Innate and adaptive immunity in human epilepsies

Inflammatory mechanisms have been increasingly implicated in the origin of seizures and epilepsy. These mechanisms are involved in the genesis of encephalitides in which seizures are a common complaint. Experimental and clinical evidence suggests different inflammatory responses in the brains of patients with epilepsy depending on the etiology. In general, activation of both innate and adaptive immunity plays a role in refractory forms of epilepsy. Epilepsies in which seizures develop after infiltration of cells of the adaptive immune system in the central nervous system (CNS) include a broad range of epileptic disorders with different (known or unknown) etiologies. Infiltration of lymphocytes is observed in autoimmune epilepsies, especially the classical paraneoplastic encephalitides with antibodies against intracellular tumor antigens. The presence of lymphocytes in the CNS also has been found in focal cerebral dysplasia type 2 and in cortical tubers. Various autoantibodies have been shown to be associated with temporal lobe epilepsy (TLE) and hippocampal sclerosis of unknown etiology, which may be due to the presence of viral DNA. During the last decade, an increasing number of antineuronal autoantibodies directed against membranous epitopes have been discovered and are associated with various neurologic syndromes, including limbic encephalitis. A major challenge in epilepsy is to define biomarkers, which would allow the recognition of patient populations who might benefit from immune-modulatory therapies. Some peripheral inflammatory markers appear to be differentially expressed in patients with medically controlled and medic

Universal scaling at field-induced magnetic phase transitions

We study field-induced magnetic order in cubic lattices of dimers with antiferromagnetic Heisenberg interactions. The thermal critical exponents at the quantum phase transition from a spin liquid to a magnetically ordered phase are determined from Stochastic Series Expansion Quantum Monte Carlo simulations. These exponents are independent of the interdimer coupling ratios, and converge to the value obtained by considering the transition as a Bose-Einstein condensation of magnons, alpha_(BEC) = 1.5. The scaling results are of direct relevance to the spin-dimer systems TlCuCl_3 and KCuCl_3, and explain the broad range of exponents reported for field-induced ordering transitions.Comment: 4 pages, 4 eps-figure

Seizures and risks for recurrence in critically ill patients: an observational cohort study

To assess the frequency and clinical characteristics of seizures in adult critically ill patients, to identify predictors of recurrent seizures not transforming into status epilepticus and to characterize their effects on course and outcome.; ICU patients at a Swiss academic medical center with seizures not transforming into status epilepticus from 2015 to 2020 were included. Recurrent seizures and associated clinical characteristics were primary, death, and return to premorbid neurologic function were secondary outcomes.; Two hundred of 26,370 patients (0.8%) with a median age of 65 years had seizures during ICU stay. Seizure semiology was described in 82% (49% generalized; 33% focal) with impaired consciousness during seizures in 80% and motor symptoms in 62%. Recurrent seizures were reported in 71% (36% on EEG) and associated with longer mechanical ventilation (p = 0.031), higher consultation rate by neurologists (p < 0.001), and increased use of EEG (p < 0.001) when compared to single seizures. The use of EEG was not associated with secondary outcomes. Acidosis at seizure onset and prior emergency operations were associated with decreased odds for seizure recurrence (OR 0.43; 95% CI 0.20-0.94 and OR 0.48; 95% CI 0.24-0.97). Epilepsy had increased odds for seizure recurrence (OR 3.56; 95% CI 1.14-11.16).; Seizures in ICU patients are infrequent, but mostly recurrent, and associated with higher resource utilization. Whenever seizures are observed, clinicians should be vigilant about the increased risk of seizures recurrence and the need for antiseizure treatment must be carefully discussed. While known epilepsy seems to promote recurrent seizures, our results suggest that both acidosis and previous emergency surgery seem to have protective/antiseizure effects.; Clinicaltrials.gov (No. NCT03860467)

Antipsychotic drug use and the risk of seizures: follow-up study with a nested case-control analysis

To investigate the association between antipsychotic drug use and the development of first-time seizures in patients with schizophrenia, affective disorders, or dementia.; We used data from the UK-based Clinical Practice Research Datalink database to conduct a follow-up study with a nested case-control analysis between 1998 and 2013. We identified patients with schizophrenia, affective disorders, or dementia, and estimated incidence rates of seizures among users of four antipsychotic drug subclasses, defined according to existing hypotheses on their seizure-inducing potential (1, olanzapine or quetiapine; 2, amisulpride, aripiprazole, risperidone, or sulpiride; 3, low-to-medium potency first-generation antipsychotic drugs [chlorpromazine, zuclopenthixol, flupenthixol, pericyazine, promazine, thioridazine]; 4, medium-to-high potency first-generation antipsychotic drugs [haloperidol, prochlorperazine, trifluoperazine]), and among those who did not use antipsychotic drugs. To adjust for confounding, we estimated odds ratios for seizures separately among patients with affective disorders or dementia, stratified by antipsychotic drug use and timing of use.; In the total cohort of 60,121 patients (who had schizophrenia, affective disorders, or dementia), the incidence rate of seizures per 10,000 person-years was 32.6 (95 % confidence interval [CI] 22.6-42.6) in users of olanzapine or quetiapine, 24.1 (95 % CI 13.2-34.9) in users of amisulpride, aripiprazole, risperidone, or sulpiride, 49.4 (95 % CI 27.7-71.0) in users of low-to-medium potency antipsychotic drugs, 59.1 (95 % CI 40.1-78.2) in users of medium-to-high potency antipsychotic drugs, and 11.7 (95 % CI 10.0-13.4) in non-users of antipsychotic drugs. Patients with dementia had significantly higher incidence rates of first-time seizures compared with patients with affective disorders, irrespective of antipsychotic drug use. In patients with affective disorders, current use of medium-to-high potency first-generation antipsychotic drugs was associated with an increased risk of seizures (adjusted odds ratio 2.51 [95 % CI 1.51-4.18]) compared with non-use, while use of other antipsychotic drugs was not associated with seizures. In patients with dementia, current use of olanzapine or quetiapine (adjusted odds ratio 2.37 [95 % CI 1.35-4.15]), low-to-medium potency first-generation antipsychotic drugs (adjusted odds ratio 3.08 [95 % CI 1.34-7.08]), and medium-to-high potency first-generation antipsychotic drugs (adjusted odds ratio 2.24 [95 % CI 1.05-4.81]) was associated with an increased risk of seizures compared with non-use, but current use of amisulpride, aripiprazole, risperidone, or sulpiride (adjusted odds ratio 0.92 [95 % CI 0.48-1.75]) was not. Use of antipsychotic drugs in patients with schizophrenia could not be investigated because of small numbers.; Current use of medium-to-high potency first-generation antipsychotic drugs was associated with a 2.5-fold increased risk of seizures compared with non-use of antipsychotic drugs in patients with affective disorders. In these patients, current use of all other antipsychotic drug subclasses was not associated with seizures. In patients with dementia, current and past use of all antipsychotic drug subclasses, except amisulpride, aripiprazole, risperidone, or sulpiride, was associated with an increased risk of seizures

Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case-Control Analysis Using the Clinical Practice Research Datalink

Antidepressant use has been associated with an increased risk of seizures. Evidence on the association between antidepressant use at therapeutic doses and seizures mainly comes from clinical trials that were not designed to investigate this potential relationship.; The objective of this study was to assess the risk of first-time seizures in association with exposure to antidepressants in patients with depressive disorders.; We conducted a retrospective follow-up study with a nested case-control analysis between 1998 and 2012, using data from the UK-based Clinical Practice Research Datalink (CPRD). We estimated crude incidence rates with 95 % confidence intervals (CIs) of seizures in depressed patients who used selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), 'other antidepressants', no antidepressants, or who had used antidepressants in the past. To adjust for potential confounding, we estimated odds ratios of antidepressant drug use among cases with seizures and matched controls in a nested case-control analysis.; Of 151,005 depressed patients, 619 had an incident seizure during follow-up. Incidence rates per 10,000 person-years were 12.44 (95 % CI 10.67-14.21) in SSRI users, 15.44 (95 % CI 8.99-21.89) in SNRI users, 8.33 (95 % CI 4.68-11.98) in TCA users, 9.33 (95 % CI 6.19-12.46) in non-users of antidepressants, and 5.05 (95 % CI 4.49-5.62) in past users of antidepressants. In the case-control analysis, relative risk estimates for seizures were increased in current users of SSRIs (adjusted odds ratio 1.98, 95 % CI 1.48-2.66) and SNRIs (adjusted odds ratio 1.99, 95 % CI 1.20-3.29), but not TCAs (adjusted odds ratio 0.99, 95 % CI 0.63-1.53), compared with non-users.; Current use of SSRIs or SNRIs was associated with a twofold increased risk of first-time seizures compared with non-use, while current use of TCAs (mostly low dose) was not associated with seizures. Treatment initiation in SSRI and SNRI users was associated with a higher risk of seizures than longer-term treatment

A review of the evidence on the risk of congenital malformations and neurodevelopmental disorders in association with antiseizure medications during pregnancy

Introduction: The majority of women with epilepsy require treatment with antiseizure medications (ASM) throughout pregnancy. However, in utero exposure to several ASM has been associated with an increased risk of congenital malformations and/or neurodevelopmental disorders (CM/NDD) in the child, but observational evidence is methodologically heterogeneous. Areas covered: We critically evaluate current evidence on the risk of CM/NDD in children of women with epilepsy after in utero exposure to different ASM. We highlight characteristics of different data sources and discuss their benefits and drawbacks. This review includes evidence published before December 2020. Expert opinion: Given the lack of randomized controlled trials, evidence on in utero safety of ASM originates from methodologically heterogeneous post-marketing observational studies based on regis tries, prospective cohorts, and large electronic health databases. It has been clearly demonstrated that valproate is associated with a high risk of CM/NDD, whereas lamotrigine and levetiracetam are relatively safe. However, evidence is less explicit for other ASM. Reported risks vary depending on the size and origin of the underlying study population, the definition of exposure and outcomes, and other aspects of the study design. Increased collaboration between data sources to increase sample size is desirable

Parkinson disease and the risk of epileptic seizures

To assess the association between incident Parkinson disease (PD) and subsequent incident epileptic seizures.; We conducted a retrospective cohort study with a nested case-control analysis using data from the U.K. Clinical Practice Research Datalink. We identified patients aged ≥40 years with an incident diagnosis of PD between 1995 and 2016 and a matched comparison group of PD-free individuals. We calculated crude incidence rates (IRs) with 95% confidence intervals (CIs) of epileptic seizures in PD patients and the PD-free comparison group, and corresponding crude incidence rate ratios (IRRs). In the nested case-control analysis, we calculated adjusted odds ratios (adj. ORs) of incident PD among cases with incident epileptic seizures and seizure-free controls overall and stratified by various seizure-provoking comorbidities.; Among 23,086 incident PD patients and 92,343 PD-free individuals, we identified 898 patients with incident epileptic seizures. The crude IR of epileptic seizures in PD patients was 266.7/100,000 person-years (95% CI = 235.6-297.7), and in PD-free individuals it was 112.4/100,000 person-years (95% CI = 103.5-121.3; IRR = 2.37, 95% CI = 2.06-2.73). The adj. OR of epileptic seizures was 1.68 (95% CI = 1.43-1.98) in PD patients compared with PD-free individuals. PD patients with comorbid brain disorders (adj. OR = 12.36, 95% CI = 8.74-17.48) or with &gt; 1 seizure-provoking comorbidity (adj. OR = 13.24, 95% CI = 10.15-17.25) were at the highest risk of epileptic seizures compared with PD-free individuals with no seizure-provoking comorbidities.; This study suggests that incident PD is associated with an increased risk of incident epileptic seizures

Antiseizure drugs and risk of developing smoking-related chronic obstructive pulmonary disease or lung cancer: A population-based case-control study

To determine whether enzyme-inducing antiseizure drugs (ASDs) affect the risk of developing chronic obstructive pulmonary disease (COPD) or lung cancer in smokers.; Cases of COPD and lung cancer and matched controls without these conditions were identified from a population of smokers with ≥1 prescription for any type of ASD in the Clinical Practice Research Datalink UK database of patients managed in primary care (1995-2016). A matched case-control study was performed utilising multivariate logistic regression analyses of exposure to enzyme-inducing ASDs compared to non-enzyme-inducing ASDs. The duration of ASD exposure and level of tobacco exposure were also assessed.; We identified 5952 incident COPD and 1373 incident lung cancer cases, and 59 328 and 13 681 matched controls, respectively. Compared with never use, ever use of enzyme-inducing ASDs was associated with slightly decreased risk estimates of COPD (adjusted odds ratio: 0.85, 95% confidence interval: 0.81-0.89) and lung cancer (adjusted odds ratio: 0.82, 95% confidence interval: 0.73-0.92). These risk estimates were attenuated in heavy smokers.; We found slightly decreased risk estimates of COPD and lung cancer among smokers taking enzyme-inducing ASDs and hypothesise that this may be related to induction of detoxification of tobacco-specific lung toxins

The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs

Older antiepileptic drugs (AEDs) are known to cause Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). However, evidence for newer AED is sparse. We quantified risks of SJS/TEN in association with use of all AEDs in the United Kingdom.; In a matched case-control study of 480 previously validated SJS/TEN cases (1995-2013) we used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs), and calculated absolute risks of SJS/TEN within separate cohorts of new users of 28 AEDs. We assessed causality between drugs and SJS/TEN in each exposed case, using an adapted version of the algorithm of drug causality for epidermal necrolysis (ALDEN) score.; We observed a strong association between SJS/TEN and new use of carbamazepine (OR 92.57, 95% CI 19.89-∞), phenytoin (OR 49.96, 95% CI 10.13-∞), and lamotrigine (OR 26.90, 95% CI 4.88-∞), where causality, according to the ALDEN score, was very probable or probable for most exposed cases. Absolute risks for SJS/TEN were highest for phenytoin (45.86 cases/100,000 exposed), lamotrigine (44.17 cases/100,000 exposed), and carbamazepine (20.38 cases/100,000 exposed). Despite increased ORs for valproate (40,941 exposed), gabapentin (116,037 exposed), pregabalin (59,967 exposed), and clobazam (4,300 exposed), ALDEN suggested no causal association. There were no observed cases of SJS/TEN among new users of levetiracetam (n = 96,77), clonazepam (n = 18,075), or topiramate (n = 11,307).; The results of our study are consistent with those of previous studies of SJS/TEN, which found increased risks of SJS/TEN in new use of carbamazepine, phenytoin, and lamotrigine. Despite frequent use, no ALDEN-score confirmed cases were observed in new users of valproate, gabapentin, pregabalin, levetiracetam, topiramate, or clonazepam