The aim of this systematic review was to collect and analyze all the RCTs and observational studies investigating the efficacy of ketogenic diet (KD) in infantile spasms (IS) patients after a 1‐ to ...6‐month follow‐up period, in terms of decrease in seizure frequency of >50% or a seizure‐free interval. Moreover, the potential effect of gender, IS etiology, age at onset of IS, and age at start of KD have been investigated. Finally, we evaluated the seizure‐free rate at 12 and 24 months of follow‐up.
In June 2016, a computer search was performed on MedLine (PubMed), EMBASE, and the Cochrane Library. Only, English language studies conducted after 1980 and those reporting in detail the variation in seizure frequency have been selected.
Thirteen observational studies (341 patients) were included in the final analysis. A median rate of 64.7% of patients experienced a spasm reduction >50% (IQR: 38.94%). The median spasm‐free rate was 34.61% (IQR: 37.94%). IS of unknown etiology seemed to have an increased probability of achieving freedom from seizures (RR: 1.72, 95%CI: 1.18‐2.53). Long‐time follow‐up data revealed a median seizure‐free rate of 9.54% (IQR: 18.23%).
Although the literature is still lacking in high‐quality studies, which could provide a stronger level evidence, our findings suggest a potential benefit of KD for drug‐resistant IS patients.
To assess incidence and predictors of acute symptomatic seizures in a prospective cohort of patients with first stroke.
Patients with first stroke hospitalized in 31 Italian centers were recruited. ...Relevant demographic data, disease characteristics, and risk factors were collected. Acute symptomatic seizures (≤7 days) were recorded and correlated to age, gender, family history of epilepsy, and vascular risk factors.
A total of 714 patients (315 women, 399 men; age 27-97 years) were enrolled. A total of 609 (85.3%) had cerebral infarction (32 cerebral infarction with hemorrhagic transformation CIHT) and 105 (14.7%) primary intracerebral hemorrhage (PIH). A total of 141 (19.7%) had a large lesion (>3 cm) and 296 (41.5%) cortical involvement. Twelve patients reported family history of seizures. Forty-five patients (6.3%) presented acute symptomatic seizures, 24 with cerebral infarction (4.2%), 4 with CIHT (12.5%), and 17 (16.2%) with PIH. In multivariate analysis, compared to cerebral infarction, PIH carried the highest risk (odds ratio OR 7.2; 95% confidence interval CI 3.5-14.9) followed by CIHT (OR 2.7; 95% CI 0.8-9.6). Cortical involvement was a risk factor for PIH (OR 6.0; 95% CI 1.8-20.8) and for CI (OR 3.1; 95% CI 1.3-7.8). Hyperlipidemia (OR 0.2; 95% CI 0.03-0.8) was a protective factor for IPH.
The incidence of acute symptomatic seizures is the highest reported in patients with first stroke with prospective follow-up. Hemorrhagic stroke and cortical lesion were independent predictors of acute symptomatic seizures. Hyperlipidemia was a protective factor for hemorrhagic stroke.
Epilepsy is a chronic condition that may be associated with several other diseases. In these cases, we should consider the following points: (1) antiepileptic drug (AED) treatment may positively or ...negatively affect comorbid disease, (2) drugs used for treatment of co‐morbid disease may influence seizure threshold, (3) AED toxicity can be affected by a comorbid condition and (4) co‐administration of AEDs with drugs used for treatment of comorbid conditions can be associated with clinically relevant drug–drug interactions. In this article, we discuss problems that are usually encountered when an appropriate AED treatment has to be selected in newly diagnosed epileptic patients who also have (an)other neurological disease(s). Comorbidity of epilepsy with cerebrovascular diseases, dementias, mental retardation, attention deficit and hyperactivity disorder, brain tumours, infections of the CNS, migraine, sleep disturbances (obstructive sleep apnoea syndrome), substance abuse and multiple sclerosis is discussed.
Perampanel is a new chemical entity recently approved in the United States (US) and European Union (EU) as adjunctive treatment of partial-onset seizures with and without secondary generalization in ...patients with epilepsy aged 12 years and older. Pharmacological studies suggest that perampanel acts with a new mechanism of action via non-competitive antagonism of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor of glutamate, the main mediator of excitatory neurotransmission in the central nervous system.
Perampanel is completely absorbed after oral administration. The drug is 95% bound to plasma proteins and is extensively metabolized by oxidation followed by glucuronidation. Perampanel has an elimination half-life of approximately 52–129h, allowing once daily dosing, with peak plasma levels observed 0.25–2h post-dose. Randomized placebo-controlled trials of adjunctive treatment have demonstrated that once-daily perampanel doses of 4–12mg/day significantly reduced partial-onset seizure frequency in patients with pharmacoresistant epilepsy along with a favorable tolerability profile. In perampanel pivotal trials, the most frequently reported treatment emergent adverse events (>10%) included dizziness, somnolence, fatigue and headache. Perampanel therapeutic response was maintained in patients included in the long term open-label extension studies for up to 4 years. Based on these data, perampanel offers a valuable option in the add-on treatment of partial-onset and secondarily generalized seizures.
Background and purpose
To identify adverse events (AEs) significantly associated with perampanel treatment in double‐blind clinical studies (RCTs). Serious AEs, study withdrawals due to AEs and ...dose–effect responses of individual AEs were also investigated.
Methods
All placebo controlled, double‐blind RCTs investigating therapeutic effects of oral perampanel were searched. AEs were assessed for their association with perampanel after exclusion of synonyms, rare AEs and non‐assessable AEs. Risk difference (RD) was used to evaluate the association of any AE (99% confidence intervals) and withdrawals or serious AEs (95% confidence intervals) with perampanel.
Results
Nine RCTs (five in pharmacoresistant epilepsy and four in Parkinson's disease) were included in our study. Almost 4000 patients had been recruited, 2627 of whom were randomized to perampanel and treated with drug doses of 0.5 mg/day (n = 68), 1 mg/day (n = 65), 2 mg/day (n = 753), 4 mg/day (n = 1017), 8 mg/day (n = 431) or 12 mg/day (n = 293). Serious AEs were not significantly associated with perampanel treatment. The experimental drug was significantly associated with an increased risk of AE‐related study withdrawals at 4 mg/day RD (95% confidence interval) 0.03 (0.00, 0.06) and 12 mg/day RD (95% confidence interval) 0.13 (0.07, 0.18). Of 15 identified AEs, five (dizziness, ataxia, somnolence, irritability and weight increase) were found to be significantly associated with perampanel and one (seizure worsening) was significantly associated with placebo.
Conclusions
Vestibulocerebellar AEs (dizziness, ataxia), sedative effects (somnolence), irritability and weight increase were significantly associated with perampanel treatment.
Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine‐resistant convulsive status epilepticus and several guidelines ...recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time‐consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine‐resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment.
Objective – A review of long‐term open‐label studies was performed with the aim of detecting differences in efficacy and/or tolerability of new antiepileptic drugs (AEDs).
Methods – From more than ...500 open studies conducted to evaluate the efficacy and tolerability of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB), tiagabine (TGB), topiramate (TPM) or zonisamide (ZNS), we selected all studies that reported or allowed us to calculate the number of patients who achieved seizure freedom for 6 months and/or the number of patients withdrawing for adverse effects and/or the number or percentage of patients continuing treatment after 1 year.
Results – No studies were found in which this information was available for OXC, PGB, TGB or ZNS. The number of patients who achieved seizure freedom for 6 months was reported in four studies each for GBP and TPM, five studies for LTG, and eight studies for LEV. The best efficacy profile using this end point was found for LEV, followed by TPM, LTG, and GBP. Twenty‐two studies reported the number of patients withdrawing due to adverse effects. LEV was the best‐tolerated AED, a little ahead of LTG, and significantly better than GBP or TPM . TPM was by far the least well‐tolerated drug. Information concerning patients continuing treatment after 1 year was reported in two GBP studies, two TPM studies, six LEV studies and five LTG studies. GBP had a very low retention rate (between 20% and 25% of patients continued the drug), while TPM and LTG had a retention rate of 40–60% and LEV had a retention rate of 60–75%.
Conclusion – One limitation of these rankings is that their statistical value is limited because of the indirect nature of the comparisons. Anyhow, this review covers the main studies published thus far on this subject and provides full updated information on the current literature about these drugs.
Deficient voluntary control of behaviour and impulsivity are key aspects of impulse control disorders. The objective of the present study was to evaluate the relationship between behavioural measures ...of impulsivity and the awareness of voluntary action. Seventy‐four healthy volunteers completed the Barratt Impulsiveness Scale (BIS), a questionnaire used to measure impulsive personality traits, and a go/no‐go task. Moreover, all participants performed a behavioural task based on the Libet's clock paradigm in which they were requested to report the time of a self‐initiated movement (M‐judgement) or the time they first feel their intention to move (W‐judgement). A positive relationship between the time in which subjects reported the intention to move (W‐judgement) and impulsivity measures emerged. Namely, the higher was the score in the attentional and motor impulsivity subscales of the BIS and the number of inhibitory failure responses in the go/no‐go task, the lower was the difference between the W‐judgement and the actual movement (i.e. the awareness of intention to move was closer to the voluntary movement execution). In contrast, no relationship emerged with M‐judgement. The present findings suggest that impulsivity is related to a delayed awareness of voluntary action. We hypothesize that in impulse control disorders, the short interval between conscious intention and actual movement may interfere with processes underlying the conscious ‘veto’ of the impending action.
Our goal was to test the hypothesis that impulsivity could be related to a delayed awareness of voluntary action. Our main finding was that in healthy participants the time between the conscious intention to move and the execution of a self‐initiated movement is related to impulsive personality traits. These data may have potential clinical implications, e.g. in Parkinson's disease, in order to identify patients at risk to develop impulse control disorders.
Systematic review and meta-analysis of the most frequent treatment-emergent central nervous system adverse events (CNS AEs) of new antiepileptic drugs (AEDs) from double-blind, add-on, ...placebo-controlled studies conducted in adult epileptic patients and identification of dose-adverse effect relationships.
Trial reports found by searching Medline and journals. Outcome was the number of patients complaining of treatment-emergent CNS AEs. Sixteen predefined CNS AEs were considered. Risk differences (RDs) were calculated for individual studies and summary statistics estimated using the random effect model. Predefined CNS AEs in patients treated with active drug (broken down into dose levels) or placebo were extracted and the RDs (95% CI) for CNS AEs were calculated.
Thirty-six suitable studies identified. No meta-analysis was possible for oxcarbazepine and tiagabine (only one study each included). For these drugs RDs were calculated from single studies. Gabapentin was significantly associated with somnolence 0.13 (0.06-0.2) and dizziness 0.11 (0.07-0.15); lamotrigine with dizziness 0.11 (0.05-0.17), ataxia 0.12 (0.01-0.24) and diplopia 0.12 (0.00-0.24); levetiracetam with somnolence 0.06 (0.01-0.11); pregabalin with somnolence 0.11 (0.07-0.15), dizziness 0.22 (0.16-0.28), ataxia 0.10 (0.06-0.14) and fatigue 0.04 (0.01-0.08); topiramate with somnolence 0.09 (0.04-0.14), dizziness 0.06 (0.00-0.11), cognitive impairment 0.14 (0.06-0.22) and fatigue 0.06 (0.01-0.12); zonisamide with somnolence 0.06 (0.02-0.11) and dizziness 0.06 (0.00-0.12). The dose-response relationship was analysed only for those CNS AEs significantly associated with the AED.
No comparison between drugs was possible. One CNS AE was significantly more frequent for levetiracetam, two for zonisamide and gabapentin, three for lamotrigine and four for pregabalin and topiramate.
Synchronization of body movements to an external beat is a universal human ability, which has also been recently documented in nonhuman species. The neural substrates of this rhythmic motor ...entrainment are still under investigation. Correlational neuroimaging data suggest an involvement of the dorsal premotor cortex (dPMC) and the supplementary motor area (SMA). In 14 healthy volunteers, we more specifically investigated the neural network underlying this phenomenon using a causal approach by an established 1-Hz repetitive transcranial magnetic stimulation (rTMS) protocol, which produces a focal suppression of cortical excitability outlasting the stimulation period. Synchronization accuracy between rhythmic cues and right index finger tapping, as measured by the mean time lag (asynchrony) between motor and auditory events, was significantly affected when the right dPMC function was transiently perturbed by "off-line" focal rTMS, whereas the reproduction of the rhythmic sequence per se (inter-tap-interval) was spared. This approach affected metrical rhythms of different complexity, but not non-metrical or isochronous sequences. Conversely, no change in auditory-motor synchronization was observed with rTMS of the SMA, of the left dPMC or over a control site (midline occipital area). Our data strongly support the view that the right dPMC is crucial for rhythmic auditory-motor synchronization in humans.
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