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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The neuropharmacology of the ketogenic diet.

The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease.

Experience in the use of the ketogenic diet as early therapy.

The ketogenic diet has traditionally been considered an anticonvulsant therapy of last resort, despite excellent efficacy and limited side effects. We hypothesized that the ketogenic diet would have similar results in patients with new-onset epilepsy. A retrospective study was conducted of patients started on the ketogenic diet since 1994. Thirteen of 460 (2.8%) patients were started on the ketogenic diet as early (zero or one prior anticonvulsant) therapy for seizures. Of those remaining on the diet, 60% (6 of 10) had a > 90% seizure reduction at 6 months and 100% (6 of 6) had a > 90% reduction at 12 months. Patients with infantile spasms were as likely to achieve > 50% seizure reduction at 6 months as patients with other seizure types (75% vs 60%; P = .6). The ketogenic diet can be a valuable therapy before epilepsy becomes intractable. In the 13 patients reported, efficacy without side effects was achieved similarly to that with patients with intractable epilepsy.

Auditory processing studied prospectively in two hemidecorticectomy patients.

Auditory processing of speech and nonspeech sounds was studied prospectively in two hemidecorticectomy patients (ages 10-11 years) with Rasmussen's syndrome. We tested auditory word recognition under four listening conditions: in quiet, in noise, after acoustic filtering, and dichotically. Recognition of environmental sounds and discrimination of tones and digitized syllables were also tested. Presurgical testing confirmed normal processing of speech and nonspeech, for both patients, under all listening conditon. One year after surgery, both patients demonstrated intact recognition of words and environmental sounds in quiet but impaired word recognition in noise. The left hemidecorticectomy patient also demonstrated impaired recognition of low-pass filtered words. These findings suggest that either hemisphere can process speech or nonspeech sounds in quiet, whereas both hemispheres are needed to process speech in background noise. Hemispheric contributions to processing speech in noise appear to differ, with the left hemisphere compensating for loss of phonologic information and the right hemisphere compensating for increased attention demands.

Neonatal hypocalcemic seizures: case report and literature review.

Seizures during the neonatal period have a broad differential diagnosis, many with a specific treatment and prognosis. In the case reported, a combination of dietary and endocrinologic abnormalities resulted in hypocalcemic seizures, which continued despite aggressive correction of serum ionized calcium levels. Serial electroencephalograms (EEG) performed during the hospitalization were markedly abnormal, and treatment with anticonvulsant drugs was considered given the persistence of seizures despite normalization of serum calcium levels. After 4 days of intravenous calcium administration, the seizure activity resolved, and the patient returned to his normal baseline level of functioning. This case highlights the clinical course of neonatal hypocalcemic seizures, EEG findings in several cases, and possible mechanisms for both hypocalcemic precipitation of seizures and anticonvulsant ineffectiveness.

The ketogenic diet.

One of the most significant trends in therapy has been the renewed popularity of the ketogenic diet. Dr. Vining discusses the history of the diet, its possible mechanisms of action and its clinical efficacy.

Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children.

CONTEXT: Little prospective long-term information is available on the effect of a ketogenic diet on plasma lipoproteins in children with difficult-to-control seizures. OBJECTIVE: To determine the effect in children with intractable seizures of a high-fat ketogenic diet on plasma levels of the major apolipoprotein B (apoB)-containing lipoproteins, low-density lipoprotein (LDL) and very LDL (VLDL); and the major apolipoprotein A-I (apoA-I)-containing lipoprotein, high-density lipoprotein (HDL). DESIGN, SETTING, AND PATIENTS: A 6-month prospective cohort study of 141 children (mean [SD] age, 5.2 [3.8] years for 70 boys and 6.1 [4.4] years for 71 girls) with difficult-to-treat seizures who were hospitalized for initiation of a high-fat ketogenic diet and followed up as outpatients. This cohort constituted a subgroup of the 371 patients accepted into the ketogenic diet program between 1994 and 2001. A subset of the cohort was also studied after 12 (n = 59) and 24 (n = 27) months. INTERVENTION: A ketogenic diet consisting of a high ratio of fat to carbohydrate and protein combined (4:1 [n = 102], 3.5:1 [n = 7], or 3:1 [n = 32]). After diet initiation, the calories and ratio were adjusted to maintain ideal body weight for height and maximal urinary ketosis for seizure control. MAIN OUTCOME MEASURES: Differences at baseline and 6-month follow-up for levels of total, VLDL, LDL, HDL, and non-HDL cholesterol; triglycerides; total apoB; and apoA-I. RESULTS: At 6 months, the high-fat ketogenic diet significantly increased the mean plasma levels of total (58 mg/dL [1.50 mmol/L]), LDL (50 mg/dL [1.30 mmol/L]), VLDL (8 mg/dL [0.21 mmol/L]), and non-HDL cholesterol (63 mg/dL [1.63 mmol/L]) (P<.001 vs baseline for each); triglycerides (58 mg/dL [0.66 mmol/L]) (P<.001); and total apoB (49 mg/dL) (P<.001). Mean HDL cholesterol decreased significantly (P<.001), although apoA-I increased (4 mg/dL) (P =.23). Significant but less marked changes persisted in children observed after 12 and 24 months. CONCLUSIONS: A high-fat ketogenic diet produced significant increases in the atherogenic apoB-containing lipoproteins and a decrease in the antiatherogenic HDL cholesterol. Further studies are necessary to determine if such a diet adversely affects endothelial vascular function and promotes inflammation and formation of atherosclerotic lesions.

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.)