Absence in childhood absence epilepsy: the horse is out of the barn.

Clinicians typically breathe a sigh of relief when they make the diagnosis of childhood absence epilepsy. The history is classic-a normal young child with myriad brief periods of staring. The clinic visit is powerful when the phenomena are replicated by having the child hyperventilate. Finally, the EEG is definitive. The ability to demonstrate to a family the abrupt eruption and cessation of spike-wave activity provides a framework for them to understand what is happening to their child. Parents are usually reassured that there are very good therapies, that seizures are typically controlled, and that their child will "outgrow" it. However, data from the multicenter Childhood Absence Epilepsy Study Group are rewriting this narrative.(1-3.)

Inter-rater agreement for diagnoses of epilepsy in pregnant women.

We report on inter-rater agreement in assessing the types of seizures exhibited by one hundred mothers ascertained in a study of the teratogenicity of maternal epilepsy and antiepileptic drugs. A summary of each woman's medical record and a one-page report of her responses to questions about her epilepsy were reviewed independently by six neurologists, three in pediatric neurology and three in adult neurology. Agreement was measured by the kappa statistic and log-linear modeling techniques. The adult neurologists agreed with each other 59% of the time, with the agreement higher when all three used information from the patients' records, such as an EEG, rather than when depending on the patients' responses to questions about their epilepsy. The pediatric neurologists agreed with each other 44% of the time and tended to rely more heavily on information in the patients' records, such as an EEG or a prior diagnosis, compared with the adult neurologists.

Novel proton MR spectroscopy findings in adenylosuccinate lyase deficiency.

Adenylosuccinate lyase (ADSL) deficiency is a rare inborn error of metabolism resulting in accumulation of metabolites including succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado) in the brain and other tissues. Patients with ADSL have progressive psychomotor retardation, neonatal seizures, global developmental delay, hypotonia, and autistic features, although variable clinical manifestations may make the initial diagnosis challenging. Two cases of the severe form of the disease are reported here: an 18-month-old boy with global developmental delay, intractable neonatal seizures, progressive cerebral atrophy, and marked hypomyelination, and a 3-month-old girl presenting with microcephaly, neonatal seizures, and marked psychomotor retardation. In both patients in vivo proton magnetic resonance spectroscopy (MRS) showed the presence of S-Ado signal at 8.3 ppm, consistent with a prior report. Interestingly, SAICAr signal was also detectable at 7.5 ppm in affected white matter, which has not been reported in vivo before. A novel splice-site mutation, c.IVS12 + 1/G > C, in the ADSL gene was identified in the second patient. Our findings confirm the utility of in vivo proton MRS in suggesting a specific diagnosis of ADSL deficiency, and also demonstrate an additional in vivo resonance (7.5 ppm) of SAICAr in the cases of severe disease.

Cognitive and EEG fluctuation in benign childhood epilepsy with central-temporal spikes: a case series.

Aware of parental reports of academic variability, we investigated month-to-month fluctuations in cognitive abilities and EEG status by repeated measures testing in six children with benign epilepsy with central-temporal spikes (BECTS). All showed greater than normal test-retest variability. Daytime EEG abnormalities were also variable. Short-term fluctuations in cognitive function appear common in children with BECTS, potentially impacting academic performance.

Sensorimotor function and sensorimotor tracts after hemispherectomy.

Hemispherectomy is currently the only effective treatment for relieving constant seizures in children with severe or progressive unilateral cortical disease. Although early hemispherectomy has been advocated to avoid general dysfunction due to continued seizures, it remains unclear whether age at surgery affects specific sensorimotor functions. Little is know about the anatomical status of sensorimotor pathways after hemispherectomy and how it might relate to sensorimotor function. Here we measured motor function and sensory thresholds of the upper and lower limbs in 12 hemispherectomized patients. Diffusion tensor imaging (DTI) was used to determine status of brainstem corticospinal tracts and medial lemniscus. Hemispherectomy subjects showed remarkable recovery in both sensory and motor function. Many patients showed normal sensory vibration thresholds. Within the smaller Rasmussen's subgroup, we saw a relationship between age at surgery and sensorimotor function recovery (i.e. earlier was better). Anatomically, we found marked asymmetry in brainstem corticospinal tracts but preserved symmetry in the medial lemniscus, which may relate to robust sensory recovery. Age at surgery predicted anatomical status of brainstem sensorimotor tracts. In sum, we found that age at surgery influences anatomical changes in brainstem motor pathways, and may also relate to sensorimotor recovery patterns.

Tonic and atonic seizures: medical therapy and ketogenic diet.

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.

High-dose oral prednisolone for infantile spasms: an effective and less expensive alternative to ACTH.

The ideal treatment of infantile spasms is unclear, but many studies advocate hormonal treatment. In the United States, intramuscular ACTH is most widely used, despite the problematic financial cost and side effect profile. Since September 2007, we have replaced ACTH with high-dose oral prednisolone (40-60 mg/day) according to the 2004 United Kingdom Infantile Spasms Study (UKISS). Ten of 15 (67%) infants with new-onset and previously treated infantile spasms became spasm free within 2 weeks; 4 later recurred. More children with an idiopathic etiology for infantile spasms were spasm free than were symptomatic cases (88% vs 43%, P=0.10). Spasm freedom was equivalent to our most recent 15 infants receiving ACTH, with 13 (87%) responding, P=0.16. Oral prednisolone had fewer adverse effects (53% vs 80%, P=0.10) and was less expensive ($200 vs approximately $70,000) than ACTH. We now routinely recommend oral prednisolone to all families of children with infantile spasms.

Walking flexibility after hemispherectomy: split-belt treadmill adaptation and feedback control.

Walking flexibility depends on use of feedback or reactive control to respond to unexpected changes in the environment, and the ability to adapt feedforward or predictive control for sustained alterations. Recent work has demonstrated that cerebellar damage impairs feedforward adaptation, but not feedback control, during human split-belt treadmill walking. In contrast, focal cerebral damage from stroke did not impair either process. This led to the suggestion that cerebellar interactions with the brainstem are more important than those with cerebral structures for feedforward adaptation. Does complete removal of a cerebral hemisphere affect either of these processes? We studied split-belt walking in 10 children and adolescents (age 6-18 years) with hemispherectomy (i.e. surgical removal of one entire cerebral hemisphere) and 10 age- and sex-matched control subjects. Hemispherectomy did not impair reactive feedback control, though feedforward adaptation was impaired in some subjects. Specifically, some showed reduced or absent adaptation of inter-leg timing, whereas adaptation of spatial control was intact. These results suggest that the cerebrum is involved in adaptation of the timing, but not spatial, elements of limb movements.

Hemispherectomy sustained before adulthood does not cause persistent hemispatial neglect.

INTRODUCTION: Hemispatial neglect has been well established in adults following acute ischemic stroke, but has rarely been investigated in children and young adults following brain injury. It is known that young brains have a tremendous potential for reorganization; however, there is controversy as to whether functions are assumed by the opposite hemisphere, or perilesional areas in the same hemisphere. Patients with intractable epilepsy who undergo hemispherectomy for treatment are missing the entire cortex on one side following surgery. In these patients, only the opposite hemisphere is available to assume function. Therefore, they provide the unique opportunity to determine in what cases the left or right hemisphere can take over the spatial attention functions of the opposite hemisphere following damage. The objective of this study was to determine the incidence and types of hemispatial neglect in children and young adults following both right- and left-sided hemispherectomy; which types of spatial attention functions can be assumed by the opposite hemisphere; and whether factors like their age at time of surgery, handedness, or gender influence recovery. METHODS: Thirty-two children and young adults who had previously undergone hemispherectomy were administered two tests to evaluate for two types of hemispatial neglect: a gap detection test and a line cancellation test. Egocentric neglect was defined as significantly more omissions of targets on the contralesional versus ipsilesional side of the page (by chi square analysis; p<.05). Allocentric neglect was defined as significantly more errors in detecting contralesional versus ipsilesional gaps in circles. RESULTS: Only one of the patients displayed statistically significant hemispatial egocentric neglect on the line cancellation test, and none of the patients displayed statistically significant egocentric or allocentric neglect on the gap detection test. CONCLUSIONS: These results imply that reorganization to the contralateral hemisphere occurs peri-hemispherectomy, as there are no perilesional areas to assume function.

Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group.

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.

A blinded, crossover study of the efficacy of the ketogenic diet.

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.

Long-term health consequences of epilepsy diet treatments.

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.

Cortical auditory dysfunction in benign rolandic epilepsy.

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.

A prospective study of the modified Atkins diet for intractable epilepsy in adults.

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.

Kidney stones and the ketogenic diet: risk factors and prevention.

A cohort study was performed of children started on the ketogenic diet for intractable epilepsy from 2000 to 2005 (n = 195). Children who developed kidney stones were compared with those without in terms of demographics, urine laboratory markers, and intervention with urine alkalinization (potassium citrate). Thirteen children (6.7%) developed kidney stones. The use of oral potassium citrate significantly decreased the prevalence of stones (3.2% vs 10.0%, P = .049) and increased the mean time on the ketogenic diet before a stone was first noted (260 vs 149 patient-months, P = .29). The prevalence of kidney stones did not correlate with younger age or use of carbonic anhydrate inhibitors (eg, topiramate or zonisamide) but trended toward higher correlation with the presence of hypercalciuria (92% vs 71%, P = .08). No child stopped the diet due to stones; in fact, the total diet duration was longer (median 26 vs 12 months, P < .001). Kidney stones continue to occur in approximately 1 in 20 children on the ketogenic diet, and no statistically significant risk factors were identified in this cohort. As oral potassium citrate was preventative, prospective studies using this medication empirically are warranted.