Changes in pediatric referrals after the 2009 ketogenic diet consensus recommendations.

BACKGROUND: In 2009, the International Ketogenic Diet Study Group published recommendations for children receiving ketogenic diet (KD) therapy for epilepsy. The document included a table listing epilepsy syndromes and conditions in which the KD has been particularly beneficial, hoping that physicians would refer children for the KD sooner. PURPOSE: To measure the impact of these 2009 recommendations on referral practice, we compared children initiated on the KD at Johns Hopkins Hospital (JHH) 10 years before and after the recommendations. RESULTS: Overall, children referred to the KD who met indications increased from the pre- to post-recommendation group, 44 % (112/256) to 69 % (175/255) (p < 0.001), with JHH neurologists specifically referring more frequently (10/112, 9 % to 58/175, 33 %) (p < 0.01). Referrals increased for Glut-1 deficiency (0 % to 2.4 %, p = 0.015), Dravet syndrome (0 % to 6.7 %, p < 0.01), Rett syndrome (0.4 % to 3 %, p = 0.018), and formula-fed only status (16 % to 31 %, p < 0.01). The chances of > 50 % seizure reduction for all children referred improved slightly between decades (56 % to 61 %, p = 0.30). CONCLUSIONS: Following the 2009 recommendations, our study shows there was an increase in referrals for children with indications at our center. Referrals from neurologists at our own institution increased the most. Ketogenic diet efficacy improved slightly over time but did not reach significance.

Does the size of a ketogenic diet admission group influence outcomes?

INTRODUCTION: Most pediatric centers admit children with epilepsy for several days when initiating the ketogenic diet (KD). At some institutions, children are admitted in groups in order to save staff time and allow families to bond together for support. It is unknown if admitting children in larger groups for the KD affects outcomes. METHODS: We performed a retrospective study of all children with intractable epilepsy admitted for KD initiation at Johns Hopkins Hospital from 2010 to 2020. Charts were reviewed for size of admission groups, 3-month seizure reduction, and total KD duration. A linear mixed effects model was used to analyze KD duration between different size admission groups. RESULTS: 245 children were started on the KD, mean age 5.2 years. Thirty-three (13%) children were admitted in one-child admission groups, 52 (21%) in 2-children groups, 78 (32%) in 3-children groups, 72 (29%) in 4-children groups, and 10 (4%) in 5-children groups. At our center, fewer large admission groups and shorter KD durations have occurred over time. After adjusting for time, the 3-children admission group had higher KD duration than 1-child (1.9 times duration, p = 0.035). Additionally, after grouping cohort sizes into small (1-2 patients) versus large (3-5 patients), KD durations in the large groups were 1.6 times those in the small groups, p = 0.036. There was no statistically significant correlation between the size of the admission groups and 3-month seizure reduction. CONCLUSIONS: Admitting children in larger groups, specifically 3 children at a time, was associated with longer KD durations. This may be due to parent support from groups, listening and learning from other parents' questions, or other factors.

Ketogenic diet therapy provision in the COVID-19 pandemic: Dual-center experience and recommendations.

The current coronavirus-19 pandemic has changed dramatically how neurologists care for children and adults with epilepsy. Stay-at-home orders and resistance to hospitalizations by patients have led epileptologists to engage in telemedicine and reevaluate how to provide elective services. Ketogenic diet therapy is often started in the hospital, with families educated in hospital-based classes, but this is difficult to do in this current pandemic. At our two academic centers, both our pediatric and adult epilepsy diet centers have had to quickly consider alternative methods to both start and maintain ketogenic diet therapy. This paper provides several examples of how ketogenic diet therapy can be provided to patients in unique ways, along with recommendations from other experts and patients, learned over the past few months.

How often is antiseizure drug-free ketogenic diet therapy achieved?

The ketogenic diet (KD) is often started not only for seizure reduction but also to potentially wean antiseizure drugs (ASDs) in children with epilepsy. Although there have been several publications regarding ASD reduction on the KD, it is unknown how often complete medication withdrawal occurs. We reviewed the charts of all children started on the KD at Johns Hopkins Hospital and Johns Hopkins All Children's Hospital from 1/11 to 4/18. Children were defined as achieving drug-free diet (DFD) status if they started the KD on at least 1 ASD and achieved a period of time where they were on the KD alone. Over the time period, 232 children were evaluated; DFD status occurred in 43 (18.5%), of which 32 (13.8% of the full cohort) remained off ASDs for the remainder of their KD treatment course. Eleven children restarted ASD after a mean of 7 months. Children achieving DFD therapy were more likely to be younger, have fewer ASDs at KD onset, have Glut1 deficiency or epilepsy with myoclonic-atonic seizures, but were less likely to have Lennox-Gastaut syndrome or a gastrostomy tube.

A Proof-of-Principle, Case-Control Study to Compensate for Potential Carbohydrates in Liquid Antiseizure Drugs in Children on the Ketogenic Diet.

INTRODUCTION: Since its creation, patients on ketogenic diet are told to avoid liquid medications due to theoretical concerns of "hidden" carbohydrates. However, switching from liquid to tablet formulations can be problematic, especially for infants and young children. We theorized that increasing the daily ketogenic ratio might compensate for liquid antiseizure drug carbohydrates. METHODS: Two tables were created (for 3:1 and 4:1 ketogenic ratios), with variables including daily volume of antiseizure drugs and calories. Cases were those who had their ratio increased and liquid medications continued. Children already on tablet formulations, emergency situations, were primarily those included as controls. RESULTS: From May 2016 through August 2018, 59 children (33 cases and 26 controls) ages 0.3-14 years were started on the classic ketogenic diet. Compensated antiseizure drugs most commonly included levetiracetam, clobazam, and valproate (mean volume 16 mL/d (range: 3-62 mL/d)). Adjusted ratios for younger children and infants on a 3:1 diet ranged from 3.1 to 3.5:1 and older children on a 4:1 diet from 4.2 to 4.7:1. There was no difference between cases and controls in achieving large ketosis (76% vs 77%), weight gain (1.4 vs 1.2 kg), 1 month >50% seizure reduction (52% vs 50%), or >90% seizure reduction (30% vs 35%). Four (12%) cases had zero or small urinary ketosis, which improved when antiseizure drugs were switched to tablets or discontinued. CONCLUSIONS: This proof-of-principle study demonstrates feasibility of compensating for carbohydrates in liquid medications by increases in the daily ketogenic ratio. This ratio adjustment protocol may help ease an already complex adjustment to dietary therapy.

Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group.

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

Evaluation of the Utility of a Dietary Therapy Second Opinion Clinic.

Fine-tuning ketogenic diets to achieve better seizure control may influence families to seek second opinions. Since 2009, Johns Hopkins Hospital has provided second opinions for children followed at other ketogenic diet centers. We retrospectively reviewed 65 consecutive children seen in this clinic; parents were also sent a 2-page survey. The mean age was 6.6 years and dietary therapy had been used a median 9 months. Seizure reduction >50% was achieved in 65%, including 35% with >90% reduction. Parent questions included how to improve seizure control (65%), ideal diet duration (18%), and confirmation of the plan (11%). The most common recommendations were anticonvulsant reduction (43%), adding oral citrates/calcium/vitamins (38%), and carnitine supplementation (31%). Diet discontinuation was more frequently suggested in those children with <50% seizure reduction (60% vs 20%, P = .001). Recommendations were successful in 78%, and the visit was reported as useful by 88%.

Impact of Child Life Services on Children and Families Admitted to Start the Ketogenic Diet.

Traditionally the ketogenic diet is started as an inpatient admission to the hospital. Starting in January 2015, child life services were made formally available during ketogenic diet admissions to help families cope. One-page surveys were then provided to 15 parents on the day of discharge and again after 3 months. Every family believed that the child life services were helpful. Children who were developmentally appropriate/mildly delayed had higher parent-reported anxiety scores than those who were moderate to severely delayed (4.4 vs 1.0, P = .02). At 3 months, child life services were deemed very helpful for the parents (mean score: 8.9, range: 5-10), and were more helpful for the parent than the child (mean 6.2, range 1-10, P = .047). One of the most helpful services was a prior phone call to parents 1 week prior. In this small pilot study, child life involvement during the start of the ketogenic diet was highly useful.

Complications During Ketogenic Diet Initiation: Prevalence, Treatment, and Influence on Seizure Outcomes.

BACKGROUND: Many centers still admit children for several days to start the ketogenic diet. The exact incidence of adverse effects during the admission and their potential later impact on seizure reduction has not been widely studied. METHODS: We performed a retrospective study of children with intractable epilepsy electively admitted for ketogenic diet initiation at our institution from 2011 to 2016. Charts were reviewed for adverse effects during the admission period and then examined for seizure reduction and compliance at three months. A rating scale (1 to 4) was created for severity of any adverse events. RESULTS: A total of 158 children were included, with the mean age 4.6 years. Potentially attributable adverse effects occurred in 126 (80%) children, most commonly emesis, food refusal, and hypoglycemia. Seventy-three (46%) children received some form of intervention by the medical team, most commonly the administration of juice (24%). Younger age was correlated with an increased likelihood of moderate to severe adverse effects during admission, often repeated hypoglycemia (3.6 versus 4.9 years, P = 0.04). Fasting was more likely to result in lethargy and a single blood glucose in the 30 to 40 mg/dL range, but it was not correlated with emesis, repeated hypoglycemia, or higher adverse effect scores. There was no statistically significant correlation between the severity of adverse effects and the three-month seizure reduction. CONCLUSIONS: Mild easily treated adverse effects occurred in most children admitted for the ketogenic diet. Younger children were at greater risk for significant difficulties and should be monitored closely. Because fasting led to more lethargy and hypoglycemia, it may be prudent to avoid this in younger children.

Diet Redux: Outcomes from Reattempting Dietary Therapy for Epilepsy.

The outcome for patients attempting dietary therapy for epilepsy a second time is unknown. Twenty-six subjects treated with the ketogenic diet as children who then began either the ketogenic diet or a Modified Atkins Diet (MAD) at least 6 months later were evaluated. The mean age at the first diet trial was 5.6 years and at the second diet trial was 11.5 years. Most restarted dietary therapy because of persistent seizures (65%) or recurrence after seizure freedom (19%). Overall, 77% had a ≥50% seizure reduction with the first diet, and 50% with the second diet, P = .04. Individual subject responses were largely similar, with 14 (54%) having identical seizure reduction both times, 9 worse (35%) with the second attempt, and 3 (16%) improved. The second diet trial was more likely to lead to >50% seizure reduction if the first trial was started at a later age (7.4 vs 3.9 years, P = .04).

Use of dietary therapies amongst patients with GLUT1 deficiency syndrome.

PURPOSE: GLUT-1 deficiency syndrome (GLUT1DS) is a neurologic disorder manifesting as epilepsy, abnormal movements, and cognitive delay. The currently accepted treatment of choice is the classic 4:1 ratio ketogenic diet. METHODS: A 2-page survey was distributed to all attendees of a family-centered conference for GLUT1DS in July 2015. The surveys were completed by parents, collected anonymously, and information analyzed in a database. RESULTS: Surveys were received from 92 families, of which 90 (98%) had been treated with dietary therapies. Diets used were extremely varied: 59 were treated with the classic ketogenic diet (KD), 29 with the Modified Atkins Diet (MAD), 4 with the Medium-chain Triglyceride (MCT) Diet and 2 with the low glycemic index treatment. The mean diet duration was 5.5 years (range: 1 month-20 years). Of those with seizures, 95% of the children had >50% seizure reduction and 80% had >90% seizure reduction. Children who were seizure-free were currently younger on average (8.2 vs. 11.6 years, p=0.01) and slightly younger at GLUT1DS diagnosis (3.8 vs. 5.3 years, p=0.05). There was an equal percentage of children seizure-free receiving the KD/MCT Diets compared to the MAD/Low Glycemic Index Treatment (74% vs. 63%, p=0.30). The majority (64%) were not receiving anticonvulsants. CONCLUSION: This represents the largest series of KD experience in children with GLUT1DS. Nearly all patients surveyed were on dietary therapies for long durations with reported excellent seizure control, often without anticonvulsant drugs. Several different ketogenic diets were utilized with similar efficacy. Early diagnosis and treatment were correlated with success.

Hepatic Dysfunction as a Complication of Combined Valproate and Ketogenic Diet.

BACKGROUND: The ketogenic diet has long been shown to be an effective therapy for children with medication-refractory seizures. Most complications of the ketogenic diet include short-lived gastrointestinal disturbances, acidosis, and dyslipidemia. Hepatic dysfunction and pancreatitis are among the less common but more serious complications of the ketogenic diet. Many patients on the ketogenic diet receive adjunct treatment with an anticonvulsant drug, and valproate is frequently used. METHODS AND RESULTS: We describe a child who developed hepatic dysfunction in association with the combined use of valproate and the ketogenic diet. After stopping the valproate and then restarting the ketogenic diet, her liver enzymes normalized, and she was able to achieve markedly improved seizure control and quality of life. CONCLUSIONS: Although caution should be advised when using both treatments simultaneously, the development of hepatic dysfunction should not preclude continuation of the ketogenic diet, as the hepatotoxic effects may be completely reversed once the valproate is stopped.

Exploring the relationship between preferences for high fat foods and efficacy of the ketogenic and modified Atkins diets among children with seizure disorders.

PURPOSE: Previous research has indicated that children with seizures may prefer high fat foods - a preference compatible with ketogenic and modified Atkins dietary therapies. The purpose of this prospective study was to examine the relationship between fat preference and efficacy of therapeutic diets in treating intractable seizures among a pediatric population. METHODS: Preference for high fat foods was directly assessed in a sample of 30 children prior to commencing either the ketogenic or modified Atkins diet. Seizure control was assessed at 1, 3, 6, and 12 months following diet initiation. Using an intent-to-treat analysis, correlations between fat preference and diet efficacy were examined at each follow-up and across the follow-up period. RESULTS: At individual follow-ups, correlations between fat preference and diet efficacy varied in terms of both strength and significance; however, modest, positive correlations with fat preference were significant when examining high levels of efficacy (100% seizure reduction, ≥90% seizure reduction) across a 1-year follow-up period. CONCLUSION: These findings provide preliminary evidence that fat preference, when directly assessed, may be a useful predictor of treatment efficacy for the ketogenic and modified Atkins diets; however, further research is necessary.

Dietary and medication adjustments to improve seizure control in patients treated with the ketogenic diet.

Unlike anticonvulsant drugs and vagus nerve stimulation, there are no guidelines regarding adjustments to ketogenic diet regimens to improve seizure efficacy once the diet has been started. A retrospective chart review was performed of 200 consecutive patients treated with the ketogenic diet at Johns Hopkins Hospital from 2007 to 2013. Ten dietary and supplement changes were identified, along with anticonvulsant adjustments. A total of 391 distinct interventions occurred, of which 265 were made specifically to improve seizure control. Adjustments led to >50% further seizure reduction in 18%, but only 3% became seizure-free. The benefits of interventions did not decrease over time. There was a trend towards medication adjustments being more successful than dietary modifications (24% vs 15%, P = .08). No single dietary change stood out as the most effective, but calorie changes were largely unhelpful (10% with additional benefit).

An update on diets in clinical practice.

Ketogenic diet therapies involve a collaborative healthcare team and therefore are typically offered in tertiary care centers. Centers that utilize these therapies with frequency gain valuable experience and become skilled in their practice. This chapter is a summary from the presentations of 5 practitioners including a nurse, pharmacist, and 3 dietitians who shared their expertise during the clinical session of the 2012 International Symposium.

A decade of the modified Atkins diet (2003­2013): Results, insights, and future directions.

The modified Atkins diet has been used since 2003 for the treatment of children and adults with refractory epilepsy.This "alternative" ketogenic diet is started in clinic, without fasting, hospitalization, and restriction of protein,calories, or fluid intake. Now after 10 years of continued use, approximately 400 patients have been reported in over 30 studies of the modified Atkins diet as treatment for intractable seizures, with results demonstrating similar efficacy to the ketogenic diet and improved tolerability. The modified Atkins diet is being increasingly used in the adult population. Clinical trials have provided insight into the mechanisms of action of dietary therapies overall. This review will discuss the past decade of experience with the modified Atkins diet as well as predictions for its role in the treatment of epilepsy a decade from now.

Alternative diets to the classical ketogenic diet--can we be more liberal?

The ketogenic diet (KD), a high-fat, adequate protein, low-carbohydrate diet has been used since 1921 for the treatment of severe medically refractory epilepsy. In the past 15 years, the use of the KD has expanded enormously and a huge amount of clinical evidence of its efficacy is available. The classical KD is however restrictive and therefore alternative more liberal varieties of the classical KD have been developed within the last 8 years. The purpose of this report is to summarise the principles and evidence of effectiveness of the alternative ketogenic diets: Medium Chain Triglyceride (MCT)-KD, modified Atkins diet (MAD) and low glycaemic index treatment (LGIT), compared to the classical KD. The clinical evidence to date suggests that the more liberal versions of the classical KD such as MCT KD, MAD and LGIT have an efficacy close to the classical KD; however, no RCT data are available for MAD and LGIT. This evidence suggests that factors such as age, epilepsy type, lifestyle and resources are important factors in deciding which diet we should start a patient on. This report intends to summarise guidelines based on the evidence available.

How do parents find out about the ketogenic diet?

It has been previously reported that child neurologists often view the ketogenic diet (KD) as a treatment of last resort. An anonymous survey was provided to parents of 107 consecutive children starting the KD at our institution. The average time from epilepsy to KD onset was 2.8years, but the average wait time for KD onset was only 1.7months after referral. The most common reason for starting the KD was seizure reduction, followed by less intense seizures, medication reduction, and cognitive improvement. The majority (72%) obtained information about the KD from their neurologist; however, more than half also had viewed related websites. The mean neurologist supportiveness score was 7.9/10; 53% reporting their neurologist as maximally supportive (score of 10). A score of 10 was more likely seen in those who also scored their pediatrician with 10 (69% vs. 15%, p<0.001) and who were self-referred from our institution (56% vs. 27%, p=0.001).

Is there an ideal way to discontinue the ketogenic diet?

It is unclear what the ideal weaning speed of the ketogenic diet should be and the resultant risk of seizure worsening. A retrospective chart review was performed of children who discontinued the ketogenic diet at Johns Hopkins Hospital from January 2000 to June 2010. Speed of discontinuation was categorized into immediate (<1 week), quick (1-6 weeks), or slow (>6 weeks) rates. One hundred and eighty-three children were identified. Children with both a longer diet duration (p=0.004) and lower seizure frequency (p<0.001) were weaned more slowly by our group. There was no significant difference in the incidence of seizures worsening between discontinuation rates. However, there was an increased risk of seizures worsening in those specifically with a 50-99% seizure reduction (30% vs. 8%, p<0.0001) and for that level of seizure improvement, in those who were receiving more anticonvulsants (1.4 vs. 0.8, p=0.01). In summary, there does not appear to be an increased risk of seizure exacerbation with rapid ketogenic diet discontinuations. Those who improved 50-99% and were receiving more anticonvulsants were at the highest risk overall. Discontinuing the ketogenic diet over weeks rather than months appears safe.