Catastrophic Epilepsy Research Articles

NARP syndrome and adult‐onset generalised seizures

ABSTRACT The neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) syndrome is a maternally inherited disorder attributable to a heteroplasmic mtDNA point mutation. Catastrophic epilepsy may accompany severe, early onset forms of NARP, but seizures seem to be rare in cases with adolescent and adult onset. We describe a patient who developed clumsiness and visual problems in her teens. She had no clinical seizures but an EEG showed generalized spike and wave discharges. At this time the patient remained without a specific diagnosis. At the age of 21, the patient developed progressive ataxia and she also experienced a tonic‐clonic status epilepticus. Further examinations revealed NARP syndrome. EEG abnormalities may precede adult onset seizures in the NARP syndrome.

Coping with Dravet syndrome: parental experiences with a catastrophic epilepsy

The aim of this study was to investigate how parents cope with and care for a child with Dravet syndrome, a severe myoclonic epilepsy with three distinct stages. Twenty-four parents of children with Dravet syndrome participated in a semi-structured interview and 17 completed the Impact of Childhood Neurologic Disability Scale (ICND) questionnaire. Children included 11 males and 13 females aged 2 to 24 years (mean age 10y 2mo [SD 5y 8mo]). Stage 1 of the syndrome was generally very difficult. Uncertainty about the diagnosis was the primary cause of stress. Seizure control was worst during this time. The primary concern in Stage 2 remained seizure control but developmental, behavioral, and sleep issues also emerged. Negative effects were noted in parents' relationships with others. Stage 3 brought better seizure control but decreased cognitive level, increased behavioral problems, and increasing social isolation for parents. Respite and relief care were hard to obtain at each stage. ICND scores mirrored the findings of the interviews. The three stages of Dravet syndrome present serious challenges for parents. Seizures are persistent and severe but developmental, behavioral, and sleep issues add to the stress. In the absence of successful medical treatment for Dravet syndrome, further attention needs to be paid to helping families cope with the disorder.

How long does it take for epilepsy to become intractable? A prospective investigation

To determine prospectively when in the course of epilepsy intractability becomes apparent. Data are from a prospective cohort of 613 children followed for a median of 9.7 years. Epilepsy syndromes were grouped: focal, idiopathic, catastrophic, and other. Intractability was defined in two ways: (1) 2 drugs failed, 1 seizure/month, on average, for 18 months (stringent), and (2) failure of 2 drugs. Delayed intractability was defined as 3 or more years after epilepsy diagnosis. Eighty-three children (13.8%) met the stringent and 142 (23.2%) met the two-drug definition. Intractability depended on syndrome (p < 0.0001): 26 (31.3%) children meeting stringent and 39 (27.5%) meeting the 2-drug definition had delayed intractability. Intractability was delayed more often in focal than catastrophic epilepsy (stringent: 46.2 vs 14.3%, p = 0.003; two-drug: 40.3 vs 2.2%, p <or= 0.0001). Early remission periods preceded delayed intractability in 65.4 to 74.3% of cases. After becoming intractable, 20.5% subsequently entered remission and 13.3% were seizure free at last contact. Intractable epilepsy may be delayed, especially in focal epilepsy. It often is preceded by a quiescent period, followed by further remissions. These findings help explain why surgically treatable epilepsies may take 20 years or longer before referral to surgery.

Hypothalamic hamartomas—clinical, neuropathological and surgical aspects

Hypothalamic hamartomas are rare congenital lesions of the tuber cinereum presenting with the classic triad of gelastic epilepsy, central precocious puberty and developmental delay. The clinical course in the majority is one of progression, commencing with gelastic seizures in infancy, deteriorating into more complex seizure disorders and resulting in a catastrophic epilepsy associated with a concomitant cognitive and behavioural decline. Electrophysiological, radiological and pathophysiological studies have confirmed the intrinsic epileptogenicity of the hypothalamic hamartoma. Secondary generalised epilepsy seen in this condition is theorised to be through propagation via the mamillothalamic pathways with attachment to the mamillary bodies identified on MRI. Indications as to timing for surgery remain ill-defined although there is a theoretical argument to intervene before the development of secondary generalised epilepsy. Currently, the most effective surgical route appears to be the transcallosal anterior interforniceal approach although newer approaches of endoscopic disconnection and radiosurgery are being assessed.

Infantile Spasms: Little Seizures, BIG Consequences

Infantile spasms is one of the "catastrophic childhood epilepsies" because of the difficulty in controlling seizures and the association with mental retardation. However, early recognition, a careful diagnostic evaluation, and proper treatment may allow some children to attain seizure control and to achieve a normal, or at least much improved, level of development. Thus, there is the opportunity to have an important impact in the lives of these unfortunate children and their families.

Current management for epilepsy in tuberous sclerosis complex

This article reviews the most significant advances in the field of epilepsy associated with tuberous sclerosis complex, with emphasis on new advances in the knowledge of the pathophysiological mechanisms of epileptogenicity, progress in identifying the epileptogenic zone, and the rationale for surgical management in individuals with intractable seizures. Advances in our understanding of the mechanisms and genetics underlying infantile spasms and catastrophic epilepsy associated with tuberous sclerosis complex may facilitate more effective interventions. Early effective seizure control could significantly reduce the adverse developmental effects of chronic epilepsy in tuberous sclerosis. Vigabatrin is the first choice in the short-term treatment of infantile spasms. Some individuals, however, develop seizures that remain highly intractable. The factors that influence the intractability of epilepsy associated with tuberous sclerosis complex remain poorly understood. Multimodality neuroimaging has improved detection of epileptogenic foci, allowing an increased number of individuals to be evaluated for resective surgery. Epilepsy surgery is often associated with significant improvement of the neurologic outcome. Epilepsy in tuberous sclerosis seems to arise from the interaction between multiple areas, all of which have increased excitability and reduced inhibition. Understanding the mechanisms of epileptogenesis might increase the availability of development of a more specific and efficacious treatment. New evidence suggests that it is possible to noninvasively identify children with tuberous sclerosis who are highly likely to become seizure free following surgical treatment.

Surgical treatment of two patients with infantile spasms in early infancy

Early surgery for catastrophic epilepsy may prevent developmental deterioration and minimize functional deficit resulting from the surgical procedure. We report two patients who had infantile spasms and underwent surgery for epilepsy in early infancy (younger than 6 months old). Magnetic resonance imaging showed cortical dysplasia in both patients. One patient underwent lesionectomy in the right perirolandic area at 49 weeks conceptional age (CA) and the other infant underwent left temporo-occipital disconnection at 45 weeks CA. Both showed Engel classification I and catch-up developmental progress. However, with the second patient, we were concerned about the high volume transfusion relative to her body weight during the extensive disconnection because of the patient's small blood volume. We discuss the benefits and potential risks of surgical treatment for intractable epilepsy in early infancy.

Early Periinsular Hemispherotomy in Children with Sturge-Weber Syndrome and Intractable Epilepsy - Outcome in Eight Patients

Periinsular hemispherotomy is used to treat catastrophic epilepsy in hemispheric lesions. It avoids complications of tissue resection performed in other hemispherectomy procedures. We report on the effectiveness, complications, and neurological sequelae in patients with Sturge-Weber syndrome (SWS). Eight patients (mean age at operation 15 months, mean surveillance time 7.1 years, 5 girls) were operated between 1994 and 2000, one with additional subpial resections of the insular cortex. Preoperatively hemiparesis was evident in all patients, mental retardation in six. Charts were reviewed for pre- and perioperative data. Outcome data were collected by structured telephone interview and questionnaires. No severe complications occurred. Five patients with unilateral angiomatosis were seizure-free without medication, rare non-disabling seizures occurred in one. Two patients with bilateral angiomatosis had seizure reduction of > 90%. Hemiparesis deteriorated in all patients with a marked deficit of hand function and less severe deficit in the lower extremity and trunk. Seven became ambulatory and achieved community language. Mental development improved with seizure control. Six patients have learning disability, two are mentally handicapped. Periinsular hemispherotomy is a valuable treatment modality in this patient group. The sequelae of hemiparesis, hemianopsia, and developmental delay must be seen in relation to the natural course in severe SWS.

TUBEROUS SCLEROSIS COMPLEX

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder resulting from mutations in TSC1 (9q34) or in TSC2 (16p13), respectively encoding for hamartin and tuberin. TSC is inherited in an autosomal dominant fashion, although up to two thirds of cases result from spontaneous mutations. The hamartin-tuberin complex plays an important role during cortical development. New schemes of CNS malformations that integrate molecular genetic and morphologic criteria have resulted in a reclassification of TSC as a disorder of cellular lineage. 90% of individuals with TSC exhibits at least one supratentorial brain lesion. Abnormalities of cellular differentiation, proliferation and migration all contribute to the formation of the various brain lesions of the TSC and to the production of very different neurological phenotypes, including seizures, mental impairment, learning disabilities and autism. About 80–90% of individuals with TSC experiences seizures. Epilepsy in TSC seems to arise from the interaction between multiple areas, all of which have increased excitability and reduced inhibition (changes in GABA-A receptors). Advances in understanding mechanisms and genetics underlying infantile spasms and catastrophic epilepsy associated with TSC may facilitate more effective interventions. Early effective seizures control could significantly reduce the adverse developmental effects of chronic epilepsy in tuberous sclerosis. Vigabatrin is the first choice drug in the short term treatment of infantile spasms. However, some individuals develop seizures that remain highly intractable. The factors that influence the intractability of epilepsy associated with TSC remain poorly understood. Multimodality neuroimaging has improved detection of epileptogenic foci, allowing an increased number of individuals to be evaluated for resective surgery. New evidences suggest that it is possible to non-invasively identify children with tuberous sclerosis who are highly likely to become seizure free following surgical treatment. Epilepsy surgery is often associated with significant improvement of the neurologic outcome.

Hemispherectomy for Catastrophic Epilepsy in Infants

To report our experience with hemispherectomy in the treatment of catastrophic epilepsy in children younger than 2 years. In a single-surgeon series, we performed a retrospective analysis of 18 patients with refractory epilepsy undergoing hemispherectomy (22 procedures). Three different surgical techniques were performed: anatomic hemispherectomy, functional hemispherectomy, and modified anatomic hemispherectomy. Pre- and postoperative evaluations included extensive video-EEG monitoring, magnetic resonance imaging, and positron emission tomography scanning. Seizure outcome was correlated with possible variables associated with persistent postoperative seizures. The Generalized Estimation Equation (GEE) and the Barnard's exact test were used as statistical methods. The follow-up was 12-74 months (mean, 34.8 months). Mean weight was 9.3 kg (6-12.3 kg). The population age was 3-22 months (mean, 11.7 months). Thirteen (66%) patients were seizure free, and four patients had >90% reduction of the seizure frequency and intensity. The overall complication rate was 16.7%. No deaths occurred. Twelve (54.5%) of 22 procedures resulted in incomplete disconnection, evidenced on postoperative images. Type of surgical procedure, diagnosis categories, persistence of insular cortex, and bilateral interictal epileptiform activity were not associated with persistent seizures after surgery. Incomplete disconnection was the only variable statistically associated with persistent seizures after surgery (p<0.05). Hemispherectomy for seizure control provides excellent and dramatic results with a satisfactory complication rate. Our results support the concept that early surgery should be indicated in highly selected patients with catastrophic epilepsy. Safety factors such as an expert team in the pediatric intensive care unit, neuroanesthesia, and a pediatric epilepsy surgeon familiar with the procedure are mandatory.

The Early Years of Hemispherectomy

Today, hemispherectomy is a well-established procedure for the treatment of some sorts of catastrophic epilepsies. This, however, has not always been the case. The technique was developed to deal with brain tumors; however, the initial results were not remarkable. Moreover, when its morbidity became evident, it was almost abandoned. Had it not been for a shift in its use, with a huge increase in operations on patients with infantile hemiplegia, this surgery would certainly have disappeared. This paper focuses on the facts that surrounded these early years.

The latest on infantile spasms

This article reviews the most significant advances in the field of infantile spasm during the past year, with emphasis on best practise for treatment, and on some new etiological genetic and metabolic causes for the spasms, and new advances in the knowledge of tuberous sclerosis. Up-to-date information comparing corticotrophin, oral steroids and vigabatrin shows that hormonal treatment is the most effective therapy in the short term. In a recent randomized trial, large doses of prednisolone were as effective as corticotrophin. There are insufficient data to recommend any treatment schedule for infantile spasms. Vigabatrin is the choice for infants with tuberous sclerosis. Visual field defects in (older) children seem to be as common as in adults. In animals, vigabatrin can induce apoptosis of the neurons in the developing brain. New rare factors associated with infantile spasms are mitochondrial diseases, mutations of the Aristales-related homeobax gene and posterior quadrantic dysplasia syndrome. The outcome in children with tuberous sclerosis and infantile spasms is better understood. The accurate determination of etiology is now becoming increasingly possible. There is still a lack of consensus about the treatment of first choice for infantile spasms. However, recent data show that hormonal treatment is the most effective therapy in the short term. Frequency of visual field defects in children treated with vigabatrin should be studied in addition to the long-term outcome in general. Advances in our understanding of brain maturation, etiologies, mechanisms and genetics underlying catastrophic epilepsy may facilitate more effective pharmacologic interventions.

Hemisferectomia funcional precoce na hemimegalencefalia associada à epilepsia refratária

Hemimegalencephaly (HME) is a rare congenital brain malformation of unknown etiology. Patients with HME can present with an early onset epileptic syndrome which is often refractory to medical treatment and associated to impaired neurological development. Functional hemispherectomy (FH) has proven to be a valuable treatment alternative in patients with refractory epilepsy in this setting. Very few children operated under the age of 6 months and bearing HME and catastrophic epilepsy (CE) have been described in the literature. This study reports on 2 kids younger than 6 months with HME and CE submitted to FH with good clinical outcome.

Bilateral Epilepsy Surgery in a 4-Year-Old Child

Reports on bilateral epilepsy surgical interventions are anecdotal because of the possible neurological deficits caused by them. We report on a four-year-old amaurotic child with catastrophic epilepsy due to bilateral occipital cortical dysplasia. After video-EEG monitoring and intraoperative electrocorticography he underwent a two-step bilateral occipital lobectomy. The first resection resulted in only temporary seizure cessation; however, he became seizure-free after the second operation (follow-up: 20 months). Patients with catastrophic epilepsy due to bilateral epileptogenic lesions but without a high risk of additional postsurgical deficit may be good candidates for epilepsy surgery.

Age Dependent Generalized EEG Findings in Pediatric Focal Epilepsy

Background: Generalized features in the clinical semiology and EEG may occur in young children with focal epilepsy as a maturational phenomenon. Study Goals and Methods: The interictal, ictal video EEG, MRIs and clinical data from 5 patients with focal epilepsy evaluated for epilepsy surgery were analyzed. Age of onset and at evaluation, localization of the epileptogenic lesion, electrographic focus and surgical outcome were noted. Results: All patients had early onset catastrophic epilepsy, evaluation occurred under age 6 years. Three lesions were frontal, 2 temporal. Histology showed developmental pathology. EEG discharges were multifocal and generalized once with 3Hz spike waves. Post-surgery all patients became seizure free and the EEG pathology remitted. Conclusion: Propagated epileptiform activity may occur in focal epilepsy in young children as a maturational phenomenon. Surgical resection of the primary epileptic lesion may result in good seizure control. Generalized EEG findings should not be considered a contraindication to surgical treatment in these cases.

Effects of epilepsy surgery on psychiatric and behavioral comorbidities in children and adolescents

When considering surgery in children, it is important to think about the potential effect on psychiatric and behavioral outcome. A growing body of evidence suggests that the type of epilepsy (benign or catastrophic) and the age of the patient affect developmental outcome. In younger children with catastrophic epilepsy, the primary goal of therapy is not only to control seizures, but also to offer the child the opportunity for the best possible development. In older children with partial seizures, the therapeutic goal is to control seizures, which may allow a more normal life and improve behavior. Epilepsy surgery generally appears to have a positive effect on behavior and development in many younger children with catastrophic epilepsy. Psychiatric and behavioral outcomes in older children with complex partial epilepsy are less clear; many patients improve, but there does appear to be a small risk of developing new psychiatric or behavioral disorders postoperatively.

SURGICAL TREATMENT OF THERAPY-RESISTANT EPILEPSY

ABSTRACT Epilepsy neurosurgery is a therapeutic option for patients with seizures resistant to medical therapy. Surgical therapy should be considered in therapy-resistant patients with epilepsy because of the increased mortality (conservatively 0.5% per year), and progressive cognitive and psychosocial morbidity associated with uncontrolled seizures over many years. Patients who continue to have disabling seizures after failure of two to three antiepileptic drugs should be evaluated at a specialty epilepsy center that offers surgery. In particular circumstances, such as catastrophic epilepsy in young children, patients ought to be urgently referred because of the risk of severe developmental disability. Epilepsy surgery encompasses a variety of resective and palliative operative procedures, and no age or gender restrictions exist. Depending on the seizure syndrome and operative procedure, 50% to 70% of patients can expect to become seizure free after resective surgery, which is superior to continued medical therapy. Surgical therapy has improved with time because of new technologies, such as neuroimaging and better operative techniques. Operative-related morbidity and mortality are generally under 5%, which is less than the risk of death from refractory epilepsy over the course of many years. Epilepsy neurosurgery, therefore, is not the treatment of last resort. Instead, surgery is a tool in the treatment of patients who are medically intractable and should be considered early in those patients with a high risk of therapy resistance to reduce seizure-related morbidity and mortality.

Following catastrophic epilepsy patients from childhood to adulthood.

As patients with catastrophic epilepsies move from childhood to adulthood, evolving and innovative therapeutic regimens are often required. However, the goal of providing the best quality of life while minimizing both seizures and side effects remains the same. Clinicians can develop appropriate care plans by being aware of patients' changing needs. Clinical symptoms of the catastrophic epilepsies may change over time; by understanding the natural history of a patient's condition, clinicians can help ease the transition from childhood to adulthood. Additionally, as children with catastrophic epilepsies become adults, medical issues (e.g., medication side effects, tolerance, and dependence) and nonmedical issues (e.g., guardian/caretaker issue, group home applications, and respite care options) must be considered when developing strategies for patient care. Regular assessment of patients, the development of emergency plans, and maintenance of consistency in the delivery of care are also important issues to consider. Finally, a multidisciplinary care plan that incorporates resources from health-care practitioners, social service professionals, and community agencies can be valuable in optimizing treatment for patients with catastrophic epilepsies.

Severe Myoclonic Epilepsy in Infancy: Toward an Optimal Treatment

Severe myoclonic epilepsy in infancy, or Dravet syndrome, is one of the catastrophic epilepsy syndromes. In the past, treatment was mainly based on valproate and phenobarbital. Recently, some of the new antiepilepsy drugs, such as topiramate and stiripentol, have been shown to be promising in the treatment of this epilepsy syndrome. The treatment regimen of 12 children with Dravet syndrome and proven mutations in the alpha subunit of the sodium channel SCN1A is reported here. Five patients on the "traditional" treatment regimen are compared with seven children on an "optimal" treatment regimen based on a combination of valproate and topiramate. With respect to the literature and our own experience, we propose guidelines for "optimal" treatment of children with severe myoclonic epilepsy in infancy. This includes prevention of hyperthermia, rigorous treatment of fever, avoiding stressful situations, maintenance treatment based on a combination of only two antiepilepsy drugs (ie, valproate and topiramate), and a strict acute seizure treatment based on benzodiazepines. To prevent long-lasting periods of status epilepticus, this acute seizure treatment must be taught to parents and caregivers.

Hemispheric malformations of cortical development

The term hemispheric malformations of cortical development (MCDs) is used in this article to represent congenital malformations that predominantly or exclusively involve complete or substantial portion of one cerebral hemisphere. Hemispheric MCDs usually present during early childhood with intractable epilepsy, cognitive delay, and contralateral hemiparesis. Early identification and selection of children who may be candidates for epilepsy surgery are important during diagnostic evaluation of hemispheric MCD. Surgical intervention at an appropriate time, whenever possible, offers the best chance for seizure freedom and improved cognitive outcome. In addition, making an accurate genetic diagnosis is imperative to offer genetic testing and counseling to the family. In this article, the authors discuss the developmental and genetic mechanisms, pathologic features, diagnosis, and treatment of hemispheric MCD that are substrates of catastrophic childhood epilepsy amenable to surgical treatment.