The ketogenic diet: additional information from a crossover study.

The purpose of this blinded, crossover study of the ketogenic diet in children with the Lennox-Gastaut syndrome was to confirm, by the addition of 60 g of glucose per day to negate the ketosis, that the effectiveness of the ketogenic diet was neither the result of a placebo effect nor due to parental expectations and commitment. We found that the additional glucose did not significantly alter the frequency of electroencephalography-assessed events, but did decrease the frequency of parent-reported "drop" seizures (P = .07). Fasting had substantial effects on both seizures and electroencephalography-assessed events. The diet remained effective in decreasing seizures of the Lennox-Gastaut syndrome at 12 days, 6 months, and 12 months. In conclusion, the ketogenic diet is effective in decreasing the drop seizures of the Lennox-Gastaut syndrome.

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.

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.

A case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms.

PURPOSE: ACTH is currently the standard first-line therapy for new-onset infantile spasms, but it has significant side effects. We hypothesized the ketogenic diet (KD), previously reported as beneficial for intractable infantile spasms, would have similar efficacy, but better tolerability than ACTH when used first-line. METHODS: We conducted a retrospective chart review of all infants started on the KD (n = 13) and high-dose ACTH (n = 20) for new-onset infantile spasms at our institution since 1996. RESULTS: Infants were spasm-free in 8 of 13 (62%) infants treated with the KD within 1 month, compared to 18 of 20 (90%) treated initially with ACTH, p = 0.06. When effective, median time to spasm freedom was similar between ACTH and the KD (4.0 vs. 6.5 days, p = 0.18). Those treated with ACTH were more likely to have a normal EEG at 1 month (53% vs. 9%, p = 0.02), however, use of the KD led to EEG normalization within 2-5 months in all eight who became spasm-free. In the five children in whom the KD was unsuccessful, four became spasm-free subsequently with ACTH or topiramate immediately. Side effects (31% vs. 80%, p = 0.006) and relapse rate after initial success (12.5% vs. 33%, p = 0.23) were lower with the KD. DISCUSSION: In this retrospective study, the KD stopped spasms in nearly two-thirds of cases, and had fewer side effects and relapses than ACTH. ACTH normalized the EEG more rapidly, however. Further prospective study of the KD as, with a 2-week time limit if unsuccesful, first-line therapy for infantile spasms is warranted.

Beware: the misuse of technology and the law of unintended consequences.

Electronic monitoring of the fetal heart rate during labor (EFM), originally designed to assess fetal stress and allow the early detection of the compromised fetus, has instead led to increasing maternal morbidity without decreasing fetal morbidity. The unintended consequences of this technologic advance have led to the creation of a pseudodisease and unwarranted intervention in response to its detection. Is it ethical to introduce a new technology without adequate assessment of its possible consequences? Are we about to repeat this (error resulting from the introduction of EFM?) There is increasing interest in monitoring the function of the newborn brain, to enable the early detection of subclinical seizures. The monitor may also be used for assessing brain function in older children and adults who are comatose or paralyzed and cannot appropriately respond to stimuli. Use of this amplitude-integrated electroencephalography (aEEG) in the newborn for detection of seizures and other brain abnormalities is not dissimilar to the use of electronic fetal heart rate monitoring. Whether seizures or subclinical seizures themselves cause harm to the developing nervous system is unclear. The effectiveness of medications for treatment of seizures in the newborn has not been established. Therefore, the consequences of introducing automated EEG for the detection of subclinical neonatal seizures are likely to be similar to the results of the introduction of EFM: creation of another pseudodisease, followed by unwarranted intervention, and increased legal liability. What are the ethics of continued approval and introduction of unevaluated technology? What is the wisdom of its use? Beware of the unintended consequences.

The ketogenic diet: one decade later.

The ketogenic diet, a high fat, adequate protein, low carbohydrate diet, has, during the past decade, had a resurgence of interest for the treatment of difficult-to-control seizures in children. This review traces its history, reviews its uses and side effects, and discusses possible alternatives and the diet's possible mechanisms of action. Finally, this review looks toward possible future uses of the ketogenic diet for conditions other than epilepsy.

EEG is an essential clinical tool: pro and con.

The authors debate whether routine EEG is an essential clinical tool for evaluation of a first seizure. One author suggests that because of the positive predictive value of interictal spikes for seizure recurrence, the EEG is a useful tool. The other author argues that since many clinicians would not treat after a single seizure, even if the EEG were abnormal, the EEG is not essential. Both authors agree that the EEG should only be ordered with forethought to answer a specific question.

The importance of parental expectations of cognitive improvement for their children with epilepsy prior to starting the ketogenic diet.

Although the success rates and complications of various treatment options for children with intractable epilepsy have been described, the actual expectations of parents for these treatments are less clear. Since 1998, parents at our institution have written their goals in a letter before starting their children on the ketogenic diet. One hundred consecutive letters were evaluated. The most common first goal was seizure improvement, second was anticonvulsant reduction, and third was cognitive improvement. Ninety percent requested improvement in cognition or alertness. These expectations were either met or exceeded at 6 months in 52-60% of children. Achieving or surpassing parental expectations for cognitive improvement correlated with longer diet duration (P=0.04), but meeting goals for seizure or anticonvulsant reduction did not. Cognitive improvement (P<0.001) and >90% seizure reduction (P=0.04) at 6 months positively correlated with longer eventual diet duration. Expectations for cognitive improvement need to be discussed prior to beginning the ketogenic diet.

The outcome of children with intractable seizures: a 3- to 6-year follow-up of 67 children who remained on the ketogenic diet less than one year.

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.

A progressive anterior fibrosis syndrome in patients with postsurgical congenital aniridia.

PURPOSE: To report the characteristics of a newly recognized clinical entity in congenital aniridia that we have termed aniridic fibrosis syndrome. DESIGN: Interventional case series. METHODS: Retrospective chart review of 155 eyes in 80 patients with congenital aniridia was carried out to identify and characterize eyes that had anterior chamber fibrosis. Histopathologic evaluation was performed in three eyes. RESULTS: Seven eyes in six patients were identified to have aniridic fibrosis syndrome. All eyes had undergone previous intraocular anterior segment surgery, some eyes with multiple procedures. Seven eyes had undergone cataract surgery with posterior chamber intraocular lens; six eyes had undergone previous implantation of tube shunt devices, and four eyes had undergone previous penetrating keratoplasty. Clinically, the syndrome was characterized by a progressive retrolenticular and retrocorneal membrane that caused forward displacement of intraocular lenses. Surgical findings indicated that the fibrotic membrane also can involve the ciliary body and anterior retina. Histopathologic evidence from three eyes indicated that the extensive fibrotic tissue originated from the root of the rudimentary iris and entrapped the intraocular lens haptics. Endothelial decompensation that was subsequent to the formation of the aniridic fibrosis syndrome was seen in all eyes. CONCLUSION: Aniridic fibrosis syndrome is characterized by the development of a progressive anterior chamber fibrosis. A possible mechanism that promotes the formation of this fibrotic material may be the proximity or touching of intraocular devices on immature vessels in the rudimentary iris found in aniridia. Patients with aniridia with a history of penetrating keratoplasty, intraocular lenses, and tube shunts should be monitored for aniridic fibrosis syndrome; early surgical intervention is recommended.

Tuberous sclerosis complex and the ketogenic diet.

PURPOSE: Tuberous sclerosis complex (TSC) is a condition that is frequently associated with intractable, early-onset epilepsy, and often is first seen as infantile spasms. If medications fail and no clear epileptogenic tuber is identified, nonpharmacologic therapies are often attempted. The use of the ketogenic diet specifically for children with TSC and epilepsy has not been previously described. METHODS: A chart review was performed of patients with TSC treated with the ketogenic diet over a 5-year period at Johns Hopkins Hospital and Massachusetts General Hospital. RESULTS: Twelve children, ages 8 months to 18 years, were identified. Eleven (92%) children had a >50% reduction in their seizures at 6 months on the diet, and 8 (67%) had a >90% response. Five children had at least a 5-month seizure-free response. Diet duration ranged from 2 months to 5 years (mean, 2 years). CONCLUSIONS: In this limited-duration case series of 12 patients, the ketogenic diet was a generally effective therapeutic modality for the intractable epilepsy occasionally seen in children with TSC.

Rasmussen's syndrome: progressive autoimmune multi-focal encephalopathy.

Rasmussen's encephalitis, originally thought to be a chronic form of viral encephalitis, is now thought to be an autoimmune disease of the brain and is more properly termed Rasmussen's syndrome. Starting in one area of one side of the brain, the disease appears to gradually and progressively involve that side of the brain causing progressive and intractable focal seizures, a hemiparesis, and expressive aphasia when the left hemisphere is involved. Immune therapy with steroids, immunoglobulins, or plasmaphoresis provide only temporary relief from seizures. Neither antibodies to Glu-R3 nor cortical biopsy are helpful in the diagnosis. Hemispherectomy of one form or another is the only curative therapy, and there is no evidence that one form of hemispherectomy is preferable to another. Immuno-ablative therapy may be a therapy of the future.

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.