Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome.

BACKGROUND: Surgical removal of one hemisphere has been performed for several decades to treat intractable unihemispheric epilepsy. A prior case series focused on the outcomes after 58 surgeries at Johns Hopkins Hospital in 1997. This series, and an additional 53 cases, were reviewed to bring the outcomes up to date. METHODS: Charts of the 111 patients undergoing hemidecortications at the Pediatric Epilepsy Center from 1975 to 2001 were reviewed and families were contacted. Three children died in the immediate perioperative period and three were lost to follow-up immediately after surgery. Follow-up ranged from 3 months to 22 years. RESULTS: Two children died several years later due to intractable seizures. Overall, 65% are seizure-free, 21% have occasional, non-handicapping seizures, and 14% have troublesome seizures. Eighty percent are on one anticonvulsant or none and 89% are able to walk without assistance. Etiology strongly predicted seizure outcome. Patients with migrational disorders are less likely to be seizure-free than all other etiologies (predominantly Rasmussen and congenital vascular injuries) combined (51% vs 71%, p = 0.05). CONCLUSIONS: Hemidecortication continues to be a beneficial procedure in reducing seizure frequency in cases of unilateral cortical epilepsy. Fewer children with migrational disorders are seizure-free.

The postoperative course and management of 106 hemidecortications.

RATIONALE: The excellent long-term outcome for most children undergoing hemispherectomy is well documented. However, the condition of these children in the immediate postoperative period is poorly described. The purpose of this study was to evaluate the short-term issues surrounding hemispherectomy and their management in a series of patients from our institution. METHODS: 106 hemispherectomies were performed at our institution from 1975 to 2001 (102 hemidecortications). Medical records were retrospectively examined for information regarding immediate postoperative problems and care. RESULTS: Three children died in the immediate perioperative period, while 3 others had significant postoperative morbidity. 82% of these children had postoperative fevers (temperature >38.5 degrees C). Of these children, 62% had lumbar punctures. Ten cases had positive CSF growth, of which 6 cases were felt to have actual meningitis. Patients with CSF growth had a significantly longer prior duration of steroid therapy and higher maximum temperature peaks. CSF pleocytosis and an ill clinical appearance neared significance for prediction of CSF growth. Shunting was performed in 19% of all children and was associated with CSF growth. CONCLUSIONS: Postoperative fevers are common after hemidecortication, but meningitis is not. Children with CSF growth tended to appear more ill and have higher temperature spikes and CSF pleocytosis. Shunting was related to CSF growth.

Effects of ketogenic diet on development and behavior: preliminary report of a prospective study.

The ketogenic diet is increasingly used for the management of difficult-to-control seizures in children. Here, we describe the first prospective study of the effects of the diet on development, behavior, and parenting stress. Participants were 65 children (36 males, 29 females) with intractable seizures, ages 18 months to 14 years 6 months, enrolled in a prospective study at the Johns Hopkins Hospital, Baltimore, MD, USA, to study the diet's efficacy. Children were assessed before diet initiation and at 1-year follow-up. At follow-up, 52% (34 of 65) children remained on the diet. Mean seizure frequency decreased from 25 per day before diet initiation to less than two per day 1 year later. At follow-up, mean developmental quotient showed statistically significant improvement (p<0.05), with significant behavioral improvements in attention and social functioning. Parental stress was essentially unchanged. No baseline factor examined predicted diet adherence, and the primary reason for diet discontinuation was insufficient seizure control. These preliminary results support prior anecdotal reports of the beneficial effects of the diet on cognition and behavior.

Levetiracetam psychosis in children with epilepsy.

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.

Risk factors for urolithiasis in children on the ketogenic diet.

Kidney stones have been associated with use of the ketogenic diet in children with refractory seizure disorders. We performed a case-control study examining risk factors for the development of stones on the ketogenic diet, and prospectively followed children initiating the ketogenic diet to evaluate the incidence of urolithiasis. Clinical characteristics of 18 children presenting with stones (8 uric acid stones, 6 mixed calcium/uric acid stones, 1 calcium oxalate/phosphate stone, 3 stones not evaluated) were compared with characteristics of non-stone-forming children initiating the ketogenic diet at Johns Hopkins since July 1996. Since July 1996, 112 children initiating the ketogenic diet have been followed for development of stones. Follow-up times on the diet range from 2 months to 2.5 years. Of 112 children, 6 have developed stones (3 uric acid, 3 mixed calcium/uric acid stones) (0.8 children developing stones/ 100 patient-months at risk). Comparisons of children presenting with stones on the ketogenic diet with characteristics of the entire cohort initiating the ketogenic diet suggest younger age at diet initiation and hypercalciuria are risk factors for the development of stones. Prospective evaluation of children initiating the ketogenic diet revealed that almost 40% of patients had elevated fasting urine calcium: creatinine ratios at baseline; this increased to 75% after 6 months on the diet. Median urine pH was 5.5 at diet initiation, and remained at 6.0 thereafter. In a subset of patients tested, urinary citrate excretion fell from a mean of 252 mg/24 h pre diet initiation to 52 mg/24 h while on the diet. Uric acid excretion remained normal. Patients maintained on the ketogenic diet often have evidence of hypercalciuria, acid urine, and low urinary citrate excretion. In conjunction with low fluid intake, these patients are at high risk for both uric acid and calcium stone formation.

Clinical efficacy of the ketogenic diet.

The ketogenic diet is an effective alternative therapy used to control intractable seizures. It was originally described in 1921 as a way to duplicate and prolong the beneficial effects that fasting appeared to have on seizure control. It involves consuming a calorie-restricted diet in which the fat:carbohydrate + protein ratio ranges from 2:1 to 5:1. Recent prospective studies in children demonstrate that about 50% of children will continue on the diet for at least a year, with 40-50% of those starting the diet having a >50% reduction in seizures after 12 months. When the diet is discontinued it is usually due to lack of efficacy. The diet is a radical medical therapy and nutritional well-being is a constant concern. Renal stones have occurred in 5-8% of children on the diet; lipids are elevated, but the significance of this is not known. The mechanism of action of the diet remains unknown, and it is difficult to assess which biochemical parameters should be monitored as adjustments are made to the diet.

Medication cost reduction in children on the ketogenic diet: data from a prospective study.

In a prospective study of the efficacy of the ketogenic diet in children with severe, refractory epilepsy, data were collected on medication changes over 1 year. Cost reductions in medications were calculated over the first year and estimated for a second year. Fifty-seven percent of the children stayed on the diet for 1 year, and 74% of these children had their number of medications reduced. Forty-eight percent of children who stayed on the diet were on no medications at 12 months follow-up. Daily medication costs were reduced by nearly 70%.

Seizures decrease rapidly after fasting: preliminary studies of the ketogenic diet.

OBJECTIVES: To evaluate the change in atonic or myoclonic seizures associated with the Lénnox-Gastaut syndrome during the initiation of the ketogenic diet, and to describe the development of a blinded crossover study of the efficacy of the ketogenic diet. DESIGN: A before-after trial. SETTING: The Johns Hopkins Hospital, Baltimore, Md. PATIENTS: Change in clinical seizure frequency was examined in 17 consecutively treated patients with atonic or myoclonic seizures. In a few patients, a 24-hour ambulatory electroencephalogram was obtained before and after diet initiation. We demonstrated the ability to manipulate the ketosis induced by fasting with the addition of glucose (dextrose) in 1 patient. INTERVENTIONS: Children fasted for 36 hours, and the diet was gradually introduced over 3 days. Parents were instructed to keep a baseline seizure frequency calendar for the month before the initiation of the diet. These calendars continued to be maintained as the diet was initiated. MAIN OUTCOME MEASURE: Seizure decrease from baseline. RESULTS: The atonic or myoclonic seizures decreased in these children by more than 50% immediately. Using a 24-hour ambulatory electroencephalogram, we documented that the seizures reported by a parent represent only a fraction of the electroclinical events; the technique could be used to measure the profound decrease in electrically documented seizures. Ketosis was eliminated with glucose, 60 g/d. CONCLUSIONS: It is feasible to evaluate the ketogenic diet's efficacy in atonic or myoclonic seizures in a blinded, crossover study. The diet can be manipulated on a short-term basis in a blinded manner, and ketosis can be achieved or eliminated.

The implementation and maintenance of the Ketogenic Diet in children.

The Ketogenic Diet is an effective treatment for epilepsy in children. At Johns Hopkins Hospital more than 400 children have been placed on the Ketogenic Diet. The implementation and maintenance of this treatment require significant collaboration between the family and Epilepsy Team. During initiation of the diet, in the hospital, parents attend classes on the history and mechanism of the diet, preparation of meals, psychological issues, complications and the management of childhood illnesses on the ketogenic diet. Many factors are considered in calculating a ketogenic formula. Age, weight, height and activity level are the obvious factors. However, secondary medical diagnoses, medications, neurological deficits, feeding issues and psychological issues are additional factors that affect the formulation of an optimal ketogenic prescription. Once this prescription has been formulated and implemented, many patients require fine-tuning of their ketogenic diets to get the best antiepileptic results while promoting growth. We believe that our success in sustaining this treatment is related to our fine-tuning and management practices.

The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children.

OBJECTIVE: The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet developed in the 1920s for the treatment of children with difficult to control seizures. Despite advances in both the pharmacotherapy and the surgery of epilepsy, many children continue to have difficult-to-control seizures. This prospective study sought to determine the ketogenic diet's effectiveness and tolerability in children refractory to today's medications. METHODS: One hundred fifty consecutive children, ages 1 to 16 years, virtually all of whom continued to have more than two seizures per week despite adequate therapy with at least two anticonvulsant medications, were prospectively enrolled in this study, treated with the ketogenic diet, and followed for a minimum of 1 year. Seizure frequency was tabulated from patients' daily seizure calendars and seizure reduction calculated as percentage of baseline frequency. Adverse events and reasons for diet discontinuation were recorded. RESULTS: The children (mean age, 5.3 years), averaged 410 seizures per month before the diet, despite an exposure to a mean of 6.2 antiepileptic medications. Three months after diet initiation, 83% of those starting remained on the diet and 34% had >90% decrease in seizures. At 6 months, 71% still remained on the diet and 32% had a >90% decrease in seizures. At 1 year, 55% remained on the diet and 27% had a >90% decrease in seizure frequency. Most of those discontinuing the diet did so because it was either insufficiently effective or too restrictive. Seven percent stopped because of intercurrent illness. CONCLUSIONS: The ketogenic diet should be considered as alternative therapy for children with difficult-to-control seizures. It is more effective than many of the new anticonvulsant medications and is well tolerated by children and families when it is effective.

A multicenter study of the efficacy of the ketogenic diet.

OBJECTIVE: To determine the efficacy of the ketogenic diet in multiple centers. DESIGN: A prospective study of the change in frequency of seizures in 51 children with intractable seizures who were treated with the ketogenic diet. SETTING: Patients were enrolled from the clinical practices of 7 sites. The diet was initiated in-hospital and the patients were followed up for at least 6 months. PATIENTS: Fifty-one children, aged 1 to 8 years, with more than 10 seizures per week, whose electroencephalogram showed generalized epileptiform abnormalities or multifocal spikes, and who had failed results when taking at least 2 appropriate anti-epileptic drugs. INTERVENTION: The children were hospitalized, fasted, and a 4:1 ketogenic diet was initiated and maintained. MAIN OUTCOME MEASURES: Frequency of seizures was documented from parental calendars and efficacy was compared with prediet baseline after 3, 6, and 12 months. The children were categorized as free of seizures, greater than 90% reduction, 50% to 90% reduction, or lower than 50% reduction in frequency of seizures. RESULTS: Eighty-eight percent of all children initiating the diet remained on it at 3 months, 69% remained on it at 6 months, and 47% remained on it at 1 year. Three months after initiating the diet, frequency of seizures was decreased to greater than 50% in 54%. At 6 months, 28 (55%) of the 51 initiating the diet had at least a 50% decrease from baseline, and at 1 year, 40% of those starting the diet had a greater than 50% decrease in seizures. Five patients (10%) were free of seizures at 1 year. Age, sex, principal seizure type, and electroencephalogram were not statistically related to outcome. CONCLUSION: The ketogenic diet is effective in substantially decreasing difficult-to-control seizures and can successfully be administered in a wide variety of settings.

Why would you remove half a brain? The outcome of 58 children after hemispherectomy-the Johns Hopkins experience: 1968 to 1996.

PURPOSE: To report the outcomes of the 58 hemispherectomies performed at Johns Hopkins between 1968 and January 1996. METHODS: Charts were reviewed of the 58 hemispherectomies performed at Johns Hopkins Medical Institutions by the Pediatric Epilepsy Group during the years 1968 to 1996. Twenty-seven operations were done for Rasmussen's syndrome, 24 operations for cortical dysplasias/hemimegalencephalies, and 7 for Sturge-Weber syndrome or other congenital vascular problems. Seizure control alone did not seem to adequately describe the outcomes of the procedure. Therefore, a score was constructed that included seizure frequency, motor disability, and intellectual handicap. This burden of illness score better described the child's handicap before and after surgery. RESULTS: Perioperative death occurred in 4 out of 58 children. Of the 54 surviving children, 54% (29/54) are seizure-free, 24% (13/54) have nonhandicapping seizures, and 23% (12/54) have residual seizures that interfere to some extent with function. Reduction in seizures was related to the etiology of the unilateral epilepsy. Eighty-nine percent of children with Rasmussen's, 67% of those with dysplasias, and 67% of the vascular group are seizure-free, or have occasional, nonhandicapping seizures. All operations were considered by the parents and the physicians to have been successful in decreasing the burden of illness. In 44 the procedure was very successful, in 7 it was moderately successful, and in 3 it was minimally successful. Success was related to the etiology, and early surgery was preferable. CONCLUSION: Hemispherectomy can be a valuable procedure for relieving the burden of seizures, the burden of medication, and the general dysfunction in children with severe or progressive unilateral cortical disease. Early hemispherectomy, although increasing the hemiparesis in children with Rasmussen's syndrome, relieves the burden of constant seizures and allows the child to return to a more normal life. In children with dysplasias, early surgery can allow the resumption of more normal development.

The ketogenic diet: 1997.

There has been a dramatic resurgence of interest in the ketogenic diet during the past several years. For many children with difficult-to-control epilepsy, the diet presents an alternative approach to trying multiple medications. The ketogenic diet's current success rate, when properly executed, greatly exceeds that of the medications which have recently become available. Its side effects, both cognitive and allergic, appear fewer than most available medications. The ketogenic diet is also cheaper than most new anticonvulsants. Even though we now know that the diet works, we still do not know how it works. Nor do we know how most anticonvulsants work. The mechanism of action of the ketogenic diet appears to rely on a fundamental change in the brain's metabolism from that of a glucose-based energy substrate to a ketone-based substrate. This change is, in some fashion, critical to the maintenance of seizure threshold. Why should the source of the energy make a difference in seizure threshold? The change in seizure threshold appears to occur without affecting the brain's ability to carry out its normal complex functions. Could the brain's utilization of an energy substrate for seizure control be different from its utilization of energy for normal brain function? If so it should it be possible to study the metabolic differences between the two and develop a biochemistry of epilepsy, which is differentiated from the biochemistry of normal cognition and function. The ketogenic diet is successful in controlling or ameliorating a broad spectrum of seizure types and etiologies. Perhaps then, common metabolic pathways, independent of seizure type, are used in the initiation and spread of electrical seizures. Based on clinical experience and limited research data, it would appear that different seizures and different epilepsies must have metabolic pathways in common that make them susceptible to treatment with a common metabolic therapy. If we could understand how the ketogenic diet "works," how changing from a glucose substrate' to a ketone body substrate is anticonvulsant, then perhaps a medication could be developed that would simulate the biochemical effects of the ketogenic diet. Such an approach would be a major departure in the study of the neuroscience of epilepsy. The ketogenic diet offers a new paradigm to think about epilepsy and its treatment, and perhaps will stimulate new approaches to this still often devastating condition.

Hemispherectomy: a hemidecortication approach and review of 52 cases.

Between 1975 and 1994, 52 hemispherectomies, of which two were anatomical and 50 hemidecortications, were performed at Johns Hopkins Medical Institutions. Eighteen patients were 2 years old or less. There were three perioperative mortalities and one patient died 9 months later from causes not related to surgery. One patient developed hydrocephalus 6 years postsurgery and has been treated effectively. Seizure control and the functional status of each patient were measured as outcome variables. Forty-six (96%) of the surviving patients were seizure free or had reduced seizures as of their last follow-up examination. Twenty-one individuals (44%) were participating in age-appropriate classes or working independently, 18 were classified as semiindependent, and nine children will likely depend on a lifetime of assisted living. The relationships between the outcome variables and the patient's age at surgery, the interval to surgery, and the etiology of the disease were compared. The authors' clinical experiences strongly suggest the importance of a multidisciplinary approach to patient selection and follow-up care. Moreover, anesthetic management of infant surgery is a major component of success.

Speech-language outcomes of hemispherectomy in children and young adults.

Children and young adults who had undergone right or left hemispherectomy for intractable seizures after a period of normal language acquisition were compared with respect to scores on speech and language tests. The majority of the subjects had full scale IQs in the borderline to mentally retarded range. Language scores were computed in relation to estimated mental age, not chronological age. On this basis, the left hemispherectomized children were more likely to show syntactic comprehension and rapid-rate auditory processing deficits than the right hemispherectomized. The two groups were similar to one another and to normal children in speech production. The findings are discussed in relation to developmental language disorders.