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 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.

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).

Infantile spasms treated with the ketogenic diet: prospective single-center experience in 104 consecutive infants.

PURPOSE: In 2002, we reported our preliminary experience using the ketogenic diet (KD) for predominantly intractable infantile spasms (IS) in 23 infants. Since that time, we have increased our use of the KD for this condition including those with new-onset IS. METHODS: Infants were referred and prospectively started on the traditional KD from 1996 to 2009 at our institution. Included subjects had documented clinical IS, hypsarrhythmia on electroencephalography (EEG), and parental consent to start the KD. Efficacy was assessed through phone communication, clinic visits, and EEG every 3 months. RESULTS: One hundred four infants, mean age 1.2 years, were started on the KD for IS, of which 74 (71%) had a symptomatic etiology. Previous therapy for this patients included a mean of 3.6 anticonvulsants; 71% including corticosteroids or vigabatrin. Using an intent-to-treat analysis, > 50% spasm improvement occurred in 64% at 6 months and 77% after 1-2 years. Thirty-eight (37%) became spasm-free for at least a 6-month period within a median 2.4 months of starting the KD. In addition, 62% reported improvement in development, 35% had EEG improvement, and 29% were able to reduce concurrent anticonvulsants. Adverse effects were noted in 33%, of which 6% had diminished linear growth. Older age at onset of IS and fewer prior anticonvulsants were more likely to be associated with > 90% spasm improvement at 6 months. DISCUSSION: The KD is an efficacious therapy for IS in approximately two-thirds of patients treated, and it should be considered strongly after failure of corticosteroids and vigabatrin.

Long-term outcomes of children treated with the ketogenic diet in the past.

PURPOSE: The ketogenic diet has well-established short- and long-term outcomes for children with intractable epilepsy, but only for those actively receiving it. However, no information exists about its long-term effects years after it has been discontinued. METHODS: Living subjects were identified who were treated at the Johns Hopkins Hospital with the ketogenic diet from November 1993 to December 2008 for >or=1 month, and had discontinued it >or=6 months prior to this study. Of 530 patients who were eligible, 254 were successfully contacted by phone or e-mail with a survey and request for laboratory studies. RESULTS: Questionnaires were completed by 101 patients, with a median current age of 13 years (range 2-26 years). Median time since discontinuing the ketogenic diet was 6 years (range 0.8-14 years). Few (8%) still preferred to eat high fat foods. In comparison to the 52% responder rate (>50% seizure reduction) at ketogenic diet discontinuation, 79% were now similarly improved (p = 0.0001). Ninety-six percent would recommend the ketogenic diet to others, yet only 54% would have started it before trying anticonvulsants. Lipids were normal (mean total cholesterol 158 mg/dl), despite most being abnormal while on the ketogenic diet. The mean Z scores for those younger than age 18 years were -1.28 for height and -0.79 for weight. In those 18 years of age or older, the mean body mass index (BMI) was 22.2. DISCUSSION: This is the first study to report on the long-term effects of the ketogenic diet after discontinuation. The majority of subjects are currently doing well with regard to health and seizure control.

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 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.

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.

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%.

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.

Lack of influence of body mass index on the efficacy of the ketogenic diet.

The ketogenic diet is carefully calculated by dietitians in an effort to achieve the child's ideal body weight, theoretically to improve seizure control. This study researched whether achieving a stable body mass index or ideal body mass index-for-age correlates with efficacy with the traditional ketogenic diet. The outcomes of 123 children started on the ketogenic diet were analyzed at clinic visits 3, 6, 9, and 12 months after diet onset. Children who were at 40% to 59% body mass index-for-age did not have higher efficacy than those at a higher or lower body mass index-for-age, except at the 12-month clinic visit (81% versus 48%; P = .02). No clear link was demonstrated between either an ideal body mass index or changes in the body mass index and seizure control in the management of children receiving a ketogenic diet. Attributing changes in seizure control to a rapid weight gain or loss may be unjustified.

Home-guided use of the ketogenic diet in a patient for more than 20 years.

A 26-year-old man with tuberous sclerosis complex and multifocal seizures presented to the ketogenic diet clinic for management of his epilepsy. He had been started on the ketogenic diet at another institution at age 6 years, and his family had managed all nutritional aspects for the previous 10 years. Despite the lack of ongoing medical care, excellent seizure control and large urinary ketosis had been maintained, and side effects were limited only to poor growth. He remains on the diet to date, now for 21 years of continuous duration.

Decreased relative efficacy of the ketogenic diet for children with surgically approachable epilepsy.

PURPOSE: In children with intractable, surgically approachable epilepsy, the ketogenic diet is often perceived as less efficacious than surgery. METHODS: A retrospective chart review was performed of 554 children started on the ketogenic diet since 1994. Forty-five children were identified as surgical candidates, with at least 2 focal routine EEGs, ictal video-EEG, and corresponding focal neuroimaging findings, of whom 24 eventually had resective surgery and were followed subsequently. A comparison cohort group was also created of 45 children matched for age and seizure frequency that received the diet but were not surgical candidates (multifocal or generalized seizures). RESULTS: Of the 24 children who received both dietary and surgical therapies, there was a higher likelihood after 6 months of both >90% seizure reduction (71% versus 17%) and seizure freedom (63% versus 0%) following surgery, both p < 0.0001. Similarly, the 45 cohort children who were not surgical candidates were more likely to be seizure-free (29% versus 13%, p = 0.041) and remained on the diet for shorter duration (10 months versus 18 months, p = 0.035) compared to the surgical group. CONCLUSION: Children with surgically approachable epilepsy do respond to the diet, but are more likely to be seizure-free following surgery.

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.

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.

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.

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.