Stiripentol for focal refractory epilepsy.

BACKGROUND: This is an updated version of the original Cochrane review published in 2014 (Issue 1). For nearly 30% of people with epilepsy, seizures are not controlled by current treatments. Stiripentol is a new antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 for the treatment of Dravet syndrome as adjunctive therapy with valproate and clobazam, with promising effects. OBJECTIVES: To evaluate the efficacy and tolerability of stiripentol as add-on treatment for patients with focal refractory epilepsy who are taking AEDs. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (10 August 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; August 2015, Issue 8)and MEDLINE (Ovid) (1946 to 10 August 2015). We contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials. SELECTION CRITERIA: Randomised controlled add-on trials of stiripentol in patients with focal refractory epilepsy. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. MAIN RESULTS: On the basis of our selection criteria, we included no new studies in the present review. However, we did include one study from the earlier review (32 children with focal epilepsy). This study adopted a 'responder enriched' design and found no clear evidence of a reduction in seizure frequency (≥ 50% seizure reduction) (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82) nor evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43) when add-on stiripentol was compared with placebo. Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47). When specific adverse events were considered, confidence intervals were very wide and showed the possibility of substantial increases and small reductions in risks of neurological (RR 2.65, 95% CI 0.88 to 8.01) or gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group). The external validity of this study was limited because only responders to stiripentol (i.e. patients experiencing a ≥ 50% decrease in seizure frequency compared with baseline) were included in the randomised add-on placebo-controlled double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol than with add-on placebo. AUTHORS' CONCLUSIONS: Since the last version of this review was published, we have found no new studies. Hence, we have made no changes to the conclusions of this update as presented in the initial review. We can draw no conclusions to support the use of stiripentol as add-on treatment for focal refractory epilepsy. Additional large, randomised, well-conducted trials are needed.

Spinal cord involvement in patients with cirrhosis.

A severe spinal cord involvement may rarely occur in patients with cirrhosis and other chronic liver diseases; this complication is usually associated with overt liver failure and surgical or spontaneous porto-systemic shunt. Hepatic myelopathy (HM) is characterized by progressive weakness and spasticity of the lower extremities, while sensory and sphincter disturbances have rarely been described and are usually less important. The diagnosis is assigned in the appropriate clinical setting on clinical grounds after the exclusion of other clinical entities leading to spastic paraparesis. Magnetic resonance imaging is often unremarkable; however, also intracerebral corticospinal tract abnormalities have been reported recently. The study of motor evoked potentials may disclose central conduction abnormalities even before HM is clinically manifest. HM responds poorly to blood ammonia-lowering and other conservative medical therapy. Liver transplantation represents a potentially definitive treatment for HM in patients with decompensated cirrhosis of Child-Pugh B and C grades. Other surgical treatment options in HM include surgical ligation, shunt reduction, or occlusion by interventional procedures.

Stiripentol for focal refractory epilepsy.

BACKGROUND: Nearly 30%of people with epilepsy do not have their seizures controlled with current treatments. Stiripentol is a new antiepileptic drug(AED) developed in France and recently approved by the European Medicines Agency (EMA) for the treatment of Dravet syndrome as an adjunctive therapy with valproate and clobazam, with a promising effect. OBJECTIVES: To evaluate the efficacy and tolerability of stiripentol as add-on treatment for patients with focal refractory epilepsy taking any AEDs. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (19 August 2013), Cochrane Central Register of Controlled Trials(CENTRAL Issue 7, The Cochrane Library July 2013), MEDLINE (Ovid) (1946 to 19 August 2013) and EMBASE (31 May 2012).(The last search in EMBASE was made on 31th May 2012. Since then we no longer have access to that database.) We also contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials. SELECTION CRITERIA: Randomised controlled add-on trials of stiripentol in patients with focal refractory epilepsy. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion and extracted data. The outcomes investigated included 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. MAIN RESULTS: Using our selection criteria, one study was included (32 children with focal epilepsy). This study adopted a 'responder enriched' design.There was no clear evidence of a reduction in seizure reduction 50% seizure reduction) (RR 1.51, 95% CI 0.81 to 2.82) or in seizure freedom (RR 1.18, 95% CI 0.31 to 4.43) with add on stiripentol compared with placebo. Add-on stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47) compared with placebo. When considered as specific adverse events, the confidence intervals are very wide and include the possibility of substantial increases and small reductions in the risk of neurological (RR 2.65, 95% CI 0.88 to 8.01) or gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36). There was no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group). The external validity of the study was limited because only responders to stiripentol (that is patients experiencing at least a 50% decrease in seizure frequency compared with baseline) were included in the randomised add on placebo-controlled double-blind phase. Furthermore, a carry-over and a withdrawal effect probably affected the outcome related to seizure frequency. Although restricted by the very limited information derived by the only one included study, adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol compared with add-on placebo. AUTHORS' CONCLUSIONS: No conclusions can be drawn to support the use of stiripentol as add-on treatment for focal refractory epilepsy. Further large, randomised,well-conducted trials are needed.

Thiamine deficiency induced neurochemical, neuroanatomical, and neuropsychological alterations: a reappraisal.

Nutritional deficiency can cause, mainly in chronic alcoholic subjects, the Wernicke encephalopathy and its chronic neurological sequela, the Wernicke-Korsakoff syndrome (WKS). Long-term chronic ethanol abuse results in hippocampal and cortical cell loss. Thiamine deficiency also alters principally hippocampal- and frontal cortical-dependent neurochemistry; moreover in WKS patients, important pathological damage to the diencephalon can occur. In fact, the amnesic syndrome typical for WKS is mainly due to the damage in the diencephalic-hippocampal circuitry, including thalamic nuclei and mammillary bodies. The loss of cholinergic cells in the basal forebrain region results in decreased cholinergic input to the hippocampus and the cortex and reduced choline acetyltransferase and acetylcholinesterase activities and function, as well as in acetylcholine receptor downregulation within these brain regions. In this narrative review, we will focus on the neurochemical, neuroanatomical, and neuropsychological studies shedding light on the effects of thiamine deficiency in experimental models and in humans.

Antiepileptic drugs for the treatment of severe myoclonic epilepsy in infancy.

BACKGROUND: Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for whose treatment stiripentol (STP) has been recently licensed for add-on use. OBJECTIVES: To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) as therapy for patients with SMEI. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (15 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4 of 12, The Cochrane Library, April 2013), MEDLINE (1946 to May 2013) and SCOPUS (1823 to May 2013). The online trials registries ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were systematically searched. The bibliographies of any identified study were searched for further references. We handsearched selected journals and conference proceedings. No language restrictions were imposed. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single-blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. The following outcomes were assessed: at least 50% seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. Outcomes were assessed using a Mantel-Haenszel meta-analysis to calculate risk ratio (RR) with 95% confidence intervals (95% CIs). MAIN RESULTS: No RCTs assessing drugs other than STP were found. Two RCTs evaluating the use of STP (total of 64 children) were included. Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 vs 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 vs 1/31; RR 7.93, 95% CI 1.52 to 41.21). No significant difference in the proportion of dropouts was found in the STP group compared with the placebo group (2/33 vs 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects; higher proportions of participants were reported to experience side effects in the STP group compared with the placebo group (100% vs 25%; RR 3.73, 95% CI 1.81 to 7.67). AUTHORS' CONCLUSIONS: Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Further adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of SMEI.

Primary visual cortex excitability in migraine: a systematic review with meta-analysis.

The objective is to update and extend previous results of a systematic review of the literature with meta-analysis performed to determine the prevalence of phosphenes and the phosphene threshold (PT) values obtained during single-pulse transcranial magnetic stimulation (TMS) in adults with migraine. Both published and unpublished controlled studies measuring PT by single-pulse TMS in adults with migraine with or without aura (MA, MwA) were systematically reviewed. Prevalence of phosphenes and PT values were assessed calculating mean difference (MD) and odds ratio (OR) with 95 % confidence intervals (CI). Fifteen trials (369 migraine patients and 269 controls), were included. Patients with MA had a statistically significant lower PT compared with controls when a circular coil was used (MD: -22.27, 95 % CI -33.44 to -11.10); with a figure-of-eight coil the difference was not statistically significant. There was a significant higher phosphene prevalence in MA compared with controls (OR: 3.57, 95 % CI 1.16-10.94). No significant differences were found either in phosphene reporting between patients with MwA and controls, or in PT values obtained by figure-of-eight coil in subjects with MwA versus controls. In general, these results slightly support the hypothesis of a primary visual cortex hyper-excitability in MA, providing not enough evidence for MwA. A significant heterogeneity across studies probably reflects relevant clinical and methodological heterogeneity.

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.

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.

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.

Triphasic waves.

Triphasic waves (TWs) are a distinctive, although non-specific EEG pattern, which are quite frequently encountered and sometimes difficult to interpret. Although initially considered pathognomonic of hepatic encephalopathy, TWs have been described in association with a large number of conditions. TWs may occur in encephalopathies (metabolic or structural) or as an ictal pattern. Nonepileptic TWs with sharply contoured morphology may resemble epileptic patterns encountered in nonconvulsive status epilepticus (NCSE), thus leading to misinterpretation and overinterpretation of this pattern as ictal, if only the EEG is considered. An electroclinical response to benzodiazepines and the evaluation of consciousness impairment should be considered when interpreting TWs. Evaluating only the EEG without considering also clinical and laboratory findings is not only useless and meaningless, but may even lead to serious consequences.

ECG myogenic artifacts during clonic seizures: a disturbing (and interesting) finding.

During motor seizures myogenic artifacts may appear on ECG. We report a patient with recurring convulsive seizures involving left side of his body in whom ECG served as a surrogate of electromyography (EMG), showing myogenic artifacts strongly correlated with clonic jerks. The possibility of standard ECG of recording myogenic potentials when clonic seizures occur is something intriguing, being at the same time both disturbing and informative. In such cases standard ECG works as an EMG, although ECG filter, sensitivity and paper speed is different from EMG currently used in neurophysiological laboratory. However, using standard ECG acquisition parameters, muscular activity may be recorded without excessive attenuation of high-frequency myogenic potentials, permitting to indicate the frequency of clonic movements. On the other hand, whenever possible, positioning of ECG surface electrodes on limbs not (or less) involved in clonic epileptic movements may permit to obtain a sufficiently informative ECG recording with less amount of myogenic artifacts, thus providing essential information on heart rate and rhythm.

Insulin sensitivity is correlated with subcutaneous but not visceral body fat in overweight and obese prepubertal children.

AIM: Our aim was to explore the relationship between insulin sensitivity, body fat distribution, ectopic (liver and skeletal muscle) fat deposition, adipokines (leptin and adiponectin), and inflammation markers (highly sensitive C-reactive protein, IL-6, IL-10, and TNF-alpha) in prepubertal children. SUBJECTS AND METHODS: Thirty overweight and obese children (16 males and 14 females with body mass index z-score range of 1.1-3.2) were recruited. Body fat distribution and fat accumulation in liver and skeletal muscle were measured using magnetic resonance imaging. Insulin sensitivity was assessed by iv glucose tolerance test. RESULTS: Insulin sensitivity was associated with sc abdominal adipose tissue (SAT) (r = -0.52; P < 0.01) and liver fat content (r = -0.44; P < 0.02) but not with visceral abdominal adipose tissue (VAT) (r = -0.193; P value not significant) and fat accumulation in skeletal muscle (r = -0.210; P value not significant). Adipokines, but not inflammation markers, were significantly correlated to insulin sensitivity. VAT correlated with C-reactive protein (r = 0.55; P < 0.01) as well as adiponectin (r = -0.53; P <0.01). Multiple regression analysis showed that only SAT and liver fat content were independently correlated to insulin sensitivity (P < 0.01; 20 and 16% of explained variance, respectively). CONCLUSIONS: In overweight and moderately obese prepubertal children, insulin sensitivity was negatively correlated with SAT and liver fat content. Furthermore, contrary to adults, VAT and inflammation markers were not correlated with insulin sensitivity in children.