Multiple Cerebral Cavernous Malformations Research Articles

Abstract 193: Cerebral Cavernous Malformation Location and Mode of Presentation Predict the Risk of Hemorrhage During Their Untreated Clinical Course: Individual Patient Data Meta-Analysis

INTRODUCTION: Cerebral cavernous malformations (CCM) are the second commonest incidental finding on brain MRI and may cause symptomatic intracranial hemorrhage (ICH). However, the risk and predictors of ICH from CCM remain uncertain. HYPOTHESIS: Presentation with ICH or non-hemorrhagic focal neurological deficit (FND) attributable to CCM, brainstem CCM location, female sex, increasing age and multiple CCM predict ICH occurrence during follow-up without CCM treatment. METHODS: Three hospital-based cohorts and two cohorts from a population-based study provided individual patient data on clinical course from CCM diagnosis until either first CCM treatment or last available follow-up. We used survival analysis of each cohort to estimate the 5-year risk of symptomatic ICH or new FND, multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in meta-analysis. RESULTS: Among 988 adults who experienced 62 ICHs during 3,232 person-years of follow-up, clinical presentation with ICH or FND (hazard ratio [HR] 7.4, 95% confidence interval [CI] 2.9-19.2) and brainstem CCM location (HR 5.7, 95% CI 3.2-10.3) were associated with a higher risk of a first ICH within five years of CCM diagnosis, but age, sex and CCM multiplicity were not. The 5-year estimated risk of ICH during untreated follow-up was 2.4% (95% CI 1.0-3.8) for 566 adults without ICH/FND from CCM outside the brainstem, 5.5% (95% CI 0-12.9) for 51 adults without ICH/FND from brainstem CCM, 10.6% (95% CI 5.1-16.1) for 198 adults with ICH/FND from CCM outside the brainstem, and 25.7% (95% CI 18.3-33.1) for 173 adults with ICH/FND from brainstem CCM. In secondary analyses of first ICH or FND, event rates increased but predictors remained unchanged. CONCLUSION: Mode of clinical presentation and CCM location are independently associated with ICH or FND within five years of CCM diagnosis, which can inform decisions about CCM treatment.

A Girl with Greig Cephalopolysyndactyly Contiguous Gene Deletion Syndrome: The Importance and Usefulness of DNA Microarray Analysis

Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disease, characterized by polysyndactyly, macrocephaly and facial dysmorphisms. GCPS can appear both by point mutations of GLI3 or contiguous gene deletion of 7p13 (GCPS-CGS). We report a 2-year-old girl with GCPS-CGS. DNA microarray analysis revealed 6.2 Mb deletion of 7p12.3p14.1 including GLI3, CCM2 and GCK. She manifests multiple cerebral cavernous malformations by deletion of CCM2. Also it is revealed that she has a high risk of developing maturity onset diabetes of the young type 2 by deletion of GCK. DNA microarray provide a definitive diagnosis and clarify the genes involved in the deletion for the proper management of the complications.

PDCD10 gene mutations in multiple cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.

Surgical management and long-term outcome of pediatric patients with different subtypes of epilepsy associated with cerebral cavernous malformations

Sufficient data on surgical treatment and seizure outcome of pediatric patients with different types of epilepsy, especially drug-resistant epilepsy and associated cerebral cavernous malformations, are scarce. The aim of this study was to carefully evaluate seizure outcome using the International League Against Epilepsy (ILAE) classification with regard to the presurgical symptom duration. Fifty-one pediatric patients younger than 19 years with cerebral cavernous malformations of all CNS localizations have been surgically treated at the authors' institution. Twenty-two patients with seizures or epilepsy who harbored cortically located supratentorial cerebral cavernous malformations underwent surgical treatment and were retrospectively analyzed. More extensive resections were used in 82% of all patients with epilepsy symptoms for longer than 2 years. Eighty-two percent of patients with symptom duration shorter than 2 years underwent circumscribed lesionectomy including the surrounding hemosiderotic rim. The overall rate of mild permanent, unanticipated postoperative deficits was 4.5%; the rate of anticipated neurological deficits was 9%. The mean follow-up was longer than 117 months in all groups. Seizure outcome was excellent in the group with symptom duration shorter than 2 years (100% ILAE Class 1). Seizure outcome was significantly worse in the group with longer symptom duration (p = 0.02). Seven patients were seizure free after surgery. Seizure outcome was stable over the years. Since seizure outcome is worse with longer seizure duration, early surgery and, if needed, interdisciplinary intervention, is recommended. Even in cases of multiple cerebral cavernous malformations and epilepsy, surgery should be considered.

Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations

Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.

Pitfalls of conservative treatments of multiple probable cerebral cavernous malformations (CCMs): clinicopathological features of CCMs coexisting with vasculogenic mimicry in an anaplastic oligodendroglioma

Developments in magnetic resonance imaging (MRI) techniques have dramatically increased the detection of cerebral cavernous malformations (CCMs). Conservative treatment is often recommended for asymptomatic cases. However, CCMs occasionally harbor malignant gliomas. Here, we describe a rare case of multiple probable CCMs and an anaplastic oligodendroglioma (AO) showing vasculogenic mimicry (VM) and discuss the potential pitfalls of conservative treatments. A 42-year-old otherwise healthy woman presented with generalized seizures. Magnetic resonance imaging (MRI) revealed multiple parenchymal hypointensities, particularly in the right frontal lobe, with hyperintensity on fluid-attenuated inversion recovery (FLAIR) images. The patient was diagnosed with multiple probable CCMs, and conservative treatment was administered. However, follow-up MRI showed a slightly enlarged hyperintense area in the right frontal lobe. The patient then underwent surgery; histological diagnosis was CCMs and AO with VM. The patient subsequently underwent radiotherapy and chemotherapy. No neurological deficits or tumor recurrence were evident 21 months after surgery. We present this rare case and emphasize the possibility of the coexistence of malignant gliomas with CCMs. Close observation with MRI is essential in cases of multiple probable CCMs, and a histological confirmation should be considered in cases showing any enlargement of hyperintensity on FLAIR images.

Surgical Resection Can Be Successful in a Large Fraction of Patients With Drug-Resistant Epilepsy Associated With Multiple Cerebral Cavernous Malformations

Abstract BACKGROUND: Multiple cerebral cavernous malformations (mCCMs) are known as potentially epileptogenic lesions. Treatment might be multimodal. Management of patients with mCCMs and epilepsy is challenging. OBJECTIVE: To evaluate (1) algorhythmic therapeutic sequences in patients with epilepsy associated to mCCMs, (2) whether there are predictive parameters to anticipate the development of drug-resistant epilepsy, and (3) seizure after epilepsy surgery compared to conservatively-treated drug-resistant patients. METHODS: All inpatients and outpatients with epilepsy associated to mCCMs from 1990 to 2010 and follow-up >12 months available were retrospectively analyzed. RESULTS: Twenty-three patients matched inclusion criteria. Epilepsy became drug-resistant in 18/23 (78%) patients. No predictors were found for development of drug-resistant epilepsy. Median follow-up for both groups was 7.8 years. Nine patients did not qualify for surgical therapy and were treated conservatively. One patient of this cohort (11%) was seizure-free (International League Against Epilepsy [ILAE] class 1). Surgical treatment was performed in 9 patients; 7/9 (78%) of these patients were seizure-free (ILAE class 1) after epilepsy surgery for at least 12 months compared with 1/9 patients in the non-operated group. In 7/9 cases (78%) the largest CCM was resected. In 8/9 (89%) not all CCMs were resected. CONCLUSION: After initial diagnosis of epilepsy associated to mCCMs, a primary conservative approach is reasonable. Surgical treatment can be successful in a large fraction of cases with drug-resistant epilepsy where an epileptogenic lesion is identified. Cases where surgery is not undertaken are likely to remain intractable.

Surgical Resection Can Be Successful in a Large Fraction of Patients With Drug Resistant Epilepsy Associated With Multiple Cerebral Cavernous Malformations

Surgical Resection Can Be Successful in a Large Fraction of Patients With Drug Resistant Epilepsy Associated With Multiple Cerebral Cavernous Malformations

Identification of a c.601C>G mutation in the CCM1 gene in a kindred with multiple skin, spinal and cerebral cavernous malformations

Cerebral cavernous malformations (CCM) are congenital vascular anomalies predominantly of the central nervous system but may include lesions in other tissues such as the retina, skin, and liver. These hamartomatous dysplasias, generally occurring sporadically, consist of dynamic clustered convoluted capillary cavities without intervening brain parenchyma that may lead to headaches, seizures, paresis, cerebral hemorrhages and focal neurological deficits. Familial forms of CCM, inherited in an autosomal dominant manner with incomplete penetrance and variable expression, are attributed to mutations in three genes, CCM1, CCM2 and CCM3. Here, we report a kindred of Persian descent exhibiting a range of clinical symptoms and features that include seizures, multiple lesions of the brain and spinal cord, and severe hyperkeratotic cutaneous capillary–venous malformations. Sanger DNA sequencing and deletion/duplication testing of the CCM1, CCM2, and CCM3 genes in the proband revealed a CCM1 c.601C>G mutation. Targeted mutation analysis in family members confirmed that this mutation segregated with the disease in the family. This family illustrates the phenotypic heterogeneity that has been observed in other reported CCM-pedigrees and highlights the importance of genetic testing for early diagnosis in familial CCM. To our knowledge, this is the first genetic investigation of CCM in the Persian population.

Focal cortical dysplasia type IIIc associates with multiple cerebral cavernomas

The distinction of isolated malformations and combined lesions constitutes a major novelty in the 2011 consensus classification of the International League against Epilepsy (ILAE) for focal cortical dysplasias (FCD). Cortical lamination abnormalities together with vascular lesions are subsumed as FCD IIIc. Little is known regarding frequency and etiology of this entity. Here, we systematically evaluated biopsy specimens from 72 drug-refractory epilepsy patients with cerebral cavernous malformations (CCM) regarding presence of associated FCD. Due to a non-perpendicular orientation of the cortical structures or absence of sufficient cortical tissue adjacent to the vascular lesion 25 samples were not classifiable. In the remaining 47 cases FCD IIIc was rare (4.3%), but significantly increased in patients with multiple CCM (28.6%; p<0.05 vs. single CCM). Association of FCD IIIc with multiple CCM may argue against FCD IIIc as an acquired lesion.

Genomic causes of multiple cerebral cavernous malformations in a Japanese population

Cerebral cavernous malformation (CCM) is a hamartomatous vascular disease affecting the central nervous system. A fraction of CCM are thought to arise in association with genomic mutations in the cerebral cavernous malformation 1 (CCM1) (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10) genes. In the present study, 18 Japanese patients with multiple CCM (10 with familial type and eight with sporadic type), underwent genomic analysis for CCM1, CCM2 and CCM3 mutations with blood samples and surgical specimens. MRI showed CCM in the cerebral hemisphere in 17 patients, the cerebellum in 10, the brainstem in 10 and the spinal cord in eight. CCM2 mutations were the most prominent, followed by CCM1 and CCM3. CCM1, CCM2 and CCM3 mutations were not identified in seven patients. Among the 10 patients with familial CCM, CCM1, CCM2 and CCM3 mutations were found in two, three and one patient, respectively, whereas four patients lacked these mutations. Among the eight patients with sporadic CCM, these mutations were found in one, three, and one patients, respectively, whereas three patients lacked these mutations. Most of the patients had a stable course during the follow-up period. Genomic mutations other than CCM1, CCM2 and CCM3 may be frequent in patients with multiple CCM in the Japanese population.

Abstract 183: Antithrombotic Therapy and Bleeding Risk in a Prospective Cohort Study of Patients with Cerebral Cavernous Malformations (CCM)

BACKGROUND: Cerebral cavernous malformation (CCM) are the most frequently diagnosed vascular malformations in the brain and are often asymptomatic. The potential risk of hemorrhage often precludes antithrombotic treatment in patients with cardiovascular disease, but no systematic study has been undertaken to evaluate the effect of blood-thinning therapy on the risk of CCM hemorrhage. PATIENTS AND METHODS: We prospectively followed consecutive patients with a diagnosis of one or more CCMs in a prospective database since 2008. Retrospective data collection was used for patients with a diagnostic event or imaging studies done prior to first assessment. Symptomatic hemorrhage and other focal neurological events during prospective follow-up were defined according to the current guidelines of the Angioma Alliance Scientific Advisory board RESULTS: A total of 87 patients were prospectively enrolled in our cohort (50 women (57%), mean age 44.8 years (SD +/- 17.6), mean follow up 3.9 years) harboring a total of 738 CCMs. N=55 patients (63%) had a single CCM, and 32 patients (37%) had multiple CCMs. Longitudinal follow-up included 16 (18%) patients receiving long-term antithrombotic therapy by antiplatelet treatment (n=11) or oral anticoagulants (n=5). During 5536 lesion-years of observation, none of the patients under antithrombotic therapy experienced CCM hemorrhage on follow up. CONCLUSION: Our observational data suggest long-term antithrombotic treatment by antiplatelet drugs or warfarin does not increase the frequency of CCM-related hemorrhage. Patients harboring single or multiple CCMs suffering ischemic stroke or heart disease should not be withheld antithrombotic therapy.

Sporadic Cerebral Cavernous Malformations: Report of Further Mutations of CCM Genes in 40 Italian Patients

Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities, affecting the central nervous system. CCMs can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (K-Rev interaction trapped 1 (KRIT1)), CCM2 (MGC4607), and CCM3 (PDCD10). CCMs occur as a single or multiple malformations that can lead to seizures, focal neurological deficits, hemorrhagic stroke, and headache. However, patients are frequently asymptomatic. In our previous mutation screening, performed in a cohort of 95 Italian patients, both sporadic and familial, we have identified several mutations in CCM genes, three of which in three distinct sporadic patients. In this study, representing further molecular screening of the three CCM genes, in a south Italian cohort of CCM patients enrolled by us in the last three years, we report the identification of other four new mutations in 40 sporadic patients with either single or multiple CCM.

Antithrombotic Therapy and Bleeding Risk in a Prospective Cohort Study of Patients With Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCMs) are one of the most frequently diagnosed vascular malformations of the brain and constitute a potential source of intracranial hemorrhage. In CCM patients suffering ischemic stroke or heart disease, the use of anticoagulants or antiplatelet therapy is generally avoided by fear of hemorrhagic complications, but no systematic studies exist to support this hypothesis. We prospectively followed-up consecutive patients with a diagnosis of one or more CCMs in a prospective database since 2008. Retrospective data collection was used for patients with a diagnostic event or imaging studies done before first assessment. Symptomatic hemorrhage and other focal neurological events during prospective follow-up were defined according to the current guidelines of the Angioma Alliance Scientific Advisory board. A total of 87 patients were prospectively enrolled in our cohort [50 women (57%), mean age 44.8 years (SD±17.6), mean follow-up 3.9 years], harboring a total of 738 CCMs. Fifty-five patients (63%) had a single CCM, and 32 patients (37%) had multiple CCMs. Longitudinal follow-up included 16 (18%) patients receiving long-term antithrombotic therapy by antiplatelet treatment (n=11) or oral anticoagulants (n=5). During 5536 lesion-years of observation, none of the patients under antithrombotic therapy experienced CCM hemorrhage on follow-up. Our observational data suggest that long-term antithrombotic treatment by antiplatelet drugs or warfarin does not increase the frequency of CCM-related hemorrhage. Patients harboring single or multiple CCMs suffering ischemic stroke or heart disease should not be withheld antithrombotic therapy.

Cavernous malformations associated with dural arteriovenous shunts in the central nervous system

Some cerebral cavernous malformations (CCMs) may be associated with vascular malformations that occur on the capillary-venous side of the cerebral circulation. The association between CCMs and dural arteriovenous shunts (DAVSs) is not well known. The purpose of this study is to investigate the relationship between CCMs and DAVSs. We retrospectively analyzed 179 patients diagnosed as intracranial DAVSs and performed with digital subtraction angiography (DSA). The DSA images were investigated for the location, cortical venous reflux (CVR), multiplicity, and treatment method/result of DAVS. MR images were investigated for the location, number, and size of CCMs and correlated with the DSA images. Six of the 179 patients with DAVSs presented with coexistent CCMs (3.4 %; M/F = 3:3; mean age, 38 ± 22 years). Five of the six DAVS patients with CCMs were associated with CVR (83 %). The total number of CCMs associated with DAVS was 20. Multiple CCMs (range, 2-7) were seen in four (66 %) of six patients. Eighteen (90 %) of the 20 CCMs were located on the ipsilateral hemisphere of the CVR (n = 10) or adjacent to the deep venous reflux (n = 8). Five de novo CCMs were detected in two patients. All de novo CCMs were located on the ipsilateral hemisphere of the DAVS with CVR or juxtapositioned to abnormally dilated deep vein. CCMs may develop in association to DAVSs. The relationship between CCMs and DAVSs suggests the venous pathogenic origin of CCMs and the role of venous hypertension in the de novo development of CCMs.

Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: A causative mutation?

Cerebral cavernous malformations (CCMs; OMIM 116860) are vascular anomalies mostly located in the central nervous system (CNS) and occasionally within the skin and retina.Main clinical manifestations are seizure, hemorrhage, recurrent headaches, focal neurological deficits and epileptic attacks. The CCMs can occur as sporadic or autosomal dominant conditions, although with incomplete penetrance and variable clinical expression.Familial CCMs were associated with causative mutations in the CCM1 [K-Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes.This study reports the identification of a previously undescribed deletion mutation in CCM2 gene exon 5, in an Italian family with multiple cerebral cavernous malformations and epilepsy. Mutation c.502_503delAG results in a frame shift causing a TGA stop codon. This truncates the mutant CCM2 gene protein, the malcavernin, to 233 amino acids, respect to 444 amino acids of the wild-type malcavernin.By using real-time RT-PCR, we have found that the mRNA resulting from two nucleotides deletion showed a 70% reduction relative to the wild-type transcript, indicating that it may be subject to a degradation mechanism such as nonsense-mediated decay (NMD).

De Novo MGC4607 Gene Heterozygous Missense Variants in a Child with Multiple Cerebral Cavernous Malformations

Cavernous malformations are angiographically occult, low-pressure neurovascular lesions with distinct imaging and clinical characteristics; main clinical manifestations are seizure, focal neurological deficits and epileptic attacks. Here we describe the molecular characterization of an Italian child, a symptomatic patient, affected by multiple cerebral cavernous malformations, without a family history of the disease and harbouring a new MGC4607 gene mutation. We identified two de novo missense variants in exon 6 of the gene both present on the same allele (cis configuration). DNA analysis for KRIT1, and PDCD10 gene variation through direct sequencing and MLPA analysis excluded further mutations. STR multiplex assay, allele-specific analysis and DHPLC analysis were performed for a better genetic characterization. Our findings emphasize the importance of the genetic test in subjects presenting multiple cerebral cavernomas for an adequate counselling, as well as for disease management since early identification of genetic abnormalities enable patients to have their lesions removed before they haemorrhage and cause deficit and/or epilepsy.

Multiple cerebral cavernous haemangiomas in an infant

Cerebral cavernous malformations (CCMs) are vascular malformations causing seizures and cerebral hemorrhages. We report a 20-month old male with multiple CCMs associated with Krev interaction trapped 1 (KRIT1) c.845 + 1 G > C heterozygous transversion mutation. This case demonstrates the importance of molecular genetic analysis in cases of multiple CCM.

Glioblastoma multiforme and cerebral cavernous malformations: intersection of pathophysiologic pathways

Cerebral cavernous malformations (CCM) are known to occur in both sporadic and familial forms. To date, there has been no identified association of CCM with glioblastoma multiforme. We present a 69-year-old woman with a 14year history of multiple CCM who developed progressive aphasia. She had no radiation exposure and had only undergone a single computed tomography scan in her entire life. MRI demonstrated irregular gadolinium enhancement in the area of a prior stable CCM, suspicious for a high grade tumor. Stereotactic biopsy revealed a glioblastoma multiforme. This is a unique case of glioblastoma multiforme arising from the “site” of a known CCM. We review the literature on the genetics of cavernous malformations and propose a mechanism for the tumorigenic potential of these vascular malformations.

Predictors of seizure freedom in the surgical treatment of supratentorial cavernous malformations

Seizures are the most common presenting symptom of supratentorial cerebral cavernous malformations (CCMs) and progress to medically refractory epilepsy in 40% of patients. Predictors of seizure freedom in the resection of CCMs are incompletely understood. The authors systematically reviewed the published literature on seizure freedom following the resection of supratentorial CCMs in patients presenting with seizures. Seizure outcomes were stratified across 12 potential prognostic variables. A total of 1226 patients with supratentorial CCMs causing seizures were identified across 31 predominantly retrospective studies; 361 patients had medically refractory epilepsy. Seventy-five percent of the patients were seizure free after microsurgical lesion removal, whereas 25% continued to have seizures. All patients had had preoperative seizures and > 6 months of postoperative follow-up. Modifiable predictors of postoperative seizure freedom included gross-total resection (OR 36.6, 95% CI 8.5-157.5) and surgery within 1 year of symptom onset (OR 1.83, 95% CI 1.30-2.58). Additional prognostic indicators of a favorable outcome were a CCM size < 1.5 cm (OR 15.4, 95% CI 5.2-45.4), the absence of multiple CCMs (OR 2.02, 95% CI 1.13-3.60), medically controlled seizures (OR 2.38, 95% CI 1.29-4.39), and the lack of secondarily generalized seizures (OR 3.33, 95% CI 2.09-5.30). Other factors, including extended resection of the hemosiderin ring, were not significantly predictive. In the surgical treatment of supratentorial CCMs, gross-total resection and early operative intervention may improve seizure outcome. While surgery should not be considered the first-line treatment for CCM-related epilepsy, it is important to understand the variables associated with seizure freedom in CCM resection given the considerable morbidity and diminished quality of life associated with epilepsy.