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Tonic and atonic seizures are typically seen in what are often referred to as the catastrophic epilepsies. In simply considering what each of the terms signifies (either the complete loss of tone or a marked increase in tone), they would appear to be at the most diverse ends of the spectrum. They would appear to be as opposite as hot and cold or hard and soft. And yet they are often found to occur in the same patient. This article examines the nature of these seizures and discusses some of the syndromes in which they are seen. Although these seizures are often very difficult to control, some of our medications/therapies have been shown to be effective. Recommendations concerning the efficacy of these therapies and a review of the newer therapies are provided. In addition, the ketogenic diet has been particularly successful in treating these seizures; this is discussed in some detail. Finally, although outcomes for these children are generally less than ideal, many can be helped with a persistent approach that balances seizure control against the side effects of medication.

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

Despite over 80 years of use, the ketogenic diet (KD) has never been tested in a blinded manner. Twenty children with intractable Lennox-Gastaut syndrome (LGS) were fasted 36 h and then randomized to receive the classic KD in conjunction with a solution containing either 60 g/day of glucose or saccharin. Parents and physicians were blinded to both the solution composition and level of ketosis. A crossover to the KD with the alternate solution occurred following the sixth day and a repeat fast. A 24-h electroencephalography (EEG) was obtained at baseline and after each arm. After administration of the solution, there was moderate evidence of a reduction in parent-reported seizures between the glucose and saccharin arms, with a median difference of 1.5 seizures per day (p = 0.07). There was no reduction in the number of EEG-identified events, with a median reduction of 7 events per day (p = 0.33). Ketosis was not completely eliminated in the glucose-added arm.

The ketogenic diet (KD) typically provides a marginally healthy diet and in recent years has been used for more protracted courses of therapy. This results in concern about the impact of the diet on the general health of the child. Studies have demonstrated poor growth, dyslipidemia, kidney stones, and numerous other problems seen less frequently. Major areas of concern are reviewed as well as some emerging evidence of more beneficial long-term health consequences beyond the expected control of seizures.

Purpose: To evaluate cortical auditory function, including speech recognition, in children with benign rolandic epilepsy (BRE)., Methods: Fourteen children, seven patients with BRE and seven matched controls, underwent audiometric and behavioral testing, simultaneous EEG recordings, and auditory-evoked potential recordings with speech and tones. Speech recognition was tested under multiple listening conditions., Results: All participants demonstrated normal speech recognition abilities in quiet, as well as normal peripheral and subcortical auditory function. BRE patients performed significantly worse than controls when speech recognition was tested under adverse listening conditions, including background noise. Five BRE patients who were impaired on two or more tests had centrotemporal spiking on awake EEG. There were no significant group differences in the latency or amplitude of early N100 cortical responses to speech or tones. Conversely, the mismatch negativity, a preattentive index of cortical processing that is elicited passively, was absent or prolonged for speech, but not tones, in BRE patients as compared to controls., Discussion: Children with BRE demonstrated specific speech recognition impairments. Our evoked potential findings indicate that these behavioral impairments reflect dysfunction of nonprimary auditory cortex and cannot be attributed solely to attention difficulties. A possible association between auditory impairments and centrotemporal spiking (>1/min) on awake EEG was identified. The pattern of speech recognition impairments observed is a known risk factor for academic difficulties in school-age children. Our results underscore the importance of comprehensive auditory testing, using behavioral and electrophysiological measures, in children with BRE.

Purpose: The ketogenic diet is not typically offered to adults with epilepsy due to the significant lifestyle alterations needed for its use. The modified Atkins diet has been recently demonstrated to be therapeutic for children without the need for an admission, fasting period, weighing of foods, or fluid, calorie, and protein restriction., Methods: A prospective, open-label study was performed of adults over 18 years of age, having at least weekly seizures and prior use of at least two anticonvulsants. Carbohydrates were initially restricted to 15 g/day, fats were encouraged, and fluids, protein, and calories were allowed ad lib., Results: Thirty patients, with age ranging from 18 to 53 years, were enrolled. Using an intent-to-treat analysis, 47% had a >50% seizure reduction after 1 and 3 months on the diet; 33% after 6 months. In those with seizure reduction, the median time to improvement was 2 weeks (range: 1-8 weeks). The mean weight loss was 6.8 kg, p < 0.001. Body-mass index (BMI) decrease correlated with efficacy at 3 months, p = 0.03. Ten subjects (30%) discontinued the diet prior to 3 months. Side effects included increased cholesterol (mean 187 to 201 mg/dL), blood urea nitrogen (BUN; 13 to 16 mg/dL), and urine calcium to creatinine ratio (0.14 to 0.19)., Conclusions: A modified Atkins diet appears to demonstrate preliminary efficacy for adults with intractable epilepsy, especially in those who lost weight. Considering the rapid response in those who improved, but somewhat high discontinuation rate, a 2-month trial period may be adequate to assess for efficacy.

The ketogenic diet remains a valuable therapeutic option for patients with intractable epilepsy. Clinical aspects of the diet's success may provide insights into epileptogenesis and anticonvulsant action. The diet's efficacy has been established primarily through large case series. The diet has been used successfully in patients with many different epilepsy syndromes in countries around the world. Potential adverse effects can be avoided with careful attention during the diet's initiation and maintenance phases. In the last decade, variations to the classical ketogenic diet have been utilized. Ketogenic diets now are being used for diseases other than epilepsy. This critical analysis of the diet should provide the impetus for further clinical and basic research into the diet's application and mechanisms of action.

Purpose: The Atkins diet may induce ketosis as does the ketogenic diet, without restrictions on calories, fluids, protein, or need for an inpatient fast and admission. Our objective was to evaluate the efficacy and tolerability of a modified Atkins diet for intractable childhood epilepsy., Methods: Twenty children were treated prospectively in a hospital-based ambulatory clinic from September 2003 to May 2005. Children aged 3-18 years, with at least three seizures per week, who had been treated with at least two anticonvulsants, were enrolled and received the diet over a 6-month period. Carbohydrates were initially limited to 10 g/day, and fats were encouraged. Parents measured urinary ketones semiweekly and recorded seizures daily. All children received vitamin and calcium supplementation., Results: In all children, at least moderate urinary ketosis developed within 4 days (mean, 1.9). Sixteen (80%) completed the 6-month study; 14 chose to remain on the diet afterward. At 6 months, 13 (65%) had >50% improvement, and seven (35%) had >90% improvement (four were seizure free). Mean seizure frequency after 6 months was 40 per week (p = 0.005). Over a 6-month period, mean serum blood urea nitrogen increased from 12 to 17 mg/dl (p = 0.01); creatinine was unchanged. Cholesterol increased from 192 to 221 mg/dl, (p = 0.06). Weight did not change significantly (34.0-33.7 kg); only six children lost weight. A stable body mass index over time correlated with >90% improvement (p = 0.004)., Conclusions: A modified Atkins diet is an effective and well-tolerated therapy for intractable pediatric epilepsy.

Purpose: To determine the long-term outcome of children with difficult-to-control seizures who remained on the ketogenic diet for <1 year., Methods: Between 1994 and 1996, 150 children with epilepsy, refractory to at least two medications, initiated the ketogenic diet according to the Hopkins protocol. Three to six years after diet initiation, all the families were contacted by telephone or questionnaire to assess their child's current seizure status, medications, and therapies., Results: Sixty-seven children discontinued the diet within 1 year of initiation. Follow-up data were available for 54 of these children. Ten subsequently had surgery, and three underwent VNS implantation. These operated-on children were significantly more likely to be >50% controlled at follow-up than were those managed with medications alone (p < 0.05). A statistically significant difference in long-term outcome was noted between those who responded while on the diet, even if they discontinued it before 1 year, and those who did not (p < 0.05), but no statistical correlation was found between length of time that they had remained on the diet and long-term prognosis., Conclusions: Almost half of the children who discontinued the diet during the first year had a decrease in seizures when assessed 3-6 years later. Twenty-two percent of these had become seizure free without surgery. We were unable to ascertain whether this may have been due to new medications. Those who saw some improvement while on the diet were more likely to have a favorable long-term outcome. Resective surgery, in children who were candidates, or vagal nerve stimulation (VNS) implantation, was more likely to result in significant seizure improvement than was management with medications alone. Whether or not the diet was effective, most families did not regret trying it and would recommend it to others.

Purpose: Although the ketogenic diet has been in use for >80 years, little agreement exists as to which patients are most likely to have dramatic, sudden, and complete seizure control., Methods: A case-control study was performed of children with intractable epilepsy started on the ketogenic diet at our institution since June 2001. Patients with a dramatic response were defined as those becoming seizure free within 2 weeks of diet onset. These children were compared with all other patients treated with the diet over the same time period in terms of patient demographics, epilepsy characteristics, and diet parameters., Results: Eighteen early, dramatic responders over a 3-year period were identified and compared with 89 patients who were not similarly improved. The absence of complex partial seizures as the predominant seizure type (0 vs. 23%; p = 0.02) correlated with this dramatic success. The presence of infantile spasms (39% vs. 20%; p = 0.09) approached significance, but all other variables did not., Conclusions: An early, dramatic response to the ketogenic diet is more likely in patients with predominant seizure types other than complex partial. It may also be more likely to occur in children who have infantile spasms. In all other patient demographics and diet parameters, an equal likelihood of similar success was found.

Purpose: Rasmussen syndrome (RS) is a rare form of epilepsy characterized by progressive destruction of a single hemisphere. To characterize the profile of cortical involvement in RS, we studied the pathological changes in the cerebral cortex of 45 hemispherectomies performed at Johns Hopkins Hospital between 1985 and 2002., Methods: The patterns of pathologic changes and stages of cortical abnormalities were studied by histology and immunocytochemistry methods. The burden of pathology (BP) was quantified in all brain regions of each of the 45 hemispheres., Results: Our study demonstrated significant heterogeneity in the stages of cortical pathology and the multifocal nature of the disease. These stages varied from early inflammation defined by infiltration of T lymphocytes and neuroglial reactions, to more severe stages with extensive neuronal cell death and cavitation of the cerebral cortex. A greater BP was significantly associated with an early age at onset (p = 0.01) and longer duration of disease (p < or = 0.001). The BP was similar in all brain regions except the occipital lobe, where the BP was significantly lower (p = 0.032)., Conclusions: The multifocal distribution of pathologic changes, as well as the heterogeneity in the stages of cortical damage in each patient, is consistent with an ongoing and progressive immune-mediated process of neuronal damage that involves neuroglial and lymphocytic responses, resembling other autoimmune CNS disorders such as multiple sclerosis.

Purpose: Long-term neuropsychological outcome was studied in 71 patients who underwent hemispherectomy for severe and intractable seizures at The Johns Hopkins Hospital between 1968 and 1997 and who agreed to participate. Seizures were due to cortical dysplasias (n = 27), Rasmussen syndrome (n = 37), or vascular malformations or strokes (n = 7). Both presurgical and follow-up results are available and reported for 53 patients., Methods: Patients and caretakers were interviewed, and patients were administered standard measures of intelligence, receptive and expressive language, visual-motor skills, adaptive/developmental functioning, and behavior., Results: Mean age at surgery was 7.2 years. At follow-up, on average 5.4 years after surgery, 65% are seizure free, 49% are medication free, and, of those responding, none rated quality of life as worse than before surgery. Mean IQ was in the 70s for Rasmussen and vascular patients and in the 30s for cortical dysplasia patients. Language and visual-motor skills were consistent with IQ. For Rasmussen patients only, language was significantly more impaired for left than for right hemispherectomy, both before surgery and at follow-up. Adaptive skills were mildly impaired, with greatest impairment in the physical domain. Cognitive measures typically changed little between surgery and follow-up, with IQ change <15 points for 34 of 53 patients; of the remainder, 11 declined and eight improved. Behavior was free of major problems, but social interactions and activities were limited., Conclusions: The most significant predictor of cognitive skills at follow-up was etiology, with dysplasia patients scoring lowest in intelligence and language but not in visual-motor skills. Regardless of etiology, most patients showed only moderate change in cognitive performance at follow-up.

Purpose: Because carbonic anhydrase inhibitors and the ketogenic diet are each known risk factors for kidney stones, simultaneous use of these therapies has been discouraged. The objective of this study was to establish the prevalence of nephrolithiasis in children in this combination-therapy population., Methods: Since 1996, 301 children have been started on the ketogenic diet at our institution. A retrospective cohort study of renal calculi in ketogenic diet patients was performed to evaluate the increased risk with combined use of a carbonic anhydrase inhibitor., Results: In 15 (6.7%) of 221 children on the ketogenic diet without the use of carbonic anhydrase inhibitors, stones developed. In five (6.3%) of the 80 children on the diet in combination with topiramate or zonisamide, stones developed. There was no difference between these two groups (p = 0.82). No child was treated with either acetazolamide or more than one carbonic anhydrase inhibitor simultaneously. Prior ketogenic diet duration was shorter (10.4 vs. 22.4 months; p = 0.03), and more children had either a family history of renal stones or significant urologic abnormalities (80 vs. 27%; p = 0.04) in the combination-therapy group., Conclusions: The combined use of carbonic anhydrase inhibitors and the ketogenic diet does not increase the risk of kidney stones. We recommend that all patients treated with combination therapy should be treated with increased hydration. Urine alkalinization should be considered for children with previous renal abnormalities, family histories of kidney stones, hematuria, or elevated urine calcium-to-creatinine ratios. If renal stones are found, we advocate discontinuation of the carbonic anhydrase inhibitor.

Purpose: Levetiracetam is a new anticonvulsant (AED) with a novel mechanism of action. Although it is generally well tolerated with a good cognitive profile, irritability and hostility have been reported in some adults taking levetiracetam. Observations in children are limited; levetiracetam is not yet approved by the Food and Drug Administration for use in children., Methods: In four young patients, acute psychosis developed within days to months of initiation of levetiracetam for seizures., Results: A 5-year-old girl began having visual hallucinations of spiders in her room 14 days after starting levetiracetam. A 13-year-old boy began having auditory hallucinations, insomnia, and screaming behavior 3 months after initiation of levetiracetam. A 16-year-old girl became acutely agitated, hyperreligious, and had persecutory delusions within 7 days of starting levetiracetam. A 17-year-old girl had auditory hallucinations telling her to sing and yell after 30 days of taking the drug. All four children had dramatic improvement within days of either discontinuing or decreasing the dose of levetiracetam. The three adolescents had historical findings consistent with mild behavioral problems before initiating levetiracetam, and all four patients had prior cognitive deficits., Conclusions: Reversible treatment-emergent psychosis associated with levetiracetam therapy was observed in four children and adolescents. Whether rapid initiation or prior neurobehavioral problems predispose to this side effect is not established.

A diffuse electrodecremental ictal pattern (DEP) has been associated with tonic seizures and, less often, with other forms of epilepsy and has been considered to reflect a generalized seizure disorder of diffuse cortical or subcortical (brainstem) origin. In some seizures associated with DEP, however, focal ictal manifestations have been observed. We reviewed the records of all patients admitted to our seizure monitoring unit for 3 years and detected 39 patients with seizures associated with DEP. In 23 of 39 patients, clinical ictal behaviors resembled seizures of unilateral supero/mesiofrontal lobe origin and interictal EEG showed a prominent unilateral frontal component. Nine of 39 had complex absences (CA)/complex partial seizures (CPS); 4 of them were of unilateral frontal lobe origin. Seven of 39 patients had tonic or atonic seizures. Seven patients were studied further with subdural electrodes. Ictal onsets showed a high-frequency frontal lobe discharge. We conclude that in a subgroup of patients a generalized electrodecremental pattern on scalp EEG results from a regional cortical high-frequency ictal discharge originating in a single frontal lobe.

Twelve children with Rasmussen's encephalitis underwent hemispherectomy and have been followed for an average of 9.15 years. Our decision-making process leads to early, rather than late operation. Because hemiplegia is inevitable with or without operation, earlier operation may allow such children to resume a more normal life. We postulate that earlier operation may prevent some of the intellectual decline that accompanies the continued seizures and their treatment. In view of the variable pathologic findings and lack of evidence of a viral etiology, we suggest either use of the term "progressive unilateral encephalopathy of childhood" or "Rasmussen's syndrome" in recognition of its heritage.

The ketogenic diet was developed in the 1920s as a treatment for intractable childhood seizures when few antiepileptic drugs (AEDs) were available. There are still children whose seizures are refractory even to modern therapy, but use of the ketogenic diet appears to be waning. At Johns Hopkins, we continue to believe that the diet is very effective and well accepted by patients and families. To reevaluate our opinion of the efficacy and acceptability of this form of therapy in patients cared for in the 1980s with the newer AEDs, we analyzed the records of 58 consecutive patients who had been started on the diet. Before using the diet, 80% of the patients had multiple seizure types and 88% were treated with multiple AEDs; these children were among our most intractable patients. Despite this, seizure control improved in 67% of patients with the ketogenic diet, and actuarial analysis indicated that 75% of these improved patients continued the diet for at least 18 months. Sixty-four percent had AEDs reduced, 36% became more alert, and 23% had improved behavior. The improvement in these patients with intractable seizures and the length of time that families maintained the regimen indicate that the ketogenic diet continues to have a very useful therapeutic role in selected patients and their families.

Psychosocial problems in adolescents with epilepsy have been of concern for many years, but have been difficult to assess. This article presents the multicenter development of the Adolescent Psychosocial Seizure Inventory (APSI), an empirically based self-report test patterned after the Washington Psychosocial Seizure Inventory, which is used to evaluate psychosocial problems in adults. After pilot work, 120 adolescents with epilepsy from five centers in North America took the APSI and were interviewed by professionals with respect to adequacy of adjustment in eight psychosocial areas. At least one parent or guardian was also interviewed. Interrater reliability of professional ratings in each area was established. Using an item-by-item, empirically based technique, eight psychosocial scales were developed as well as three validity scales. Reliability of the scales was established by both internal consistency and test-retest procedures. Results for each adolescent are presented in profile form. These results give a visual display of the types and extent of problems that likely would be identified in a detailed professional assessment. It is anticipated that the APSI will be of value in a variety of treatment and research contexts.

Age-specific epilepsy syndromes raise important questions about developmental susceptibility to seizures and epileptogenesis and about the effect of seizures on function. The diagnosis and treatment of these syndromes has been enhanced by the use of modern science and technology. Epidemiologic studies have changed our approach to febrile convulsions. This developmental seizure disorder is benign and self-limited. We have been forced to think carefully about threshold, therapy, and whether other seizures in childhood may be equally benign. This framework of developmental specificity can also be applied to West syndrome, especially with respect to neurophysiology, neurochemistry, neuroimaging, and epidemiology--the types of seizures, clustering, variations associated with sleep, PET scans, and therapy. Rasmussen's syndrome and other unilateral developmental epilepsies are progressive but remain confined to a single hemisphere. However, they usually are devastating to global neurologic function. They are models for examining the impact of epilepsy in one pathologic hemisphere on the function of the entire brain. Current therapy for this condition is hemispherectomy. Recovery of function after this major surgery is striking and provides clues to brain organization. The analysis of these three syndromes provides windows on the dynamic, changing central nervous system of the child and may lead to better understanding and therapy for other seizure disorders.

Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.