Outpatient initiation of the ketogenic diet in children with pharmacoresistant epilepsy: An effectiveness, safety and economic perspective.

BACKGROUND: Children with pharmacoresistant epilepsy usually receive ketogenic diet (KD) as an inpatient, which makes it an expensive treatment. OBJECTIVE: To compare the effectiveness, safety, and costs of outpatient versus inpatient initiated KD. DESIGN: Retrospective observational non-inferiority study. PATIENTS/SETTING: Patients (1-18 years of age) who started KD either inpatient or outpatient. MAIN OUTCOME MEASURES: Effectiveness was defined as ≥50% seizure reduction. Safety was measured by the numbers of emergency visits and complications. Economic impact was analyzed by calculating total costs of treatment. STATISTICAL ANALYSES: Non-inferiority of outpatient initiation was tested using 95% confidence intervals of the differences in effectiveness and safety endpoints between groups with non-inferiority margins of 10%. Nonparametric bootstrap techniques were used to derive a 95% confidence interval for the mean difference in total costs between the groups. RESULTS: Hundred and five patients started KD in the period 2001 to 2017: 43 inpatient and 62 outpatient. At three months, the KD was effective in 61% of outpatients versus 63% of inpatients. The KD was considered safe in 36% of the outpatients, as compared to 29% in the inpatients. Outpatient initiation was shown to be non-inferior to inpatient initiation in terms of safety. Total health care costs of outpatient initiation were € 2901, as compared to € 8195 of inpatient initiation per patient (mean difference € 5294, 95% CI; -€ 7653 to -€ 2935). CONCLUSIONS: Our study suggests that outpatient KD initiation is no worse than inpatient initiation in terms of effectiveness and safety, while carrying lower health care costs.

Dieta cetogénica en epilepsia refractaria / Ketogenic diet in refractory epilepsy

CONTEXTO CLÍNICO: La epilepsia constituye un trastorno neurológico crónico caracterizado por la afectación paroxística y repetida de la actividad eléctrica cerebral. La proporción estimada de la población general con epilepsia activa (con convulsiones continuas o necesidad de tratamiento) oscila entre 4 y 10 cada 1.000 personas. Sin embargo, algunos estudios realizados en países de bajos y medianos ingresos sugieren una proporción mayor, entre 7 y 14 cada 1.000 personas.1 Un documento de la Liga Internacional Contra la Epilepsia (ILAE, su sigla del inglés International League Against Epilepsy) afirma que el conocimiento actual es insuficiente para determinar una clasificación científica de las epilepsias, y propone una sistematización de las mismas, permitiendo mayor flexibilidad.2 Si bien en muchos casos se enumeran las epilepsias según la edad de inicio, este abordaje permite que sean organizadas por el parámetro de elección, como tipo de convulsión, registro electroencefalográfico o marcadores en imágenes. Esta sistematización incluye dos dominios: los síndromes electro-clínicos y la etiología. TECNOLOGÍA: La dieta cetogénica (DC) es una dieta alta en grasa, adecuada en proteínas (1 gramo / kg) y muy baja en hidratos de carbono, que produce cambios metabólicos a menudo asociados con el estado de inanición, ya que este tipo de estado ha demostrado asociación con disminución en las convulsiones. Se consideran que los mecanismos por los cuales actúa la dieta cetogénica son multifactoriales. La cetosis es un estado metabólico en el que el cuerpo utiliza cuerpos cetónicos, producidos a partir de la descomposición de los ácidos grasos en el hígado, en lugar de los carbohidratos como fuente principal de energía.3 El KD clásico (cKD) tiene una proporción de grasa a carbohidrato más proteína de Los principales eventos adversos asociados a la dieta cetogénica son el síndrome gastrointestinal, pérdida de peso, el aumento de ácidos grasos de bajo peso molecular, trigliceridemia y en casos más graves se pueden producir alteraciones en el funcionamiento renal. Se desconocen las consecuencias a largo plazo de la dieta cetogénica. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de la dieta cetogénica en pacientes con epilepsia refractaria. MÉTODOS; Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron un ECA, cuatro RS, un estudio de serie de casos, cinco GPC y un informe de políticas de cobertura sobre dieta cetogénica en epilepsia refractaria. CONCLUSIONES: Evidencia de moderada calidad sugiere que en pacientes con epilepsia refractaria, el mantenimiento de una dieta cetogénica agregada a los cuidados habituales podría disminuir la frecuencia de los episodios convulsivos. La mayoría de las guías de práctica clínica que han sido relevadas consideran la dieta cetogénica como una alternativa de tratamiento en niños y adolescentes con epilepsia refractaria. No se encontraron políticas de cobertura de financiadores de salud tanto públicos como privados que mencionen explícitamente la cobertura de esta dieta. Un financiador privado de los Estados Unidos otorga cobertura a la hospitalización previa al inicio de la dieta cetogénica. No se hallaron estudios económicos que evalúen la costo-efectividad de la dieta cetogénica en epilepsia refractaria.

The modified ketogenic diet for adults with refractory epilepsy: An evaluation of a set up service.

PURPOSE: The ketogenic diet (KD) has been proven to be effective in children with refractory epilepsy and is recommended by the National Institute of Health and Care Excellence (NICE). There is no randomised control trial (RCT) evidence for the clinical or cost effectiveness of KD in adults, for whom the KD is not currently recommended. We assessed the feasibility of the modified ketogenic diet (MKD) in adults with refractory epilepsy along with the willingness of patients to participate in a future RCT. METHODS: The service evaluation was undertaken in two parts; questionnaire and diet evaluation. RESULTS: 102 patients completed a questionnaire, of which 51 patients were willing to try the MKD for 3 months to assess effect on seizures. Forty three patients were willing to participate in a clinical trial to investigate deliverability, efficacy and tolerability. Thirty seven of which would still be willing to participate if the trial were randomised. Of the 17 patients who commenced the diet, 9 completed the 12 week period, 7 of which stayed on the diet for the longer term. Constipation (n=6) and loose stools (n=3) were the only reported adverse effects. CONCLUSION: Our results indicate that there is demand for a ketogenic diet service in adults. The MKD is well tolerated, feasible and financially viable to deliver to adults with epilepsy in the NHS. There is also interest in and willingness to participate in a UK based RCT that would ultimately inform decisions about commissioning appropriate services.

Long-term clinical outcomes and economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy.

OBJECTIVE: To examine long-term retention rate, clinical outcomes, cost-utility and cost-effectiveness of the Ketogenic Diet (KD) compared with care as usual (CAU) in children and adolescents with intractable epilepsy from a societal perspective. METHODS: Participants were randomized into a KD or CAU group. Seizure frequency, quality adjusted life years (QALYs), side-effects, seizure severity, health care costs, production losses, patient and family costs were assessed at baseline and during 16-months of follow-up. Incremental cost-effectiveness ratios (ICERs) (i.e. cost per QALY and cost per responder) and cost-effectiveness acceptability curves are presented. RESULTS: 48 children were included in the analyses of this study (26 from KD group). In total, 58% of the KD group completed the follow-up of 16 months; 11 dropped-out for various reasons. At 16 months, 35% of the KD participants had a seizure reduction≥50% from baseline, compared with 18% of the CAU participants. Mean costs per patient in the CAU group were €53,367 (extrapolated) compared to €61,019 per patient in the KD group, resulting in an ICER of €46,564 per responder. Cost per QALY rose well above any acceptable ceiling ratio. At 4-months' follow-up, the KD group showed significantly more gastro-intestinal problems compared to the CAU group. At 16 months, the KD group reported fewer problems compared to CAU. Furthermore, 46.2% of the KD group reported a decrease in severity of their worst seizure compared to 32% of the CAU group. CONCLUSION: The KD group resulted in more responders and showed greater improvement on seizure severity. Furthermore, the KD did not lead to worsening of side-effects other than gastro-intestinal problems (only at 4 months' follow-up). However, as only a minimal difference in QALYs was found between the KD group and the CAU group, the resulting cost per QALY ratios were inconclusive.

Changes in quality of life as a result of ketogenic diet therapy: A new approach to assessment with the potential for positive therapeutic effects.

There are difficulties inherent in measuring Quality of life (QoL) in patients with chronic illness, including agreement on definitions of quality of life and the type of measure used, disease specific or generic. Well validated QoL instruments for epilepsy exist but focus on capturing common themes pertinent to children and families as a group instead of focusing on themes important to individual patients and their families/carers. In addition, it is common for numerous items on these inventories to be left incomplete or responded to with "not applicable" since many of the items are not suitable for children with disabilities and their families. This led us to devise a way to capture individual quality-of-life measures that are linked to parental/carer expectations in families of children undergoing ketogenic diet therapy for epilepsy. As part of our routine clinical assessment, parents/carers were asked to describe what they would like to see happen or change as a result of their child being on ketogenic diet therapy. A simple unstructured form was designed to facilitate the assessment process. Parents were then asked to rate their own QoL against these criteria on a Likert scale of 0-10 prior to commencement of the diet. This assessment was repeated at subsequent visits with parents/carers initially blinded to their original responses. Our assessments indicated that ketogenic diet therapy improves quality of life over a twelve-month period when measured against parental expectations. This ideographic approach has demonstrated changes in parental Qol and parental perceptions of their child's quality of life that would not have been captured by other validated measures. A lengthy questionnaire is avoided and is replaced by a skilled supportive conversation that identifies goals for treatment that are important to parents. This helps parents to reflect on the progress their child makes on the diet by revisiting their previously stated aspirations, and assessing whether they have been achieved. This is particularly helpful for those parents who express a sense of failure or helplessness relating to their child's intractable epilepsy. As a result, future work will center on developing this approach as a clinical tool.

The changing face of dietary therapy for epilepsy.

UNLABELLED: Ketogenic diet is an established and effective non-pharmacologic treatment for drug-resistant epilepsy. Ketogenic diet represents the treatment of choice for GLUT-1 deficiency syndrome and pyruvate dehydrogenase complex deficiency. Infantile spasms, Dravet syndrome and myoclonic-astatic epilepsy are epilepsy syndromes for which ketogenic diet should be considered early in the therapeutic pathway. Recently, clinical indications for ketogenic diet have been increasing, as there is emerging evidence regarding safety and effectiveness. Specifically, ketogenic diet response has been investigated in refractory status epilepticus and encephalopathy with status epilepticus during sleep. New targets in neuropharmacology, such as mitochondrial permeability transition, are being studied and might lead to using it effectively in other neurological diseases. But, inefficient connectivity and impaired ketogenic diet proposal limit ideal availability of this therapeutic option. Ketogenic diet in Italy is not yet considered as standard of care, not even as a therapeutic option for many child neurologists and epileptologists. CONCLUSIONS: The aim of this review is to revisit ketogenic diet effectiveness and safety in order to highlight its importance in drug-resistant epilepsy and other neurological disorders. WHAT IS KNOWN: • Ketogenic diet efficacy is now described in large case series, with adequate diet compliance and side effects control. • Ketogenic diet is far from being attempted as a first line therapy. Its availability varies worldwide. What is New: • New pharmacological targets such as mitochondrial permeability transition and new epileptic syndromes and etiologies responding to the diet such as refractory status epilepticus are being pointed out. • Ketogenic diet can function at its best when used as a tailor-made therapy. Fine tuning is crucial.

An economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy: An interim analysis.

OBJECTIVES: To gain insight into the cost-effectiveness of the ketogenic (KD) diet compared with care as usual (CAU) in children and adolescents with intractable epilepsy, we conducted an economic evaluation from a societal perspective, alongside a randomized controlled trial. METHODS: Participants from a tertiary epilepsy center were randomized into KD (intervention) group or CAU (control) group. Seizure frequency, quality adjusted life years (QALYs), health care costs, production losses of parents and patient, and family costs were assessed at baseline and during a 4-month study period and compared between the intervention and control groups. The incremental cost-effectiveness ratios (ICERs) (i.e., cost per QALY and cost per responder), and cost-effectiveness acceptability curves (CEACs) were calculated and presented. RESULTS: In total, 48 children were included in the analyses of this study (26 KD group). At 4 months, 50% of the participants in the KD group had a seizure reduction ≥50% from baseline, compared with 18.2 of the participants in the CAU group. The mean costs per patient in the CAU group were €15,245 compared to €20,986 per patient in the KD group, resulting in an ICER of €18,044 per responder. We failed, however, to measure any benefits in terms of QALYs and therefore, the cost per QALY rise high above any acceptable ceiling ratio. It might be that the quality of life instruments used in this study were not sufficiently sensitive to detect changes, or it might be that being a clinical responder is not sufficient to improve a patient's quality of life. Univariate and multivariate sensitivity analyses and nonparametric bootstrapping were performed and demonstrated the robustness of our results. SIGNIFICANCE: The results show that the KD reduces seizure frequency. The study did not find any improvements in quality of life and, therefore, unfavorable cost per QALY ratio's resulted.