Quantitative Evaluation of Medial Temporal Lobe Morphology in Children with Febrile Status Epilepticus: Results of the FEBSTAT Study.

BACKGROUND AND PURPOSE: The pathogenesis of febrile status epilepticus is poorly understood, but prior studies have suggested an association with temporal lobe abnormalities, including hippocampal malrotation. We used a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus. MATERIALS AND METHODS: Brain MR imaging was performed in children presenting with febrile status epilepticus and control subjects as part of the Consequences of Prolonged Febrile Seizures in Childhood study. Medial temporal lobe morphologic parameters were measured manually, including the distance of the hippocampus from the midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. RESULTS: Temporal lobe morphologic parameters were correlated with the presence of visual hippocampal malrotation; the strongest association was with left temporal horn width (P < .001; adjusted OR, 10.59). Multiple morphologic parameters correlated with febrile status epilepticus, encompassing both the right and left sides. This association was statistically strongest in the right temporal lobe, whereas hippocampal malrotation was almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persisted when the analysis was restricted to cases with visually normal imaging findings without hippocampal malrotation or other visually apparent abnormalities. CONCLUSIONS: Several component morphologic features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum.

The role of EEG in febrile status epilepticus (FSE).

Febrile status epilepticus is an important neurological emergency and a risk factor for later development of epilepsy. There are guidelines recommending against the use of EEG in the evaluation of simple febrile seizures but the role in febrile status epilepticus is not well established. This article reviews the literature on the role of EEG in the evaluation of the patient with prolonged febrile seizures, summarizes the findings, and concludes with some simple recommendations based upon the existing knowledge. At least 30-40% of EEGs obtained within one week of febrile status epilepticus will contain abnormalities including focal slowing. In some series focal slowing appears to be associated with development of a spike focus in the same location. Prospective series with large numbers of patients and follow-up are required to ascertain whether such abnormalities are associated with later development of epilepsy.

Phenomenology of prolonged febrile seizures: results of the FEBSTAT study.

BACKGROUND: Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent mesial temporal sclerosis and temporal lobe epilepsy. However, little is known about the semiology of FSE. METHODS: A prospective, multicenter study of the consequences of FSE included children, aged 1 month through 5 years, presenting with a febrile seizure lasting 30 minutes or more. Procedures included neurologic history and examination and an MRI and EEG within 72 hours. All information related to seizure semiology was reviewed by three epileptologists blinded to MRI and EEG results and to subsequent outcome. Inter-rater reliability was assessed by the kappa statistic. RESULTS: Among 119 children, the median age was 1.3 years, the mean peak temperature was 103.2 degrees F, and seizures lasted a median of 68.0 minutes. Seizure duration followed a Weibull distribution with a shape parameter of 1.68. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. In one third of cases, FSE was unrecognized in the emergency department. Of the 119 children, 86% had normal development, 24% had prior febrile seizures, and family history of febrile seizures in a first-degree relative was present in 25%. CONCLUSIONS: Febrile status epilepticus is usually focal and often not well recognized. It occurs in very young children and is usually the first febrile seizure. Seizures are typically very prolonged and the distribution of seizure durations suggests that the longer a seizure continues, the less likely it is to spontaneously stop.

The ontogeny of partial seizures in infants and young children.

PURPOSE: To describe the clinical manifestations of partial seizures in the pediatric population as a function of age. METHODS: Using the database of the pediatric epilepsy monitoring unit (Children's Hospital of New York), clinical and EEG characteristics of partial seizures were distributed by age groups 0-2, 2-6, and 6+ years for 123 patients who had at least one such seizure with a clear EEG correlate during their admission. chi2 tests for trend were used to examine clinical and EEG features as a function of age. RESULTS: The frequency of aura, limb automatisms, dystonic posturing, secondary generalization, and unresponsiveness increased with age, whereas asymmetric clonus and symmetric tonic posturing decreased with age. There were no clear changes in the types of EEG ictal patterns observed with age; however, partial seizures emanating from the anterior regions of the brain tended to increase with age, whereas those from the posterior regions tended to decrease with age. CONCLUSIONS: Important differences exist in the clinical expression of seizures between young children and adults. These findings will contribute to a better understanding of ictal ontogeny that will promote more accurate classification of seizures and of the epilepsies in young patients. Such efforts can be used to identify young patients for focal epilepsy surgery and to select appropriate anticonvulsive medications.

Experience with the ketogenic diet in infants.

OBJECTIVE: To evaluate the effectiveness, tolerability, and adverse effects of the ketogenic diet in infants with refractory epilepsy. METHODS: A retrospective review of 32 infants who had been treated with the ketogenic diet at a large metropolitan institution. RESULTS: Most infants (71%) were able to maintain strong ketosis. The overall effectiveness of the diet in infants was similar to that reported in the literature for older children; 19.4% became seizure-free, and an additional 35.5% had >50% reduction in seizure frequency. The diet was particularly effective for patients with infantile spasms/myoclonic seizures. There were concomitant reductions in antiepileptic medications. The majority of parents reported improvements in seizure frequency and in their child's behavior and function, particularly with respect to attention/alertness, activity level, and socialization. The diet generally was well-tolerated, and 96.4% maintained appropriate growth parameters. Adverse events, all reversible and occurring in one patient each, included renal stone, gastritis, ulcerative colitis, alteration of mentation, and hyperlipidemia. CONCLUSION: The ketogenic diet should be considered safe and effective treatment for infants with intractable seizures.

Selection and evaluation of children for epilepsy surgery.

Major determinants of the success of epilepsy surgery are the proper selection and evaluation of the patient. Candidates should have medically intractable, disabling epilepsy. The evaluation requires a unified, systematic approach by a comprehensive team of health professionals. Key points, common to most evaluations, are enumerated and provide a useful tool for mental organization. In general, the greater the degree of congruent information derived from these investigations, the better the candidacy for surgery. After this, completeness of resection and etiology are other important predictors of success. Children present unique challenges and opportunities owing to the vulnerability and plasticity of the developing nervous system. Surgery for intractable epilepsy can be a rewarding therapy, and in select children, the only chance for cure and substantial development progress.

Advances in our understanding of early childhood epilepsies: 1999-2000.

Epilepsy is frequent in early childhood, but poorly understood. Management of very young children with refractory epilepsy is particularly challenging, but recent advances in classification, medical therapy, and surgical treatment are helping. We summarize work in each area, focusing on developments in the past 2 years. Classification schemes unique to the needs of very young children will likely improve our ability to accurately diagnose and treat those with refractory seizures. Medication studies are now being done that address some of the specific epilepsy syndromes seen in infants and young children, with promising results in some circumstances. Progress is also being made in the identification of good candidates for early, effective epilepsy surgery. For a variety of reasons and incentives, it is likely that research focusing on infants and young children will continue at a brisk pace.

Special needs of the adolescent with epilepsy.

Adjustment to the inherent changes of adolescence is a challenge for many children, even healthy ones. Epilepsy may make successful adjustment even more difficult by disrupting self-control, adversely affecting the ability to conform to one's peers, and interfering with independence. Epilepsy and its treatment may affect education, employment, use of alcohol and illicit drugs, sexual activity, and pregnancy. These issues, in turn, may affect seizure control. Matching the medicine to the patient is particularly important in teenagers, a group of patients with special needs. Common seizure syndromes presenting in adolescence are briefly reviewed and used to illustrate key issues that may arise in the selection of an antiepileptic medication (AED). Compliance, interaction with other medications including oral contraceptive medications, cosmetic effects, teratogenicity, and impact on behavior are all factors to be considered. Newer medications may have some advantages over older compounds in this regard, and evidence of their utility is reviewed in the specific context of the epilepsy syndromes. In addition to prescribing medication, other important parts of the therapeutic management involve education, counseling, support, and advocacy. To identify issues and to provide appropriate counseling, it is beneficial to devote some of the office visit to an independent interaction with the patient, apart from the parents. One study questionnaire indicated that nurse specialists may be particularly valuable in supporting and meeting the needs of patients in this age group. Some centers have developed elegant methods of helping the patient make the transition from child neurology to adult neurology.

Epilepsy surgery in children, with special attention to focal cortical resections.

Epilepsy surgery is an important alternative for children and adolescents with medically intractable epilepsy. Advances in imaging have allowed the visualization of epileptogenic regions, including cortical dysplasia. The presurgical evaluation will likely become less invasive as imaging technology improves. Long-term development is a critical outcome measure, in addition to seizure control. The long-term prognosis after epilepsy surgery may be related to factors other than seizure control, including the timing of the intervention and the cause of the epilepsy. It may be useful to independently analyze children based on cause, and further studies examining the long-term outcome should become feasible as surgical experience grows.

Prospective magnetic resonance imaging identification of focal cortical dysplasia, including the non-balloon cell subtype.

The purpose of this study was to determine the role of high-resolution T2-weighted fast multiplanar inversion-recovery (FMPIR) magnetic resonance (MR) imaging in detecting and delineating microscopic focal cortical dysplasia (FCD). We performed MR scans with FMPIR on 42 patients with suspected neocortical epilepsy. Ten MR studies were read prospectively as showing FCD; these case histories, electroencephalographic studies, and neuroimaging data were reviewed. Eight of these patients subsequently underwent focal cortical resection guided by intraoperative electrocorticography. The MR findings were correlated with pathological findings in these 8 patients. For purposes of radiological-pathological correlation, the FCD lesions were divided into two classes. Radiological classification was based on the absence (type A) or presence (type B) of T2 prolongation of the subcortical white matter. Pathological grading as type I or type II was based on a previously described pathological grading system. Specific MR findings associated with FCD included focal blurring of the gray-white matter interface (n = 9), thickening of the cortical ribbon (n = 7), and T2 prolongation of the subcortical white matter (n = 4). In 3 patients, the only MR finding that suggested FCD was localized blurring of the gray-white matter junction. In 2 of these 3 patients, the MR diagnosis of FCD could be made only by FMPIR. FCD was confirmed histologically in 7 of 8 patients, with insufficient tissue for complete histopathological evaluation in 1 case. Radiological classification of FCD agreed with pathological classification in 5 of 7 cases. Correlation of MR findings with intraoperative electrocorticography results indicated that the MR study localized the epileptogenic lesion correctly in 8 of 8 cases. Scalp ictal electroencephalographic studies localized the epileptogenic lesion in 5 of 8 cases; positron emission tomographic scans were focally abnormal in 3 of 3 cases. FMPIR MR imaging permitted accurate diagnosis and localization of FCD in all patients with pathologically proved FCD. MR identification of FCD aided presurgical planning and intraoperative management of these patients.

L-carnitine supplementation in childhood epilepsy: current perspectives.

In November 1996, a panel of pediatric neurologists met to update the consensus statement issued in 1989 by a panel of neurologists and metabolic experts on L-carnitine supplementation in childhood epilepsy. The panelists agreed that intravenous L-carnitine supplementation is clearly indicated for valproate (VPA)-induced hepatotoxicity, overdose, and other acute metabolic crises associated with carnitine deficiency. Oral supplementation is clearly indicated for the primary plasmalemmal carnitine transporter defect. The panelists concurred that oral L-carnitine supplementation is strongly suggested for the following groups as well: patients with certain secondary carnitine-deficiency syndromes, symptomatic VPA-associated hyperammonemia, multiple risk factors for VPA hepatotoxicity, or renal-associated syndromes; infants and young children taking VPA; patients with epilepsy using the ketogenic diet who have hypocarnitinemia; patients receiving dialysis; and premature infants who are receiving total parenteral nutrition. The panel recommended an oral L-carnitine dosage of 100 mg/kg/day, up to a maximum of 2 g/day. Intravenous supplementation for medical emergency situations usually exceeds this recommended dosage.

Valproate therapy: predisposition to bone fracture?

A 13-year-old girl on valproate therapy had 20 fractures over a 4-year period between the ages of 5 years and 9 years. Once valproate was withdrawn, no further fractures occurred over the ensuing 4 years. Three other children manifested at least two fractures while on valproate antiepileptic therapy. These reports suggest that valproate, along with other known causes of demineralization (e.g., lack of exercise, diet, and genetic factors), predisposes patients to fractures.

Recognition and classification of seizures in infants.

PURPOSE: We wished to assess the reliability of the International League Against Epilepsy (ILAE) seizure classification system applied to infantile seizures and to test a proposed new classification. METHODS: We first analyzed 39 seizures in 20 infants (aged 1-26 months) recorded with simultaneous closed-circuit television and EEG (CCTV/EEG). EEGs and videotapes of all seizures were independently analyzed by two epileptologists blinded to clinical histories. Videotapes of each seizure were reviewed without simultaneous EEG (phase 1), and printouts of ictal EEGs were assessed without behavioral correlates (phase II). The observers classified seizures according to ILAE criteria. Interrater agreement was assessed by the kappa statistic. RESULTS: Agreement on EEG features (phase II) was moderate (= 0.54) in identifying focal ictal onsets and substantial (= 0.79) in identifying generalized onsets. In contrast, analysis of videotapes showed substantial disagreement between observers in terms of classifying seizures as partial or generalized. Therefore, agreement between observers for partial was slight (= 0.14) and fair for generalized seizures (= 0.26). Similarly, conclusions of the observers as compared with those of a consensus panel were divergent for both partial (= 0.18) and generalized seizures (= 0.30). We therefore developed an alternative classification scheme and retested interrater agreement in a review of 50 seizures in 25 other infants. With this classification scheme, there was substantial agreement between observers (= 0.72). CONCLUSIONS: With clinical observations and interictal EEGs, seizures in infants cannot be reliably classified by current ILAE criteria. In contrast, a proposed new classification scheme based solely on semiology showed substantial reliability.

Reversible signal abnormalities in the hippocampus and neocortex after prolonged seizures.

PURPOSE: To investigate the phenomenon of reversible increased signal intensity of medial temporal lobe structures and cerebral neocortex seen on MR images of six patients with recent prolonged seizure activity. METHODS: After excluding patients with known causes of reversible signal abnormalities (such as hypertensive encephalopathy), we retrospectively reviewed the clinical findings and MR studies of six patients whose MR studies showed reversible signal abnormalities. MR pulse sequences included T2-weighted spin-echo coronal views or conventional short-tau inversion-recovery coronal images of the temporal lobes. RESULTS: All six MR studies showed increased signal intensity within the medial temporal lobe, including the hippocampus in five studies. All follow-up MR examinations showed partial or complete resolution of the hyperintensity within the medial temporal lobe and the neocortex. In one patient, results of a brain biopsy revealed severe cerebral cortical gliosis. Temporal lobectomy performed 4 years later showed moderate cortical gliosis and nonspecific hippocampal cell loss and gliosis. CONCLUSION: Significant hyperintensity within the temporal lobe is demonstrable on MR images after prolonged seizure activity, suggestive of seizure-induced edema or gliosis. Damage to medial temporal lobe structures by prolonged seizure activity indicates a possible mechanism of epileptogenic disorders.

Fetomaternal hemorrhage as an etiology of neonatal stroke.

We report a term infant who presented with focal seizures and was diagnosed with a large left hemispheral infarct. Evaluation revealed extensive fetomaternal hemorrhage and subsequent neuroimaging disclosed a classic border zone infarct consistent with a hypoperfusion injury. We postulate that fetomaternal hemorrhage should be considered in the differential causation of neonatal stroke. The unilaterality of the lesion in this patient is difficult to explain.

Antibodies against monomorphic determinants of the alpha chain of class I human leukocyte antigens inhibit the reaction of human lymphocytes to mitogen and tetanus toxoid.

Monoclonal antibodies directed against the alpha chain of Class I Major Histocompatibility Complex (MHC) antigens inhibit the reactivity of human T lymphocytes to mitogen or antigen. In contrast, monoclonal antibodies to beta 2 microglobulin do not suppress human T cell proliferation to these same stimuli. As antigen presentation by accessory cells involves Class II and not Class I MHC antigens, the inhibition of human T cell proliferation in response to mitogen or antigen may occur at the level of the responder cell. The differential effect seen between monoclonal antibodies directed against the alpha chain of Class I MHC framework determinants and antibodies reactive with the polymorphic determinants suggests functionally separate components of the Class I MHC molecules.