How to diagnose and treat post‐stroke seizures and epilepsy

Stroke is one of the commonest causes of seizures and epilepsy, mainly among the elderly and adults. This seminar paper aims to provide an updated overview of post‐stroke seizures and post‐stroke epilepsy (PSE) and offers clinical guidance to anyone involved in the treatment of patients with seizures and stroke. The distinction between acute symptomatic seizures occurring within seven days from stroke (early seizures) and unprovoked seizures occurring afterwards (late seizures) is crucial regarding their different risks of recurrence. A single late post‐stroke seizure carries a risk of recurrence as high as 71.5% (95% confidence interval: 59.7–81.9) at ten years and is diagnostic of PSE. Several clinical and stroke characteristics are associated with increased risk of post‐stroke seizures and PSE. So far, there is no evidence supporting the administration of antiepileptic drugs as primary prevention, and evidence regarding their use in PSE is scarce.     

Characteristic phasic evolution of convulsive seizure in PCDH19‐related epilepsy

PCDH19‐related epilepsy is a genetic disorder that was first described in 1971, then referred to as “epilepsy and mental retardation limited to females”. PCDH19 has recently been identified as the responsible gene, but a detailed characterization of the seizure manifestation based on video‐EEG recording is still limited. The purpose of this study was to elucidate features of the seizure semiology in children with PCDH19‐related epilepsy. To do this, ictal video‐EEG recordings of 26 convulsive seizures in three girls with PCDH19‐related epilepsy were analysed. All seizures occurred in clusters, mainly during sleep accompanied by fever. The motor manifestations consisted of six sequential phases: “jerk”, “reactive”, “mild tonic”, “fluttering”, “mild clonic”, and “postictal”. Some phases were brief or lacking in some seizures, whereas others were long or pronounced. In the reactive phase, the patients looked fearful or startled with sudden jerks and turned over reactively. The tonic and clonic components were less intense compared with those of typical tonic‐clonic seizures in other types of epilepsy. The fluttering phase was characterised initially by asymmetric, less rhythmic, and less synchronous tremulous movement and was then followed by the subtle clonic phase. Subtle oral automatism was observed in the postictal phase. The reactive, mild tonic, fluttering and mild clonic phases were most characteristic of seizures of PCDH19‐related epilepsy. Ictal EEG started bilaterally and was symmetric in some patients but asymmetric in others. It showed asymmetric rhythmic discharges in some seizures at later phases. The electroclinical pattern of the phasic evolution of convulsive seizure suggests a focal onset seizure with secondary generalisation. Based on our findings, we propose that the six unique sequential phases in convulsive seizures suggest the diagnosis of PCDH19‐related epilepsy when occurring in clusters with or without high fever in girls. [Published with video sequences online]     

Brivaracetam as add‐on treatment in focal epilepsy: A real‐world time‐based analysis

The study assessed the clinical response to add‐on brivaracetam (BRV) in real‐world practice by means of time‐to‐baseline seizure count methodology. Patients with focal epilepsy who were prescribed add‐on BRV were identified. Primary endpoint was the time‐to‐baseline seizure count defined as the number of days until each patient experienced the number of focal seizures that occurred in the 90 days before BRV initiation. Subgroup analysis was performed according to levetiracetam (LEV) status (naive vs prior use). Three‐hundred eighty‐seven patients were included. The overall median time‐to‐baseline seizure count was 150 (95% confidence interval [CI] = 130‐175) days. The median time‐to‐baseline seizure count was 198 (lower limit of 95% CI = 168) days for LEV‐naive patients, 126 (95% CI = 105‐150) days for patients with prior LEV use and withdrawal due to insufficient efficacy, and 170 (95% CI = 128‐291) days for patients who discontinued LEV due to adverse events (P = .002). The number of prior antiseizure medications (adjusted hazard ratio [_adjHR] = 1.07, 95% CI = 1.02‐1.13, P = .009) and baseline monthly seizure frequency (_adjHR = 1.004, 95% CI = 1.001‐1.008, P = .028) were independently associated with the primary endpoint. Add‐on BRV improved seizure control in LEV‐naive and LEV‐prior patients. The time‐to‐baseline seizure count represents an informative endpoint alongside traditional study outcomes and designs.     

Minimally resective epilepsy surgery in MRI‐negative children

Aim. Performing epilepsy surgery on children with non‐lesional brain MRI often results in large lobar or multilobar resections. The aim of this study was to determine if smaller resections result in a comparable rate of seizure freedom. Methods. We reviewed 25 children who had undergone focal corticectomies restricted to one aspect of a single lobe or the insula at our institution within a 5.5‐year period. Data collected in the comprehensive non‐invasive pre‐surgical evaluation (including scalp video‐EEG, volumetric MRI, functional MRI, EEG source localization, and SPECT and PET), as well as from invasive recordings performed in each patient, was reviewed. Data from each functional modality was identified as convergent or divergent with the epileptogenic zone using image coregistration. Specific biomarkers (from extra‐operative and invasive testing) previously indicated to be indicative of focal epileptogenicity were used to further tailor each resection to an epileptogenic epicentre. Tissue pathology and postoperative outcomes were obtained from all 25 patients. Results. Two years postoperatively, 15/25 (60%) children were seizure‐free, three (12%) experienced >90% reduction in seizure frequency, two (8%) had a 50–90% reduction in seizure frequency, and the remaining five (20%) had no change in seizure burden. There was no significant difference in outcome based on numerous pre‐ and postoperative factors including location of resection, the number of preoperative functional tests providing convergent data, and tissue pathology. Conclusion. In MRI‐negative children with focal epilepsy, an epileptogenic epicentre within a larger epileptogenic zone can be identified when specific biomarkers are recognized on non‐invasive and invasive testing. When such children undergo resection of a small, well‐defined epileptogenic epicentre, favourable outcomes can be achieved.     

Clinical‐radiological‐pathological correlation in an unusual case of refractory epilepsy: a two‐year journey of whodunit!

New‐onset refractory focal epilepsy poses significant challenges to the clinician in the absence of specific diagnostic biomarkers. Differential diagnoses based on imaging may be expanded by a veritable spectrum of peri‐ictal imaging findings that may mask the underlying substrate. We report a 13‐year‐old girl who presented with refractory focal seizures of left parieto‐occipital origin with cytotoxic gyral oedema noted over the same region on imaging. Despite an initial negative autoantibody profile, the patient was treated with immunosuppression, followed by serial relapses requiring immune‐modulation. Over the next year, her syndrome persisted as focal left posterior cortex epilepsy that necessitated occipital lobectomy, following a relapsing‐remitting radiological profile, consistent with peri‐ictal MRI changes. Histopathology was inconclusive for any definitive substrate. After a period of quiescence, she developed focal motor seizures of right hemispheric origin with progressive encephalopathy, at which point a repeat cerebrospinal fluid anti‐N‐methyl‐D‐aspartate receptor antibody profile returned positive. The patient was managed with steroids and rituximab with a good clinical outcome. We hypothesise that persistent or relapsing‐remitting focal gyral oedema in unexplained refractory focal epilepsy mandates consideration of focal encephalitis secondary to autoimmunity, and late appearance of intrathecal auto‐antibody synthesis correlates with evolution into a more diffuse disease.     

Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta‐analysis

Second and third generation AEDs have been directly compared to controlled‐release carbamazepine (CBZ‐CR) as initial monotherapy for new‐onset focal epilepsy. Conversely, no head‐to‐head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta‐analysis (NMA). Randomized, double‐blinded, parallel group, monotherapy studies comparing any AED to CBZ‐CR in adults with newly diagnosed untreated epilepsy with focal‐onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12 months, the occurrence of treatment‐emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ‐CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR‐CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6‐ and 12‐month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ‐CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ‐CR (OR 0.659, 95% CrI 0.428‐0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ‐CR     

Risk factors for early post‐operative psychiatric symptoms in patients undergoing epilepsy surgery for temporal lobe epilepsy

Objective – De‐novo psychiatric symptoms may develop within 3 months after a temporal lobectomy for epilepsy. The objective of this study was to identify presurgical risk factors for psychiatric symptoms. Methods – Twenty‐seven patients who had a temporal lobectomy for epilepsy were included. Twenty‐four had hippocampal sclerosis or gliosis, and three had cavernous haemagiomata. Twelve had operations on the left, and 15 on the right side. Twenty‐four patients were rendered free of seizures (SZ) with loss of awareness, three had early post‐operative convulsions, one continued to have habitual SZ. Results – Nine patients (33%) developed low mood, anxiety and emotional lability within 3 months after surgery. Patients with early post‐operative psychiatric symptoms were younger (27.9/34.8 years, P = 0.01), and more anxious on the presurgical Hospital Anxiety and Depression Scale (12/8.44, P = 0.02) than patients without post‐operative psychiatric symptoms. There was also an association between right temporal lobectomies and early post‐surgical symptoms (P = 0.02 Fisher’s exact test). Conclusion – Potential risk factors were age, anxiety and operation on the right side. Larger studies are required to determine if these risk factors are independent.     

Computed tomographic changes of the brain and clinical outcome of patients with seizures and epilepsy after an ischaemic hemispheric stroke.

It is not well established whether seizures and epilepsy after an ischaemic stroke increase the disability of patients. Seventy-two patients with delayed seizures after a hemispheric infarct (37 with a single seizure and 35 with epilepsy) were included in the study. The modified Rankin scale was used to compare disability of the patients at 1 month after stroke and at 2 weeks after single or the last seizure, in case of epilepsy. The size of the X-ray hypoattenuation zone was compared on computed tomographic (CT) scans, performed in the weeks after the stroke and 1 week after single or repeated seizures. Lesion size was determined by superimposing the CT slices on digital cerebral vascular maps, on which the contours of the infarct area were delineated. The extent of the infarcts was expressed as the percentage fraction of the total surface area of the cerebral hemisphere. Groups with a single seizure and with epilepsy were mutually compared. Infarcts predominated in the parieto-temporal cortical regions. In the overall group the median Rankin score worsened significantly after seizures. The average size of the X-ray hypoattenuation zone was also significantly increased on the CT scans after the seizures, compared with those after stroke, without clear evidence of recent infarction. Mutual comparison of patients with a single seizure episode and of those with epilepsy showed only a trend of more severe disability and of increase in lesion size in the post-stroke epilepsy group. Delayed seizures and epilepsy after ischaemic stroke are accompanied by an increase in lesion size on CT and by worsening of the disability of the patients. This study does not allow to determine whether this is due to stroke recurrence or due to additional damage as a result of the seizures themselves.     

Late adult‐onset epilepsy in a patient with hemimegalencephaly

Hemimegalencephaly is a malformation of cortical development that normally manifests in childhood with seizures and cognitive impairment. We present a case of hemimegalencephaly in a 55‐year‐old developmentally‐normal woman who developed focal impaired awareness seizures with bilateral tonic‐clonic spread. Her interictal EEG showed left‐sided multifocal spikes, and ictal EEG showed seizures starting in the left hemisphere. Imaging showed hemimegalencephaly. This case may represent the oldest age for a first seizure in a patient with hemimegalencephaly.     

Long‐term health‐related quality of life in drug‐resistant temporal lobe epilepsy after anterior temporal lobectomy

Epilepsy surgery is beneficial to patients suffering from drug‐resistant temporal lobe epilepsy in the short term, but fewer reports of long‐term outcomes have been published. To clarify the long‐term outcomes of seizure control and health‐related quality of life after epilepsy surgery, we enrolled 48 patients suffering from drug‐resistant temporal lobe epilepsy. All of the patients received comprehensive presurgical evaluations, including the Quality of Life in Epilepsy Inventory‐89 (QOLIE‐89) questionnaire to measure their health‐related quality of life. Among the patients, 28 patients received surgery (surgical group) and 20 patients remained under medication (medical group). Eight years later, the seizure frequency and QOLIE‐89 were evaluated. The seizure‐free rate was much higher in the surgical group (53.6%) than in the medical group (5%), eight years after the initial evaluation. The follow‐up QOLIE‐89 score was significantly higher in the surgical group than in the medical group. Moreover, the seizure frequency inversely correlated to the QOLIE‐89 score, regardless of the treatment group. Our results provide evidence that epilepsy surgery confers benefits with respect to seizure control and health‐related quality of life for drug‐resistant temporal lobe epilepsy patients based on long‐term follow‐up.