Distinctive MRI features of the epileptogenic zone in children with tuberous sclerosis.

OBJECTIVE: Localization of the epileptogenic zone (EZ) is challenging in children with tuberous sclerosis complex (TSC). We sought to ascertain whether brain MRI could identify the EZ in TSC patients independent of the clinical and diagnostic data. METHODS: Presurgical MRI's of 34 children with TSC who underwent epilepsy surgery at Miami Children's Hospital were retrospectively reevaluated by experts blinded to all other data. Changes typical of TSC (tubers, calcifications, cystic changes) and abnormalities of the perituberal cortex typical of focal cortical dysplasia (FCD) (increased cortical thickness, abnormal gyration, transmantle change, gray/white matter junction blurring) were identified and their localization was compared with the resection site. Sensitivity, specificity and accuracy of individual MRI features to localize the EZ were determined and statistically compared between postoperatively seizure-free and non-seizure-free patients as well as clusters of features typical of FCD and TSC. RESULTS: MRI alone correctly localized the resection cavity in all 19 postoperatively seizure-free patients and 12 of 15 non-seizure-free subjects. Sensitivity, specificity and accuracy of MRI features typical of FCD to localize EZ (90%, 96% and 96%, respectively) were superior to those typical of TCS (79%, 75% and 75%, p<0.0001). Increased cortical thickness and abnormal gyral formation outside tubers occurred only in the resection site. Resection sites were better predicted by MRI in seizure-free than in non-seizure-free patients. CONCLUSION: Thorough MRI evaluation identifies the EZ in a significant proportion of TSC patients. Epileptogenic regions were mostly characterized by "FCD-like" changes outside cortical tubers. The findings may have important practical consequences for surgical planning in TSC.

Treatment strategies.

There has been important progress in the identification of antiepileptic compounds and their indications in children over the past 15 years: their number has doubled and specific pediatric trials are being performed to document their effect according to seizures and syndromes as well as their tolerability in pediatrics. The improved understanding of pharmacokinetics and drug-drug interactions has helped to optimize treatment. Specific issues specific of infants have also been studied although new antiepileptic drugs are still dramatically lacking for this age group. Before reaching a syndromic diagnosis, the choice of a first- line agent goes to compounds with the largest range of efficacy and least identified risks. Subsequent choices are mainly based on the epilepsy syndrome and seizure type in addition to good clinical practice to determine dose, adverse effect profile, risk of aggravating seizures and drug interactions, clinician's experience, cultural habits, and availability of drugs. If there are several options, preference is given to the compound that exhibits the best risk/benefit ratio, or the most rapid titration when seizure frequency is the major issue. For new antiepileptic compounds, price is often a limiting factor in countries with poor insurance coverage. Third generation anti-epileptic drugs are emerging which also seem to be promising.

Predictors of seizure freedom after incomplete resection in children.

OBJECTIVE: Incomplete resection of the epileptogenic zone (EZ) is the most important predictor of poor outcome after resective surgery for intractable epilepsy. We analyzed the contribution of preoperative and perioperative variables including MRI and EEG data as predictors of seizure-free (SF) outcome after incomplete resection. METHODS: We retrospectively reviewed patients <18 years of age with incomplete resection for epilepsy with 2 years of follow-up. Fourteen preoperative and perioperative variables were compared in SF and non-SF (NSF) patients. We compared lesional patients, categorized by reason for incompleteness, to lesional patients with complete resection. We analyzed for effect of complete EEG resection on SF outcome in patients with incompletely resected MRI lesions and vice versa. RESULTS: Eighty-three patients with incomplete resection were included with 41% becoming SF. Forty-eight lesional patients with complete resection were included. Thirty-eight percent (57/151) of patients with incomplete resection and 34% (47/138) with complete resection were excluded secondary to lack of follow-up or incomplete records. Contiguous MRI lesions were predictive of seizure freedom after incomplete resection. Fifty-seven percent of patients incomplete by MRI alone, 52% incomplete by EEG alone, and 24% incomplete by both became SF compared to 77% of patients with complete resection (p = 0.0005). CONCLUSIONS: Complete resection of the MRI- and EEG-defined EZ is the best predictor of seizure freedom, though patients incomplete by EEG or MRI alone have better outcome compared to patients incomplete by both. More than one-third of patients with incomplete resection become SF, with contiguous MRI lesions a predictor of SF outcome.

Incomplete resection of focal cortical dysplasia is the main predictor of poor postsurgical outcome.

BACKGROUND: Focal cortical dysplasia (FCD) is recognized as the major cause of focal intractable epilepsy in childhood. Various factors influencing postsurgical seizure outcome in pediatric patients with FCD have been reported. OBJECTIVE: To analyze different variables in relation to seizure outcome in order to identify prognostic factors for selection of pediatric patients with FCD for epilepsy surgery. METHODS: A cohort of 149 patients with histologically confirmed mild malformations of cortical development or FCD with at least 2 years of postoperative follow-up was retrospectively studied; 113 subjects had at least 5 years of postoperative follow-up. Twenty-eight clinical, EEG, MRI, neuropsychological, surgical, and histopathologic parameters were evaluated. RESULTS: The only significant predictor of surgical success was completeness of surgical resection, defined as complete removal of the structural MRI lesion (if present) and the cortical region exhibiting prominent ictal and interictal abnormalities on intracranial EEG. Unfavorable surgical outcomes are mostly caused by overlap of dysplastic and eloquent cortical regions. There were nonsignificant trends toward better outcomes in patients with normal intelligence, after hemispherectomy and with FCD type II. Other factors such as age at seizure onset, duration of epilepsy, seizure frequency, associated pathologies including hippocampal sclerosis, extent of EEG and MRI abnormalities, as well as extent and localization of resections did not influence outcome. Twenty-five percent of patients changed Engel's class of seizure outcome after the second postoperative year. CONCLUSIONS: The ability to define and fully excise the entire region of dysplastic cortex is the most powerful variable influencing outcome in pediatric patients with focal cortical dysplasia.

The impact of epilepsy surgery on quality of life in children.

OBJECTIVE: To determine if epilepsy surgery is effective in improving the quality of life (QOL) of children with intractable seizures using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). METHODS: The authors conducted a prospective study of the families of 35 children with intractable epilepsy who underwent epilepsy surgery. Parents completed the QOLCE preoperatively and again 6 to 18 months after surgery. At both assessment dates parents indicated the severity of their child's seizures during the past 6 months and the frequency of their child's seizures during the past 4 weeks on Likert-type scales. Children were split into two groups according to surgery outcome: seizure free vs persistent seizures. Statistical analyses were conducted to determine if children rendered seizure free showed a greater improvement in QOL compared to those with persistent seizures postoperatively. RESULTS: Greater improvement in QOL was documented for children rendered seizure free vs children with persistent seizures. This was significant for the overall QOLCE QOL score and subscales assessing cognitive, social, emotional, behavioral, and physical domains of life. CONCLUSIONS: Epilepsy surgery improves the quality of life of children rendered seizure free. Families can be counseled preoperatively of the potential benefits of surgery beyond seizure reduction.

Distinct clinicopathologic subtypes of cortical dysplasia of Taylor.

BACKGROUND: Two pathologic subtypes based on the presence or absence of balloon cells have been described in cortical dysplasia of Taylor (CDT). OBJECTIVE: To determine whether the pathologic subtype has any distinct clinical or MRI features that are relevant to management. METHODS: The histopathologic, clinical, and MRI features of 34 children with CDT who underwent epilepsy surgery at Miami Children's Hospital from 1990 to 2001 were investigated. RESULTS: Bizarre neuronal cytomegaly was the primary pathologic feature of 15 patients with the dysplasia-only subtype, and 19 cases showed additional characteristics including balloon cells and marked white matter abnormalities. Both groups presented with severe intractable epilepsy of very-early-onset, multiple daily seizures, cognitive disability, and focal neurologic deficits. The dysplasia-only subtype had higher rates of neonatal onset, hemiparesis, and severe mental retardation (p < 0.05). The MRI features of focal cortical thickening with associated cortical T2 signal change showed excellent sensitivity (94%) and reasonable specificity (73%) for the diagnosis of the balloon cell subtype. The overall surgical outcome was 59% seizure freedom at 2 years. CONCLUSIONS: Children with cortical dysplasia of Taylor type have in common a very-early-onset, severe epilepsy with neurologic co-morbidity. Patients with the non-balloon cell pathologic subtype have a more severe phenotype. A trend toward a better outcome in the balloon cell group suggests that preoperative identification of these subtypes may impact surgical planning.

Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society.

OBJECTIVE: To determine the current best practice for treatment of infantile spasms in children. METHODS: Database searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme. RESULTS: Adrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis. CONCLUSIONS: ACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective.

Absence of hippocampal sclerosis in children with multiple daily seizures since infancy.

We report a series of nine children with multiple daily seizures since infancy who underwent functional hemispherectomy that included en bloc resection of the hippocampus and the temporal neocortex. In all cases, the hippocampi were normal by conventional histology despite the fact that these patients had suffered from recurrent seizures over a long period of time. This observation suggests that extremely frequent seizures in childhood are not invariably associated with the development of hippocampal sclerosis.

Outcome of corpus callosotomy and other pediatric epilepsy surgery: parental perceptions.

PURPOSE: Parental perceptions regarding the outcome of epilepsy surgery in their children were assessed preoperatively via telephone survey. METHODS: Twenty-seven parents - sixteen mothers (MO), eleven fathers (FA) - of sixteen children (nine boys, seven girls; ages 6 months-18 years) with intractable epilepsy (refractory to > or = 3 anticonvulsants) were interviewed. Twenty-four questions were posed during single, 20-minute sessions to both parents. RESULTS: A majority of parents (63% MO, 82% FA) would consider epilepsy surgery successful if it achieved > or = 75% seizure reduction. Incomplete seizure control would even be acceptable if the overall number of seizures were reduced (69% MO, 18% FA). In order to gain seizure remissions, behavioral deterioration would be accepted (57% MO, 50% FA). Less than total seizure control would be accepted if surgery produced behavioral improvement (57% MO, 51% FA, Kappa > 0.6). For seizure reduction, parents would accept: visual field deficits (82% MO, 67% FA), short-term memory deficits (33% MO, 75% FA), and speech problems (56% MO, 17% FA). CONCLUSION: Parents of children with medically-resistant seizures perceive adverse physical and behavioral consequences of epilepsy surgery to be acceptable if there is adequate seizure control. Their acceptance of postoperative deficits underscores the magnitude of the handicap produced by chronic childhood epilepsy.

Recent advances in candidate selection for pediatric epilepsy surgery.

Many patients who were once considered inoperable are candidates for a wide variety of surgical procedures. This trend is particularly striking at pediatric centers that serve patients with diverse forms of epilepsy that compromise development. Newer diagnostic techniques, including structural and functional imaging, EEG monitoring, and surgical technology, can provide a complete representation of the etiology and expression of the epileptic focus, including accurate cortical localization. This review focuses on several forms of epilepsy that, until recently, were not regarded to be surgically amenable. The adverse seizure and neurobehavioral prognosis in patients with these disorders provides the justification to search for innovative treatments. With more sophisticated tools for preoperative evaluation and an expanding knowledge base, it is likely that the number of surgical candidates will continue to increase in the future.

Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome.

PURPOSE: Children with tuberous sclerosis complex (TSC) benefit from excisional surgery if seizures can be localized to a single tuber. We evaluated the role of noninvasive studies to localize the epileptogenic tuber/region (ET/R) and the outcome of focal resection. METHODS: We identified 21 children with TSC, ages 3 months to 15 years (mean 4.8 years). All had video-(electroencephalogram) EEG and magnetic resonance imaging (MRI) scans, and 18 also had ictal single photon emission-computed tomography (SPECT) studies. An ET/R was localized in 17 patients. Thirteen patients underwent resection guided by intraoperative electrocorticography (n = 7) or subdural monitoring (n = 6). RESULTS: Interictal EEG revealed a principal spike focus (PSF) that corresponded to the ET/R in 14 children. In seven, PSFs occurred in rhythmic runs. PSFs were not observed remote from the ET/R. Focal polymorphic slowing and attenuation occurred in the region of the PSF in 11 patients. Sixteen patients demonstrated an ictal focus corresponding to the ET/R. Ictal SPECT revealed focal hyperperfusion correlating with the ET/R in 10 patients. Although the MRIs in all children revealed multiple tubers, the ET/R corresponded to a large discrete tuber in 8 patients and a calcified tuber in 13 patients. Patchy calcified tubers were also seen elsewhere in six patients. At a mean follow-up of 26 months, 9 of the 13 children who underwent surgery were seizure-free, one had greater than 75% reduction in seizures, two were unchanged, and one was lost to follow-up. New seizures developed in one child from a contralateral tuber. CONCLUSIONS: Surgical resection of an ET/R alleviates seizures in most children with TSC and intractable epilepsy. The scalp EEG and MRI help define the ET/R and improve case selection when ictal SPECT is nonlocalizing.

Aberrant neural circuits in malformations of cortical development and focal epilepsy.

Malformations of cortical development (MCD) account for a high proportion of medically resistant partial seizures in children and figure prominently in pediatric surgical series. In contrast to the results of epilepsy surgery for postnatally acquired lesions, seizure freedom in patients with MCD is less certain owing to difficulties in defining the epileptic zone, and fully excising the epileptogenic cortex. The authors present evidence that, compared with postnatally acquired lesions such as those due to tumors or trauma, focal epileptogenesis associated with MCD is best conceptualized as a disorder of widespread and patchy disturbance of cortical networks. This developmental perspective implies that the epileptogenic region in MCD is rarely discrete even in patients with focal anatomic lesions, and may include remote cortical or subcortical areas. Preoperative investigative protocols based on this model have improved surgical results, but outcome remains far from optimal and further progress in understanding the complex developmentally based features of MCD is required.

Cognitive outcome of children with epilepsy and malformations of cortical development.

OBJECTIVE: To assess intellectual functioning (IQ) in 54 children and adolescents with intractable epilepsy who later underwent cortical resection due to unilateral malformations of cortical development acquired in utero. METHODS: Lesion type was classified into circumscribed mass lesions and diffuse cortical dysplasia based on histopathologic analysis of surgical tissue. Cortical dysplastic lesions were further graded as mild, moderate, or severe according to specific microscopic features. Laterality of lesion was determined through neurologic examination and electrophysiologic and neuroradiologic procedures. Classification of lesion type was corroborated by its significant relationship with other disease-related variables known to be related to clinical severity (age at seizure onset, age at resection, and extent of lesion). RESULTS: Analyses of covariance revealed that circumscribed lesions had a less deleterious effect on nonverbal IQ than did diffuse cortical dysplasia, after controlling for age at seizure onset and extent of lesion. This effect was also found on verbal IQ measures, but only in subjects with right-sided lesions. Subjects with left-sided lesions performed significantly more poorly on verbal IQ measures than those with right-sided lesions. Additionally, younger age at onset and greater extent of lesion were associated with poorer cognitive outcome. CONCLUSIONS: Cortical dysplasia and early left hemisphere lesions have a significantly worse impact on cognitive functioning than circumscribed lesions or right hemisphere developmental lesions in children with epilepsy.

Predictors of outcome in pediatric epilepsy surgery.

OBJECTIVE: To determine the correlation between pre- and perioperative variables on the outcome of children undergoing focal resections for medically intractable partial epilepsy. METHODS: Retrospective analysis of pre- and perioperative variables in a cohort of 75 patients younger than 12 years of age who underwent excisional surgery and had at least 1 year of follow-up. Outcome, measured by postoperative seizure frequency, was analyzed as a function of age at seizure onset, duration of epilepsy, presence of cognitive impairment, lobe of seizure origin, presence of a lesion, histopathology, and completeness of resection. Completeness of resection was defined on the basis of excising both the entire structural lesion if present and the region revealing prominent interictal and ictal abnormalities on intracranial EEG. RESULTS: Seventy-seven percent of patients had good outcomes (class 1 or 2), and 59% were seizure-free. Lesional status, site of resection, and pathologic diagnoses were not significant predictors of outcome except for in multilobar resection, for which overall outcome was relatively poor (44% class 3 or 4; 22% seizure-free). Completeness of resection was the only significant predictor of good outcome (p < 0.001), with 92% of patients who underwent complete resection of the epileptogenic zone achieving good outcome compared with 50% of patients who had incomplete resections. CONCLUSION: In this series of pediatric patients, complete resection of the lesion and the electrographically abnormal region was the main determinant of outcome after focal resections. Except for multilobar resections, other factors examined in this study did not significantly influence postoperative seizure prognosis and should not influence candidate selection for the surgical process.

Selection criteria and preoperative investigation of patients with focal epilepsy who lack a localized structural lesion.

Children with medically resistant epilepsy are often referred for surgical evaluation. The absence of a specific focal lesion on MRI may render the work-up difficult. In response to the need to localize the primary area of epileptogenesis, surgery protocols are being developed which rely on clinical semiology, EEG and functional imaging data. In selected cases, intracranial EEG monitoring may be required. While testing more often depends on the convergence of modalities, it is possible to localize seizure origin in the majority of children, and fully excise the epileptogenic region. This review presents the etiology and preoperative modalities available for children with intractable, non-lesional epilepsy.

Clinical spectrum of cortical dysplasia in childhood: diagnosis and treatment issues.

Disorders of cortical development form a spectrum of lesions produced by insults to the developing neocortex. These conditions typically first manifest in childhood with epilepsy, developmental delay, and focal neurologic signs. Although the clinical and electrophysiologic findings are often nonspecific, high-resolution magnetic resonance imaging facilitates diagnosis during life, and assists in delineating specific clinical syndromes. While many patients are dysmorphic and severely affected by mental retardation and epilepsy, some have normal or near-normal cognitive function and no seizures. Molecular studies of dysplastic cortex are providing new insights into the basic mechanisms of brain function and development, while pathologic analysis of tissue removed at surgery is helping to define epileptic circuitry. Treatment of the epilepsy associated with cortical dysplasia is often frustrating, but surgical approaches based on accurately defining epileptogenic regions are proving increasingly successful. Genetic diagnosis is important for accurate counseling of families.

A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group.

OBJECTIVE: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures. BACKGROUND: Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children. METHODS: We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period. RESULTS: Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy. CONCLUSIONS: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.