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Long-term seizure outcome after epilepsy surgery in patients with mild malformation of cortical development and focal cortical dysplasia.

ABSTRACT: Focal cortical dysplasia (FCD) and mild malformation of cortical development (mMCD) are frequent histopathologic diagnoses in patients who undergo surgery for refractory epilepsy. Literature concerning surgical outcome in patients with mMCD, as well as its contrast with FCD, has been scarce. We studied 88 patients with a histopathologic diagnosis of isolated FCD (n = 57) or mMCD (n = 31), revised according to the latest International League Against Epilepsy (ILAE) guidelines, who underwent resective or disconnective surgery. Our findings suggest differences between mMCD and FCD in clinical presentation and surgical outcome after surgery. Patients with mMCD developed seizures later in life, and their lesions had a predilection for location in the temporal lobe and remained undetected by magnetic resonance imaging (MRI) more frequently. A diagnosis of mMCD has a less favorable surgical outcome. Still, 32% of these patients reached continuous seizure freedom (Engel class 1A) at a latest median follow-up duration of 8 years, compared to 59% in FCD. A histopathologic diagnosis of mMCD, extratemporal surgery, and indication of an incomplete resection each were independent predictors of poor outcome.

SUBMITTER: Veersema TJ

PROVIDER: S-EPMC6398095 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Long-term seizure outcome after epilepsy surgery in patients with mild malformation of cortical development and focal cortical dysplasia.

Veersema Tim J TJ Swampillai Banu B Ferrier Cyrille H CH van Eijsden Pieter P Gosselaar Peter H PH van Rijen Peter C PC Spliet Wim G M WGM Mühlebner Angelika A Aronica Eleonora E Braun Kees P J KPJ

Epilepsia open 20181213 1

Focal cortical dysplasia (FCD) and mild malformation of cortical development (mMCD) are frequent histopathologic diagnoses in patients who undergo surgery for refractory epilepsy. Literature concerning surgical outcome in patients with mMCD, as well as its contrast with FCD, has been scarce. We studied 88 patients with a histopathologic diagnosis of isolated FCD (n = 57) or mMCD (n = 31), revised according to the latest International League Against Epilepsy (ILAE) guidelines, who underwent resec ...[more]

PMID: 30868127

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Project description:Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe focal cortical dysplasia. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established focal cortical dysplasia model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human Ras homolog enriched in brain (RHEB) plasmid, an activator of mTOR complex 1. We characterized the model by quantifying electrocorticographic and behavioural abnormalities, both in mice developing spontaneous generalized seizures and in mice only exhibiting interictal discharges. Injection of AAV9-CAMK2A-EKC in the dysplastic region resulted in a robust decrease (∼64%) in the frequency of seizures. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal discharges or behaviour in mice without generalized seizures. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.

Project description:ObjectiveFocal cortical dysplasia (FCD) represents a heterogeneous group of disorders of the cortical formation and is one of the most common causes of epilepsy. Magnetic resonance imaging (MRI) is the modality of choice for detecting structural lesions, and the surgical prognosis in patients with MR lesions is favorable. However, the surgical prognosis of patients with MR-negative FCD is unknown. We aimed to evaluate the long-term surgical outcomes and prognostic factors in MR-negative FCD patients through comprehensive presurgical data.MethodsWe retrospectively reviewed data from 719 drug-resistant epilepsy patients who underwent resective surgery and selected cases in which surgical specimens were pathologically confirmed as FCD Type I or II. If the epileptogenic focus and surgical specimens were obtained from brain areas with a normal MRI appearance, they were classified as MR-negative FCD. Surgical outcomes were evaluated at 2 and 5 years, and clinical, neurophysiological, and neuroimaging data of MR-negative FCD were compared to those of MR-positive FCD.ResultsFinally, 47 MR-negative and 34 MR-positive FCD patients were enrolled in the study. The seizure-free rate after surgery (Engel classification I) at postoperative 2 year was 59.5% and 64.7% in the MR-negative and positive FCD groups, respectively (p = 0.81). This rate decreased to 57.5% and 44.4% in the MR-negative and positive FCD groups (p = 0.43) at postoperative 5 years. MR-negative FCD showed a higher proportion of FCD type I (87.2% vs. 50.0%, p = 0.001) than MR-positive FCD. Unilobar cerebral perfusion distribution (odds ratio, OR 5.41) and concordance of interictal epileptiform discharges (OR 5.10) were significantly associated with good surgical outcomes in MR-negative FCD.ConclusionIn this study, MR-negative and positive FCD patients had a comparable surgical prognosis, suggesting that comprehensive presurgical evaluations, including multimodal neuroimaging studies, are crucial for obtaining excellent surgical outcomes even in epilepsy patients with MR-negative FCD.

Project description:Since prediction of long-term seizure outcome using preoperative diagnostic modalities remains suboptimal in epilepsy surgery, we evaluated whether interictal spike frequency measures obtained from extraoperative subdural electrocorticography (ECoG) recording could predict long-term seizure outcome. This study included 61 young patients (age 0.4-23.0 years), who underwent extraoperative ECoG recording prior to cortical resection for alleviation of uncontrolled focal seizures. Patient age, frequency of preoperative seizures, neuroimaging findings, ictal and interictal ECoG measures were preoperatively obtained. The seizure outcome was prospectively measured [follow-up period: 2.5-6.4 years (mean 4.6 years)]. Univariate and multivariate logistic regression analyses determined how well preoperative demographic and diagnostic measures predicted long-term seizure outcome. Following the initial cortical resection, Engel Class I, II, III and IV outcomes were noted in 35, 6, 12 and 7 patients, respectively. One child died due to disseminated intravascular coagulation associated with pseudomonas sepsis 2 days after surgery. Univariate regression analyses revealed that incomplete removal of seizure onset zone, higher interictal spike-frequency in the preserved cortex and incomplete removal of cortical abnormalities on neuroimaging were associated with a greater risk of failing to obtain Class I outcome. Multivariate logistic regression analysis revealed that incomplete removal of seizure onset zone was the only independent predictor of failure to obtain Class I outcome. The goodness of regression model fit and the predictive ability of regression model were greatest in the full regression model incorporating both ictal and interictal measures [R(2) 0.44; Area under the receiver operating characteristic (ROC) curve: 0.81], slightly smaller in the reduced model incorporating ictal but not interictal measures (R(2) 0.40; Area under the ROC curve: 0.79) and slightly smaller again in the reduced model incorporating interictal but not ictal measures (R(2) 0.27; Area under the ROC curve: 0.77). Seizure onset zone and interictal spike frequency measures on subdural ECoG recording may both be useful in predicting the long-term seizure outcome of epilepsy surgery. Yet, the additive clinical impact of interictal spike frequency measures to predict long-term surgical outcome may be modest in the presence of ictal ECoG and neuroimaging data.

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Long-term seizure outcome after epilepsy surgery in patients with mild malformation of cortical development and focal cortical dysplasia.

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Long-term seizure outcome after epilepsy surgery in patients with mild malformation of cortical development and focal cortical dysplasia.

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