Publications by authors named "Elizabeth Neal"

9 Publications

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Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group.

Epilepsia Open 2020 Sep 13;5(3):354-365. Epub 2020 Aug 13.

Department of Neurology and Pediatrics Vagelos College of Physicians and Surgeons at Columbia University New York NY USA.

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. linical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.
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http://dx.doi.org/10.1002/epi4.12414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469861PMC
September 2020

Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomised controlled trial.

Trials 2017 04 26;18(1):195. Epub 2017 Apr 26.

UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: The incidence of epilepsy is greatest in the first 2 years of life, an age group where there is generally a poor prognosis for both seizure control and neurodevelopmental outcome. Early control of seizures can be associated with better developmental outcome but many of the epilepsies presenting in infancy are poorly responsive to antiepileptic medication. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet designed to mimic the effects of starvation on the body. Dietary fat is converted into ketones in the body and used as an energy source by the brain. The KD has been shown to be successful in controlling seizures in many observational studies, and in two randomised controlled trials (RCTs) in older children. However, little evidence is available in the very young.

Methods/design: An open-label RCT where eligible children (age 3 months to 2 years with epilepsy who have failed two antiepileptic drugs (AEDs)) undergo baseline assessment, including medical and seizure history. Participants then start an observation period (7 or 14 days) with documentation of seizure frequency. Randomisation will occur on day 8 or day 15 to receive the KD or a further AED; the allocated treatment will commence on day 15, with instruction and training. A second assessment (4 weeks after start of treatment) will include a clinical review and tolerability questionnaire (modified Hague Scale of Side Effects - for those allocated to the KD group). Assessments will be repeated at 8 weeks after the start of treatment including biochemical investigations, after which, according to patient response, KD (diet group) or AED (standard AED group) will then be continued or changed. Those in the AED group who have failed to achieve seizure control at the 8-week assessment will then be offered KD outside the context of the trial. Those in the KD arm who fail to achieve seizure control will be changed to standard clinical management. All patients will be followed up for 12 months from randomisation for retention, seizure outcome, quality of life and neurodevelopmental status.

Discussion: The slow rate of recruitment is an ongoing practical issue. There is a limitation to the number of eligible patients compared to what was predicted, mainly due to the nature of this patient group. After a substantial amendment to widen inclusion criteria and reduce the baseline period to 7 days for patients with a high seizure burden, the rate of recruitment steadily increased. A number of operational concerns regarding dietetic time were also highlighted impacting on the recruitment rate. However, the combination of a low dropout rate and the opening of further centres, the trial should successfully meet the final recruitment target. All nine centres are now recruiting and we hope to open further centres within the UK.

Trial Registration: ClinicalTrials.gov, identifier: NCT02205931 . Registered on 16 December 2013.
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http://dx.doi.org/10.1186/s13063-017-1918-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406967PMC
April 2017

Ketogenic diet guidelines for infants with refractory epilepsy.

Eur J Paediatr Neurol 2016 Nov 17;20(6):798-809. Epub 2016 Jul 17.

UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, London, UK. Electronic address:

Background: The ketogenic diet (KD) is an established, effective non-pharmacologic treatment for drug resistant childhood epilepsy. For a long time, the KD was not recommended for use in infancy (under the age of 2 years) because this is such a crucial period in development and the perceived high risk of nutritional inadequacies. Indeed, infants are a vulnerable population with specific nutritional requirements. But current research shows that the KD is highly effective and well tolerated in infants with epilepsy. Seizure freedom is often achieved and maintained in this specific patient group. There is a need for standardised protocols and management recommendations for clinical use.

Method: In April 2015, a project group of 5 experts was established in order to create a consensus statement regarding the clinical management of the KD in infants. The manuscript was reviewed and amended by a larger group of 10 international experts in the KD field. Consensus was reached with regard to guidance on how the diet should be administered and in whom.

Results: The resulting recommendations include patient selection, pre-KD counseling and evaluation, specific nutritional requirements, preferred initiation, monitoring of adverse effects at initiation and follow-up, evaluation and KD discontinuation.

Conclusion: This paper highlights recommendations based on best evidence, combined with expert opinions and gives directions for future research.
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http://dx.doi.org/10.1016/j.ejpn.2016.07.009DOI Listing
November 2016

An update on diets in clinical practice.

J Child Neurol 2013 Aug 14;28(8):1015-26. Epub 2013 May 14.

Children's Hospital of Wisconsin and The Charlie Foundation, Milwaukee, WI, USA.

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.
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http://dx.doi.org/10.1177/0883073813487597DOI Listing
August 2013

Dietary therapies for epilepsy: future research.

Epilepsy Behav 2011 Sep 26;22(1):17-22. Epub 2011 Mar 26.

The John M. Freeman Pediatric Epilepsy Center, The Johns Hopkins Hospital, Baltimore, MD 21287, USA.

Since 1921, dietary therapies have remained valuable options in the treatment of intractable childhood epilepsy. The traditional ketogenic diet has been well demonstrated, including in a recent randomized, controlled trial, as being highly effective. More recent alternative diets such as the medium-chain triglyceride diet, modified Atkins diet, and low-glycemic-index treatment have expanded the use of this modality to more children as well as adults. In this review, we discuss our top 10 most pressing research topics related to the ketogenic diet that warrant future study. As well, two promising ketogenic diet clinical researchers discuss their past and current research to help answer some of these questions.
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http://dx.doi.org/10.1016/j.yebeh.2011.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776748PMC
September 2011

The ketogenic diet--update on recent clinical trials.

Epilepsia 2008 Nov;49 Suppl 8:6-10

UCL-Institute of Child Health, London, UK.

The ketogenic diet (KD) has been used in the treatment of epilepsy for almost 100 years. Several cohort studies have emphasized its possible benefit, although use became less at the introduction of anticonvulsant medication. However, the KD has regained recognition over the past 15 years. Resources remain scarce and its availability for children may be limited. One argument has been the lack of evidence from suitably designed trials. Systematic reviews and meta-analyses have revealed that studies are limited to class 3 and 4 data. A recently published randomized controlled trial has shown that the benefit of the KD is equivalent to any of the new anticonvulsant medications, emphasizing the need for more resources to ensure greater diet availability.
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http://dx.doi.org/10.1111/j.1528-1167.2008.01822.xDOI Listing
November 2008

A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy.

Epilepsia 2009 May 19;50(5):1109-17. Epub 2008 Nov 19.

UCL-Institute of Child Health & Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.

Purpose: To conduct the first randomized trial on classical and medium-chain triglyceride (MCT) versions of the ketogenic diet, examining efficacy and tolerability after 3, 6, and 12 months.

Methods: One hundred forty-five children with intractable epilepsy were randomized to receive a classical or an MCT diet. Seizure frequency was assessed after 3, 6, and 12 months. Treatment withdrawals were documented. Tolerability was assessed by questionnaire, and blood ketone levels were measured.

Results: Of the 61 children who started a classical diet and the 64 who started an MCT diet, data from 94 were available for analysis: 45 classical and 49 MCT. After 3, 6, and 12 months there were no statistically significant differences in mean percentage of baseline seizures between the two groups (3 months: classical 66.5%, MCT 68.9%; 6 months: classical 48.5%, MCT 67.6%; 12 months: classical 40.8%, MCT 53.2%; all p > 0.05). There were no significant differences between groups in numbers achieving greater than 50% or 90% seizure reduction. Serum acetoacetate and beta-hydroxybutyrate levels at 3 and 6 months were significantly higher in children on the classical diet (p < 0.01); this was the case at 12 months for acetoacetate. There were no significant differences in tolerability except increased reports in the classical group of lack of energy after 3 months and vomiting after 12 months.

Discussion: This study has shown classical and MCT ketogenic diet protocols to be comparable in efficacy and tolerability; both ways of implementing the diet have their place in the treatment of childhood epilepsy.
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http://dx.doi.org/10.1111/j.1528-1167.2008.01870.xDOI Listing
May 2009

Growth of children on classical and medium-chain triglyceride ketogenic diets.

Pediatrics 2008 Aug;122(2):e334-40

University College London-Institute of Child Health, London, England.

Objective: The objectives of this study were to examine growth in children on classical and medium-chain triglyceride ketogenic diets and to investigate any association between growth and calorie or protein intake.

Methods: Weight, height, and BMI z scores were recorded for children who were initiated on 1 of 2 ketogenic diets at baseline and after 3, 6, and 12 months, if continued. Mean calorie and protein intakes during treatment were calculated for children who completed 12 months on the diet. Changes in growth were compared between the 2 diets, and the association between growth and dietary intake was examined.

Results: Seventy-five children provided growth data. Weight z scores decreased significantly between baseline and 3, 6, and 12 months; height z scores showed no change at 3 months but decreased significantly by 6 and 12 months. This was more significant in the younger and ambulatory children. Subdivision according to diet type showed weight z scores to decrease significantly in the medium-chain triglyceride group only at 3 and 6 months and in both groups at 12 months. Height z scores decreased significantly in both groups by 6 and 12 months. Forty children completed 12 months of treatment; in this group, the slopes of best-fit regression lines of serial z-score measures were used to represent growth trend. There were no significant differences in mean slope between classical and medium-chain triglyceride diet groups for weight, height, or BMI. There was no significant difference in mean calorie intake during the 12 months between the 2 diets, but the medium-chain triglyceride group had significantly higher protein intake. There was no significant correlation between calorie or protein intakes and the slope of the best-fit line for weight, height, or BMI.

Conclusions: Both weight and height z scores decreased during diet treatment. By 12 months, there was no difference in outcome between classical and medium-chain triglyceride protocols despite the increased protein in the latter diet.
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http://dx.doi.org/10.1542/peds.2007-2410DOI Listing
August 2008

The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial.

Lancet Neurol 2008 Jun 2;7(6):500-6. Epub 2008 May 2.

Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, University College London, London, UK.

Background: The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial.

Methods: 145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915.

Findings: 73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62.0%vs 136.9%, 75% decrease, 95% CI 42.4-107.4%; p<0.0001). 28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0.0582). There was no significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes. The most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger.

Interpretation: The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy.

Funding: HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council.
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http://dx.doi.org/10.1016/S1474-4422(08)70092-9DOI Listing
June 2008