MD -28.33; 95 % CI -36.09 to -20.58); a similar result was found in MwA patients (MD -17.12; 95 % CI -23.81 to -10.43); using a figure-of-eight coil the difference was not statistically significant. There was a significantly higher phosphene prevalence in MA patients compared with control subjects (OR 4.21; 95 % CI 1.18-15.01). No significant differences were found either in phosphene reporting between patients with MwA and controls, or in PT values obtained with a figure-of-eight coil in MA and MwA patients versus controls. Overall considered, these results support the hypothesis of a primary visual cortex hyper-excitability in MA, providing not enough evidence for MwA. A significant statistical heterogeneity reflects clinical and methodological differences across studies, and higher temporal variabilities among PT measurements over time, related to unstable excitability levels. Patients should therefore be evaluated in the true interictal period with an adequate headache-free interval. Furthermore, skull thickness and ovarian cycle should be assessed as possible confounding variables, and sham stimulation should be performed to reduce the rate of false positives. Phosphene prevalence alone cannot be considered a measure of cortical excitability, but should be integrated with PT evaluation.

Focal nonconvulsive seizures during detoxification for benzodiazepine abuse.

Chronic benzodiazepine (BDZ) abuse is currently treated with detoxification using a low-dose flumazenil infusion, a relatively recently developed and promising procedure. Given the possibility reported in the literature of the occurrence of generalized seizures during therapeutic BDZ detoxification, we usually administer preventive antiepileptic drug (AED) therapy. We describe two patients with no previous history of seizures or evidence of intracerebral lesions who, during detoxification for benzodiazepine abuse, developed repetitive focal nonconvulsive seizures instead of generalized seizures, even with appropriate doses of preventive AED therapy. There are no previous reported cases of focal nonconvulsive seizures occurring during this procedure or, more generally, during abrupt BDZ discontinuation. The cases we describe suggest that during detoxification for BDZ abuse, not only generalized, but also focal nonconvulsive seizures may occur. In this context, the focal seizures probably result from a diffuse decrease in the seizure threshold (caused by a generalized excitatory rebound), which may trigger focal seizures arising from cortical regions with higher intrinsic epileptogenicity. Detoxification for benzodiazepine abuse, even if performed with adequate-dosage AED treatment, may not be as safe a procedure as previously considered, because not only convulsive, but also nonconvulsive seizures may occur and go unnoticed. It is therefore strongly advisable to perform this detoxification under close medical supervision and to maintain a low threshold for EEG monitoring in the event of sudden onset of behavioral changes.

The breach rhythm.

Electroencephalography (EEG) recordings obtained after craniotomy are difficult to interpret because of the presence of a breach rhythm (BR) consisting of unfiltered high-voltage physiological waveforms, sometimes with a spiky and irregular morphology, that can mimic interictal epileptiform abnormalities and may therefore lead to misinterpretations. In this article, we review EEG features of BR and give some technical tips to properly interpret BR and to make a correct differential diagnosis with epileptiform abnormalities. As BR itself has no relationship to epilepsy, it is very important to adopt a "conservative" reading, having a high threshold to call epileptiform abnormalities.

Infliximab-related seizures: a first case study.

Seizures following infliximab treatment are very rare and, to date, there is no detailed description of EEG abnormalities with cerebral radiological findings reported in cases with infliximab-related seizures. We describe a patient who acutely developed seizures temporally related to infliximab treatment, which disappeared after drug withdrawal. MRI showed encephalopathy involving mainly cortical regions and EEGs showed focal paroxysmal activity which completely disappeared a few days after infliximab withdrawal. No other plausible cause of the seizures was identified. The clear temporal association between seizure onset and infliximab treatment as well as the clinical improvement and disappearance of focal epileptiform activity after drug withdrawal indicated an evident correlation between seizures and infliximab therapy. The coexistence of pathological findings on MRI suggested that seizures were secondary to the encephalopathy. Further studies are required to evaluate whether infliximab per se has an epileptogenic effect or whether the seizures are caused by encephalopathy involving cortico-subcortical regions.