Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20

Ketogenic diet and childhood neurological

disorders other than epilepsy: an overview

A Verrotti, G Iapadre, S Pisano & G Coppola

To cite this article: A Verrotti, G Iapadre, S Pisano & G Coppola (2016): Ketogenic diet
and childhood neurological disorders other than epilepsy: an overview, Expert Review of
Neurotherapeutics, DOI: 10.1080/14737175.2017.1260004

To link to this article: http://dx.doi.org/10.1080/14737175.2017.1260004

Accepted author version posted online: 14

Nov 2016.

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Download by: [University of Western Ontario] Date: 16 November 2016, At: 01:49
Publisher: Taylor & Francis

Journal: Expert Review of Neurotherapeutics

DOI: 10.1080/14737175.2017.1260004

Review

Ketogenic diet and childhood neurological disorders other than epilepsy: an overview

Authors: Verrotti A1 , Iapadre G2 , Pisano S3 , Coppola G4 .

1. Department of Pediatrics, University of L'Aquila, San Salvatore Hospital, L'Aquila, Italy. Electronic

address: alberto.verrottidipianella@univaq.it

2. Department of Pediatrics, University of L'Aquila, San Salvatore Hospital, L'Aquila, Italy. Electronic

address: giuliah@live.it

3. Department of Child and Adolescent Neuropsychiatry, University of Salerno, Italy. Electronic address:

pisano.simone@gmail.com
4. Department of Child Neuropsychiatry, University of Salerno, Italy. Electronic address:

gcoppola@unisa.it

Abstract:

INTRODUCTION: In the last years, ketogenic diet (KD) has been experimentally utilized in various childhood

neurologic disorders such as mitochondriopathies, alternating hemiplegia of childhood (AHC), brain tumors,

migraine, and autism spectrum disorder (ASD). The aim of this review is to analyze how KD can target these

different medical conditions, highlighting possible mechanisms involved.

AREAS COVERED: We have conducted an analysis on literature concerning KD use in mitochondriopathies,

AHC, brain tumors, migraine, and ASD.

EXPERT COMMENTARY: The role of KD in reducing seizure activity in some mitochondriopathies and its

efficacy in pyruvate dehydrogenase deficiency is known. Recently, few cases suggest the potentiality of KD

in decreasing paroxysmal activity in children affected by AHC. A few data support its potential use as co-

adjuvant and alternative therapeutic option for brain cancer, while any beneficial effect of KD on migraine

remains unclear. KD could improve cognitive and social skills in a subset of children with ASD.
Keywords:

ketogenic diet , mitochondrial diseases , alternating hemiplegia , brain tumors , migraine , autism

1. Introduction

1.1 Ketogenic diet: composition and metabolism

Ketogenic diet (KD) is high in fat, moderate in protein and low in carbohydrate dietary regimen. Classic KD

is performed on a ratio of grams of fat to grams of protein plus carbohydrate (generally, 4:1, but also 3:1,

2:1, and 1:1 are possible) [1]. Daily energy intake is generally restricted to 80-90% of recommended values.

The classic long chain triglyceride (LCT) diet is the more largely used, even if the medium chain triglyceride

(MCT) type is to prefer in some cases [2]. In fact, MCT oils provide more ketones per kilocalorie of energy,

moreover they are more efficiently absorbed and rapidly transported to the liver; unfortunately, they can

cause more frequently gastrointestinal discomfort [3]. For all these reasons, a modified MCT diet, with 30%

of energy deriving from MCT and 30% from LCT, is more widely accepted [4]. Another form of KD is the

modified Atkins diet (MAD); it includes a ketogenic ratio of 1:1, a very slow and gradual implementation of

carbohydrate daily consumption and no limitations on proteins, fluids and calories, making it easier to

adhere to the dietary regimen [5]. KD can be administered also as an all-liquid, formula based diet, even to
enterally fed children and to infants not yet weaned. Once initiated, KD should be maintained for at least 3

months; if successful, its discontinuation should be considered after a time of 2 years; (greater periods can

be evaluated in children diagnosed with Pyruvate dehydrogenase deficiency (PDHD) or intractable

epilepsy)[4].

1.2 Limitations of Ketogenic diet

As for all medical treatments, KD has also potential adverse effects: fortunately, in most cases, only minor

side effects have been reported (gastrointestinal symptoms, hyperuricemia, hypomagnesemia, renal

calculi, dyslipidemia) [6], which are commonly transient and easy to manage, not requiring KD

discontinuation [4]. Anyway, KD has not the same level of efficacy and safety for different neurological

disorders. There are specific conditions in which KD has been reported as particular beneficial, such as two

distinct disorders of brain metabolism, glucose transporter type 1 deficiency syndrome (GLUT1-DS) and

PDHD. KD has also shown great efficacy in certain epilepsy and genetic syndromes, including Dravet

Syndrome, infantile spasms, myoclonic-astatic epilepsy and tuberous sclerosis complex. In all these medical

conditions, KD can be offered early. On the other hand, KD is contraindicated in many specific disorders of

fatty acid transport and oxidation; therefore, before initiating KD, inborn errors of metabolism that could

lead to a severe metabolic crisis, should be ruled out [4]. Finally, the best candidates for KD should be

appropriately selected, basing on the presence of prerequisites to start the diet in order to ensure safety

and to maximize the chance of success. In this regard, it is crucial counseling families before initiating the

diet, the dietary supplementation, and the management of children on KD with respect to nutrition,

laboratory evaluation, potential adverse effects and possible discontinuation. Thus, a successful

management of children receiving KD requires a strict medical evaluation that must be performed in

experienced specialized centers.

1.3 Ketogenic diet and childhood neurological disorders: an overview

KD is a generally accepted and effective nonpharmacological treatment for children with refractory

epilepsy [2,7-10]. Nevertheless, in the last decade it has been tested for a wide range of neurological
disorders. For example, among the large spectrum of mitochondriophaties, KD is currently considered as

the treatment of choice for PDHD [4]; more recently although based on case studies, KD has been reported

to have positive effect, especially in reducing seizure activity, also in children with respiratory chain

complex (RCC) defects [11] and other mitochondrial diseases. Patients affected by alternating hemiplegia of

childhood (AHC) could benefit from KD, too, as reported in small case series [12-14]. Concerning autism

spectrum disorders (ASD), there are some data suggesting its potential role not only in treating epilepsy

related to autism, but also in modifying clinical course of disease in terms of social and cognitive skills,

although in this field we are at a very early stage [15,16]. Data to support its use as a coadjuvant,

alternative, therapeutic option for malignant brain tumors are available, but still based on small case series

[17-21]. Its efficacy in reducing frequency and intensity of migraine attacks has been reported in few cases,

for which further studies are required [22-24].

The aim of this review is to evaluate advantages and efficacy of KD in some childhood neurologic disorders,

in order to individuate new fields of KD employment for the future.

The article is the result of the analysis of literature concerning the use of KD in various childhood neurologic

disorders starting from 1975. A research has been conducted on PubMed search indexed for MEDLINE and

EMBASE to identify studies using terms “ketogenic diet”, “mitochondrial diseases”, “PDH deficiency”,

“alternating hemiplegia”, “brain tumors” “migraine”, “autism”, as key words. Only articles in English

language have been reviewed and bibliography has been used for the research of other manuscripts of

interest. The date of our latest research was July 2016. We have examined 187 articles focusing on year of

publication, author, pediatric studies, number of patients, and type of articles. The different data have been

compared and evaluated critically by all authors.

2. Ketogenic diet and Mitochondrial Diseases

2.1 Mitochondrial diseases: role of Ketogenic diet

Mitochondrial diseases are a heterogeneous group of genetic disorders affecting different organs (brain,

muscles, heart, etc). They are caused by mutations located in genes either in the mitochondrial DNA

(mtDNA) or in the nuclear DNA (nDNA) which code mitochondrial proteins, leading to mitochondrial

dysfunction [25]. Although for many years mitochondrial diseases have been considered rare diseases,

more recent epidemiological studies suggest that at least 1 in 5000 children can be affected [26]. Though

the prevalence of individual mutations is much higher, approaching 1 in 200 live births, [27,28], but only a

small proportion of individuals harbouring these mutations develops disease [29]. Indeed, because of the

presence of multiple copies of mtDNA in each cell (1000 to 100000), both wild type mtDNA and mutant

mtDNA molecules can coexist in variable amount, a condition known as “heteroplasmy”. Hence, the

biochemical defect in the cell and the phenotypic expression of disease depend on the percentage of

mutant mtDNA which must exceed the tissue-specific critical threshold level. More than 300 mutations

have been reported to be involved in the large spectrum of mitochondrial diseases [30]. Although during

the last two decades, several new mutations of mtDNA and nDNA have been identified, and our

understanding of their underlying pathological mechanisms has been considerably improved, this has not

lead to the development of an effective therapy; in fact, currently no curative treatment exists for

mitochondrial disorders, except for primary deficiency of coenzyme 10.

However, several symptomatic strategies, including dietary measures and changes in lifestyle,

pharmacological treatments and gene therapy can be adopted in order to improve the quality of life and to

achieve a better outcome. Therapeutic strategies available for this group of diseases generally tend to

increase mitochondrial biogenesis, regulate mitochondrial autophagy, inhibit mitochondrial apoptosis,

scavenge toxic compounds, and bypass electron transfer chain defects and nuclear transfer [31].

KD can restrict glycolysis, increase fatty acid oxidation and provide ketones as an alternative fuel source for

cerebral, cardiac and skeletal tissues; then ketone bodies are converted to acetyl-CoA that enters the

tricarboxylic acid (TCA) cycle and is oxidized to feed the respiratory chain (RC) and produce ATP through

oxidative phosphorylation (OXPHOS). Ketosis is also related to an augmented expression of OXPHOS genes,
probably due to a starvation-like response, which would determine the activation of several transcription

factors and cofactors resulting in increased mitochondrial biogenesis [32].

KD has also been shown to influence the heteroplasmy rate in cells harbouring mtDNA mutations, resulting

in the achievement of subthreshold levels. The exposition to ketogenic media of cybrid cell lines led to a

decrease in the heteroplasmy rate of their mutant mtDNA and to a recovery of mitochondrial function [25],

through a process of selective autophagy of mitochondria with a mtDNA mutation, carried out by lysosomal

apparatus [33].

Several mechanisms have been proposed to explain the role of KD in reducing seizure activity; the increase

of mitochondrial ATP production and the decrease of ATP, generated from glycolysis, can determine a

selective activation of ATP-sensitive potassium channel resulting in a stabilizing effect on the neuronal cell

membrane [34,35]. The neuronal hyperpolarization deriving from the disruption of excitatory glutamate

synaptic transmission and the increase of inhibitory γ-aminobutyric acid (GABA) in the cerebral tissue

would stabilize synaptic properties and lead to an increased resistance to epileptiform activity. KD is also

associated with a neuromodulating activity ruled by circulating factors, which could modulate neuronal

excitability altering the extracellular environment. In addition, increased polyunsatured fatty acid levels

could alter membrane composition, activate nuclear receptor proteins and diminish reactive oxygen

species (ROS) production through the upregulation of mitochondrial uncoupling protein activity [34].

For all these reasons, in recent years, it has been hypothesized a potential role of KD in the treatment of

several mitochondrial disorders. Data from literature over the last decades have reported that the

exposition to a ketogenic environment for cultured human cells promoted a heteroplasmic shifting, an

increase in the proportion of non-mutated mitochondrial DNA both among cells (intercellular selection) and

within cells (intracellular selection), and an augmentation of mitochondrial proteins synthesis [36]. Hence,

the effectiveness of KD in mitochondrial diseases due to complex I deficiency could derive from its ability to

increase fatty acid β-oxidation that would shift reducing equivalents to complex II, and would bypass a

deficient complex I [37].

2.2 Ketogenic diet and mitochondrial diseases: data from animal models

KD could have benefic effects even in lethal mitochondrial cardiomyopathy, as shown in a hypomorphic

mouse with a missense mutation of one of the subunits of the Mediator, that showed a significant extend

of the lifespan while on KD [38]. The Mediator is a transcriptional regulatory complex, which is essential for

promoting preinitiation complex assembly. In mice, this kind of mutation causes a progressive and selective

decrease in the transcription of genes necessary for OXPHOS and mitochondrial integrity, resulting in a

progressive cardiomyopathy that invariably leads to cardiac failure. Probably, a small percentage of primary

cardiomyopathies in human pediatric cases could be positively affected by KD in terms of morbidity and

mortality. Also in the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial

myopathy, KD was able to slow down progression of the disease. The authors reported a reduction of the

amount of cytochrome c oxidase negative muscle fibers and a blockage of further mitochondrial

ultrastructural abnormalities in the muscle. These findings can be related to an augmentation of

mitochondrial biogenesis and a restoration of liver lipid levels; nevertheless, no changes have been found in

the rate or the quality of mutant mtDNA [39].

2.3 Ketogenic diet and Pyruvate dehydrogenase deficiency

Among the large spectrum of mitochondrial disease, KD is recommended as treatment of choice for PDHD

[4]. The Pyruvate dehydrogenase complex is a multienzyme complex, which plays a crucial role in cellular

energy metabolism and acid base equilibrium, since it provides the link between glycolysis and the Krebs

cycle. Non-sense mutations in one of its five component enzymes are generally responsible for PDHD; the

most frequently involved subunit is the E1 subunit, which is encoded by the X-linked PDHA1 gene [40]. This

enzyme normally catalyzes the oxidation of pyruvate to acetyl-CoA and its defect can lead to a variety of

clinical presentations ranging from sever infantile lactic acidosis to chronic neurological dysfunction or

ataxia [41], including recurrent demyelination [42]. In these patients, a strict KD should be initiated as soon

as possible, since it provides ketone bodies as alternative sources of acetyl-CoA. In particular, KD was seen

to positively affect the epileptogenesis in PDHD, which is caused by energy failure and abnormal

neurotransmitter metabolism, progressively altering neuronal excitability. The effectiveness of KD in the

PDHD has been documented in some cases [43-47]. In a study conducted among seven boys with E1

deficiency who received KD with varying degrees of carbohydrate restriction, better clinical outcomes in

terms of longevity and improved mental development were seen both for patients who had the diet

initiated earlier in life or for those who were placed on greater carbohydrate restriction, even among

subjects with identical mutations [43]. More recently, a 39-month-old male with a neonatal onset of PDHD,

who failed to adhere to the standard KD, once put on a less restrictive dietary regimen continued to show

clinical progress. He was a child who developed early in life hypotonia, hyporeflexia, growth and motor

delay, and sporadic episodes of seizure-like activity; when the diagnosis of PDHD was made, Thiamine was

started and, at the age of 15 months, KD was introduced resulting in the achievement of seizure and

hyperventilation cessation. Unfortunately, after 6 months, he was no longer able to tolerate the diet and a

less restrictive dietary regimen was initiated; despite this “modified diet” the child gained weight and

continued to show cognitive-behavioural development progress [46]. In another study, a 3-year-old boy

with PDHD was put on KD and obtained considerable results; the patient, presenting with generalized

hypotonia, severe psychomotor development delay, and refractory epilepsy, within 6 months from the

beginning of KD, showed reduction in seizure frequency and improvement in psychomotor development.

Unfortunately, the diet was maintained just for a period of 6 months, when complications occurred

(hypercholesterolemia and hypertriglyceridemia in association with viral respiratory infections) and the

child was forced to interrupt KD [47]. (All case studies are reported in Table 1).

Nevertheless, available data to promote its use are still based on a few uncontrolled case reports; analysing

dietary regimens of proven cases of PDHD over the last decades, a great variability of the percentage of

daily caloric intake from fat and carbohydrate, within and among patients, and a lack of specificity in fatty

acid composition, emerged [48]. In particular, the quantity and the quality of dietary fatty acid composition

could deeply affect the long term safety and efficacy of KD, since tissue insulin sensitivity and plasma

clearance of low density lipoproteins have been correlated inversely with the saturation degree of long

chain fatty acid [49,50]. Moreover, among polyunsatured acids, omega 3 fatty acid are reported to improve

insulin sensitivity of peripheral tissues, decrease serum levels of circulating lipoproteins by inhibiting their
hepatic synthesis and secretion, and turn around the upregulation of piruvate dehydrogenase kinase

activities in heart and skeletal muscle [51]. In addition, long-term complications in children on KD for a

period longer than 2 years have not been systematically reviewed.

2.4 Ketogenic diet and Respiratory Chain Complex defects

Although in the past the use of KD has been avoided in patients with RCC defects [52], more recent studies

have reported good outcomes in terms of seizure rate for individuals with RCC defects treated with KD [53].

In particular, a retrospective study was conducted to investigate the clinical efficacy and safety of KD in 14

refractory epileptic children diagnosed with RCC defects (9 with Complex I defects, 1 with Complex II

defect, 3 with Complex IV defects, and 1 with combined Complex I and IV defects). All patients have been

monitored for at least 6 months from the initiation of KD. Seven individuals achieved seizure freedom with

the introduction of the diet, 3 of whom were able to successfully complete the dietary period without

relapse; 4 patients, including two diagnosed with Leigh disease, did not respond to the diet or were forced

to discontinue KD because of complications [11]. KD had a favorable effect in the treatment of

ophthalmoplegia of a young male aged 7 years with Complex I deficiency; the boy had an early-onset

ophthalmoplegia with a progressive development of cerebellar ataxia, dystonia and spasticity. KD led to an

improvement in ocular palsy, without affecting other neurological findings [54]. Recently, a case of a female

infant with Ohtahara Syndrome, associated with mitochondrial RCC I defect was reported; the baby,

affected by NADH dehydrogenase deficiency, showed epileptic seizures refractory to antiepileptic drugs

(AEDs)-polytherapy. The baby achieved seizures control and cessation of suppression-burst-patterns within

3 months from the beginning of KD; unfortunately, she experimented seizures relapse 2 months after KD

cessation due to maintenance problems [55]. (These data are reported in Table 1).

2.5 Ketogenic diet and other mitochondrial diseases

Favorable outcomes in terms of seizure frequency after KD were reported also for a young girl affected by

Alpers-Huttenlocher Syndrome. At the age of 55 months, while on AEDs polytherapy, the patient presented

epilepsia partialis continua; after the initiation of KD, clinical improvement including increased alertness,
memory function, a return of bladder and bowel control, ability to speak in 3–4-word sentences and to

walk with assistance were reported, in addition to a remarkable EEG improvement. She remained seizure

free for seven months, when an intercurrent infection occurred and she was no longer able to reinitiate

dietary regimen [56].

KD was also reported to improve mitochondrial dysfunction in Mitochondrial Encephalopathy with lactic

acidosis and stroke-like episodes (MELAS), as reported in a case of a 22-year-old Chinese girl. She suffered

from MELAS due to mutation in the MT-TL1 gene, showing recurrent episodes of status epilepticus,

multiple cortical stroke-like episodes, normal development and recurrent headaches. From the introduction

of KD and magnesium supplementation, the patient achieved seizure freedom, a decrease in the frequency

of stroke-like episodes and cortical lesions; she was maintained successfully on KD for 1 year [37]. (All cases

described above are included in Table 1).

2.6 Contraindications to the use of Ketogenic diet

Conversely, KD is not recommended in some specific disorders: in particular, an absolute contraindication

to the use of KD exists for fatty acid transport and β-oxidation disorders, including carnitine deficiency,

carnitine palmitoyltransferase (CPT) I or II deficiency, carnitine translocase deficiency, β-oxidation defects,

pyruvate carboxylase deficiency and porphyria [4]. In fact, carnitine, thanks to the facilitating action of CPT

and carnitine translocase, is responsible for long-chain fatty acid transport across the mitochondrial

membrane. Once in the mitochondria, fatty acid are β-oxidized leading to the formation of two carbon

units of acetyl-CoA which can feed the Krebs cycle and serve for ATP production or ketones generation.

Thus, congenital alteration at any step along this pathway could cause severe catabolic crisis in patients

that are fasting or on KD [57,58]. Similarly, in the pyruvate carboxylase deficiency, a mitochondrial enzyme

catalyzing the conversion of pyruvate to oxaloacetate, KD should be avoided since it would further impair

the tricarboxylic acid cycle activity and energy production, which are already damaged by the lack of the

enzyme. Also in porphyria, a low carbohydrate dietary intake would worsen the course of the disease [59].

2.7 Conclusions
In conclusion, KD is worldwide considered particularly beneficial in PDHD; although the last knowledges

confirm the efficacy of KD in reducing epilepsy frequency, it seems not to deeply modify the progressive

course of mitochondrial disease [60]. Recently, encouraging data about the usefulness of KD in various

mitochondriopathies are emerging; in particular, in RCC defects. (Data from literature are reported in Table

1).

3. Ketogenic diet and Alternating Hemiplegia of Childhood

AHC is a rare neurologic condition. It is characterized by episodes of hemiplegia starting in the first months

of life, various non-epileptic paroxysmal and non-paroxysmal manifestations which lead to a progressive

global neurological impairment [61,62]. Recently, heterozygous mutations in the ATP1A3, the gene

encoding the neuron-specific Na+/K+-ATPase 3 subunit, have been identified as the causal mechanism of

AHC [63-65]; although the disease has also been associated with rare mutations in other genes, such as

CACNA1A, ATP1A2, SCN1A, SLC2A1 and SLC1A3, showing a great genetic heterogeneity. Flunarizine can

reduce severity, duration and frequency of the attacks in some cases [62-66], but no curative treatment

exists. KD and one of its variants, the MAD, have shown efficacy in the treatment of paroxysmal movement

disorders related to GLUT1-DS [67]. GLUT1-DS is a neurological disorder characterized by an impaired

transport of glucose across the blood-brain barrier due to SLC2A1 gene mutation [68]. In GLUT1-DS, KD

provides an alternative fuel source ad its efficacy might be enhanced by its anticonvulsant action.

Moreover, in these patients, KD also has a positive effect on movement disorders such as hypotonia, ataxia,

dystonia, and paroxysmal exertion-induced Dystonia (PED); seizure and movement disorders control can be

achieved by a 2:1 or 3:1 ketogenic ratio [69]. GLUT1-DS and AHC share several paroxystic and

nonparoxystic features so that it has been hypothesized that AHC could benefit from KD, too. According to

this, in a cohort of ten unrelated patients from Spain and Greece, who were diagnosed with AHC, three of

them showed remarkable improvement in the frequency and the severity of the attacks from the

institution of KD [12]. More In detail, one girl who showed no clinical benefits while on flunarizine, at the

age of 11 years started KD and continued the diet for 1 year, reporting notable advances in behavioral and
sociability context. Similarly, in other two patients who showed a poor response to the administration of

flunarizine or benzodiazepines, KD led to a complete cessation of hemiplegic attacks and improvement in

cognitive functions. In another paper, a case of a female child with a diagnosis of familial AHC due to

ATP1A3 p.Asp923Asn maternally inherited mutation was reported. The young girl, presenting

tonic/dystonic and plegic attacks (mostly triggered by exercise), was started on MAD at the age of 3 and 5

months, with a complete disappearing of the attacks for a period of 15 months [13]. Similarly, a 10-year-old

girl (with AHC harboring a de novo mutation in the ATP1A3 gene, together with a duplication and insertion

in the SLC2A1 gene), showed a great clinical improvement while on KD. After an ineffective flunarizine

therapy, KD led to a marked decrease in frequency, length and intensity of paroxysmal events, in addition

to changes in hemiplegic attacks, which became less frequent [14]. (The three case studies are included in

table 2).

In the reported cases of AHC, the decision to start KD has been generally made empirically, before

molecular diagnosis was established. It was found to be more effective in patients with frequent

paroxysmal attacks who poorly responded to other conventional treatments. The successful use of KD was

reported especially for patients carrying mutations in ATP1A3, sharing clinical features with GLUT1-DS, one

of them harboring a SLC2A1 rare variant.

The rationale for the use of KD therapy in AHC has not been yet clarified; nevertheless, reasons to

encourage its use are based on findings of impaired cerebral glucose metabolism as detected by FDG-PET

studies in a cohort of Japanese AHC patients [70] and the potential role of KD in reducing neuronal

excitability. In fact, this is altered in AHC, due to ATP1A3 dysfunction; hence, the stabilizing effect on

neuronal membrane would lead to less frequent and severe paroxysmal activity in AHC.

4. Ketogenic diet and brain tumors

Brain tumors are the most frequent solid-type tumors and have the highest mortality rate amongst all

forms of pediatric malignant tumors. The main tumor types described are glial tumors followed by Primitive

Neuroectodermal tumors or PNET, Plexus Choroid tumors and Craniopharyngiomas.

Medulloblastoma is the most common form of brain tumors in children, comprising almost 25% of all

central nervous system (CNS) malignant tumors before the age of 15 years. This tumor may have the onset

at any age (birth up until adulthood), but the majority is diagnosed between 5 and 10, with a male

predominance of 2:1.

Half of all CNS tumors are glial tumors. The overall 5-year survival for malignant gliomas, which infiltrate

the brain stem, is approximately 0% and for optical pathway low-grade gliomas is approximately 90%.

Survival for CNS tumors improved significantly from 57% to 65% [71]. However, brain tumors represent the

first cause of death from disease in children and adolescents; malignant tumors in general being the second

cause of death in this age group after accidents [72,73].

Beyond the classical treatment options for brain tumors including extensive surgical resections,

chemotherapy, radiotherapy and surgical treatment of tumor complications( raised intracranial pressure

and obstructive hydrocephalus), in the last years, there is a growing evidence for the anticancer,

antiangiogenic and proapoptotic effect of disrupting glycolytic metabolism through dietary intervention

[74].

There may be a possible link between some pediatric brain tumors and mitochondriopathies. Recent

studies have reported that mitochondrial genome and tumor proteome are important factors contributing

to brain tumor risk in children. Indeed, findings from these studies [75] on pediatric tumor brain samples

including protein expression, mtDNA sequence variation, mtDNA copy number variation and oxidative

damage, have shown that these factors may have a significant contribution in the development of pediatric

brain tumors.

4.1 Ketogenic diet and brain tumors: animal based studies

KD has been suggested as adjunctive or alternative option for the treatment of brain tumors, such as

gliomas. Experimental studies on the effect of ketogenesis in animal models of brain tumors seem to

support the potential efficacy in humans [76-80]. In a study [76], a calorie restricted KD supplemented with

a low dose of 2-deoxy-D-glucose (25 mg/kg) reduced the CT-2A malignant mouse astrocytoma more than a

dietary restriction or 2-DG alone, indicating a synergistic interaction between the drug and the diet. Overall,

in these animal models, a calorie restricted diet showed to be effective as an alternative therapeutic option

for malignant brain cancer. In other three studies of glioma models [77,78,80], effects of KD were assessed

in immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma. In the first study [77]

patterns of gene expression were compared in tumors vs normal brain from animals fed either with KD or

with a standard diet. Animals received intracranial injections of bioluminescent GL261-luc cells and tumor

growth was monitored in vivo. KD treatment significantly reduced the rate of tumor growth and was

associated with prolonged survival. Moreover, KD decreased ROS production in tumor cells, altered also the

gene expression involved in modulating ROS levels, including those as cyclooxygenase 2, glutathione

peroxidases 3 and 7, and pyroredoxin 4. In the second study [78] KD decreased tumor microvasculature and

expression of vascular endothelial growth factor receptor 2 and other tumor growth markers. In the third

study [80], KD significantly enhanced the anti-tumor effect of radiation, suggesting a potential use as an

adjuvant to the current standard of care for the treatment of human malignant gliomas. More recently, KD

has not been able to suppress tumor growth in a genetically engineered mouse model of medulloblastoma

[79]; indeed, serum insulin was significantly decreased in mice fed with KD, with no effect on PI3 kinase

activity.

4.2 Ketogenic diet and brain tumors: human based studies

Clinical studies found their rationale and support on pre-clinical studies in mouse models of brain tumors;

in fact, heightened glycolysis, even in the presence of oxygen and reduced use of ketone bodies, are

specific features of tumoral cells [79]. Few evidences in small series or single cases in human population

(especially in adults, more rarely in children) are available [17-21]. Of five patients with advanced brain

tumors and favorable response [17,18], 3 were children affected, respectively, by anaplastic astrocytoma
stage IV, cerebellar low-grade astrocytoma grade III, and juvenile pilocytic astrocitoma. All three children

aged three and half, five, and eight responded to the diet, showing remission of five, four and one year,

respectively. One child, aged 3 and half, received KD as monotherapy, while the other two were on

simultaneous multimodal therapy. The duration of response in the remaining two adult patients with

malignant glioblastoma lasted about 4 months. It is noteworthy that in one patient a rapid tumor

regression was observed two months after starting a KD (600 kcal/day) associated with a mean blood

glucose of less than 60 mg/dl, whereas MRI evidence of tumor recurrence was found 10 weeks after the

diet discontinuation. In further 20 adult patients with recurrent glioblastoma treated with a not-rigidly

calculated and not supervised KD [19], three patients discontinued the diet for poor tolerability, two had a

stable disease and one had a minor response after 6 weeks. Median progression-free survival of all patients

was 5 weeks (range, 3-13) and median overall survival from the start of the diet was 32 weeks. A trend

towards an increase in progression-free survival was reported in patients with stable ketosis compared to

others. Globally, KD was demonstrated to be feasible and safe.

A retrospective review [20] of 53 patients with high-grade glioma, revealed that 6 of them were

additionally fed with a KD during treatment, including radiotherapy and chemotherapy. Four of six patients

were alive at a median follow-up of 14 months. No major side effects due to KD have been reported in any

of these patients. In another retrospective small study [81], which included five children with Tuberous

Sclerosis Complex, three of them had progression of a known tumor or tumors or the development of a

new tumor while on KD. More recently, in two adult patients, aged 55 and 52 years, with malignant

glioblastoma [21] treated with KD after therapeutic failure with standard treatments (including tumor

excision, radiotherapy and chemotherapy), clinical and radiological evidence of tumor progression has been

reported after 4 and 12 weeks, respectively. Possible explanations of KD failure were the difficulty in

keeping low blood sugar levels, a positive expression of ketolytic mitochondrial enzymes such as BDH-1 and

OXCT-1 in tumor tissue with persisting ability of cancer cells to metabolize ketones and deriving energy for

subsequent growth. (All data are reported in Table 3).

5. Ketogenic diet and migraine.

Headache is the most frequently reported somatic disorder in children and adolescents. Headache

prevalence in pediatric age is highly variable, ranging between 5.9% and 82%. The primary headaches are

the most common, and include migraine with and without aura, tension-type headache and, exceptionally,

cluster headache. Migraine headache [82] typically lasts from hours to several days with prominence of

nausea and/or vomiting, photophobia and phonophobia. In children, however, migraine headache is

commonly localized bifrontally or bitemporally and is usually of shorter duration if compared to adults. A

waxing and waning dull pain, distributed as a “hat band”, usually allowing the child to continue his daily

activities, characterizes the tension-type headache. The international headache society classification

differentiates a sporadic (<12 attacks a year), a frequent (1-15 days a month) and a chronic (>15 days a

month) form of tension-type headache [83,84].

Management of primary headache disorder in children is based on acute therapy of migraine attacks and

on a pharmacological prophylaxis to be started when migraine attacks are more than 4/month and if no -

pharmacological measures have failed. The latter have usually significant success rates in juvenile headache

disorders, comprising general measures like life style modification, measures of behavioural medicine,

relaxation techniques, biofeedback programs, cognitive-behavioural therapy (extended also to parents),

and avoidance of trigger factors. A potential role of dietary treatment (i.e. KD) in migraine disorder has

been supposed. In fact, recent studies have suggested that at least some subtypes of migraine may be

related to mitochondrial defect. Such a relationship between mitochondria and migraine relay upon

deficient OXPHOS, mitochondrial morphological abnormalities and genetic evidence including specific

mtDNA mutations and polymorphisms [85]. Furthermore, it has been hypothesized that there may be a

different epigenetic status including mitochondrial methylation between healthy controls and individuals

with migraine [86].

5.1 Ketogenic diet and migraine: clinical studies

Recently, few reports are available on the potential role of KD in patients with overweight/obesity and

recurrent headache, in whom several prophylactic treatments had failed. The rationale may be linked to

the modulation of cortical excitability by ketone bodies [87], dampening of inflammation,

neuroinflammatory phenomena [88], inhibition of oxidative stress (leading to a reduced free radical

formation) in neurons [89] and to cortical spreading depression phenomena [90]. More in detail, KD was

found to be effective in improving high-frequency migraine without aura in two 47-year-old twin sisters

who were taking the diet in order to lose weight [22]. Before starting the diet, both patients experienced an

average of 5-6 attacks/month of severe headache with related symptoms, including phono-photophobia,

nausea and occasional vomiting. Several prophylactic treatments had failed in the past. According to the

dietary protocol, a ketogenic regimen was adopted for repeated 4-week cycles separated by two-month

interval during which patients followed a transitional low-calorie, non-ketogenic low-carbohydrate diet.

Both sisters, using headache diaries, experimented the disappearance of migraine concomitantly with each

ketogenic period. Migraine improvement seemed to be more linked to ketogenesis and less probably to the

weight loss itself. Following this observation, the same Authors recruited from a diet clinic 96 overweight

females suffering from recurrent migraine attacks [23]. Patients were randomized to a KD (n=45) or a

standard diet (n= 51) prescription. At baseline and at 6-month follow-up, the following variables were taken

into consideration: baseline attack frequency, number of days with headache, and tablet intake per month.

In the KD group, all these variables were significantly reduced after the first month of diet. After a slight

worsening of each variable in the second month, there was a sustained improvement up to month 6, as

compared to standard diet group. KD efficacy in migraine disorder could be related to its ability to enhance

mitochondrial energy metabolism and counteract neural inflammation. In a previous prospective, open-

label study [24], 8 adolescents, aged 12-19 years, with chronic daily headaches (minimum of 15 headaches

per week) for at least 3 months’ duration, were treated with MAD. All patients had failed at least two

pharmacological preventative drugs prior to enrollment. Adolescents were restricted to 15 g/day of

carbohydrates. Three patients (38%) completed the 3-month period study, while the other five

discontinued because of lack of efficacy and restrictiveness. None had any reduction in headache

frequency. These results could be due to the difficulty of carrying on such a restrictive dietary regimen in
teenagers, who are probably poorly motivated by being normal weight at baseline. Anyway, also this

conclusion can not be firmly drawn, since the efficacy of KD in migraine has not yet been proven and is

currently not supported by consistent data. (All data are reported in Table 4). Furthermore, no data are

available so far for headache in mitochondriopathies treated by KD.

6. Ketogenic diet and Autism

ASD, according to the latest version of the DSM-5, includes all syndromes and clinical conditions defined

previously as pervasive developmental disorders in DSM-IV-TR. New diagnostic criteria for ASD are: a)

persistent deficits in social communication and social interaction across contexts; b) restricted, repetitive

patterns of behaviour, interests, or activities; c) symptoms must be present in early childhood (but may not

become fully manifest until social demands exceed limited capacities; d) symptoms limit and impair

everyday functioning [91].

In order to improve social interaction and communication, the most effective intervention program is

worldwide considered the applied behavioural analysis; while among the evolutionary approaches, the

Denver model has given promising results. As for the pharmacological intervention, literature is unanimous

in recognizing that no specific drugs for ASD treatment are so far available [92]. Therefore, antipsychotics

are among the most widely used drugs for treating challenging behaviours in these subjects (hyperactivity,

inattention, compulsions and rituals, mood swings, irritability, self- and hetero- aggressiveness, sleep

disorders). However, such drugs are often disappointing and ineffective, also resulting in not negligible side

effects [93].

For this reason, KD has been recently introduced, with the aim of decreasing severity of challenging

behaviours and improving mood stability in these patients. The rationale is, basically, the same of headache

disorder. Indeed, as for the relationship between KD and ASD, we need to distinguish the role of KD in the

treatment of seizures associated with ASD, the use of the KD in the treatment of the core symptoms of ASD

and, the KD in animal models of autism.

6.1 Ketogenic diet and animal models of autism

Clinical data about the potential role of KD in autistic disorder are substantiated by experimental mouse

models of autism. In mouse models of ASD ,i.e., Rett syndrome [94], BTBR model [95], and prenatal valproic

acid (VPA) model of ASD [96], the use of the KD has improved behavioural abnormalities (increased

sociability and decreased self-directed repetitive behavior) and/or decreased the number of seizures,

normalized ataxia, and increased life span of mutant mice. However, while KD was originally designed to be

administered under controlled caloric intake, most of the mouse studies have been performed under ad

libitum conditions and/or for a relatively short period [95]. In another study, pregnant animals received a

single-intraperitoneal injection of 600 mg/kg VPA. In the offspring group fed with KD, there were

improvements in social behaviour. In fact, these mice displayed higher scores in sociability index and social

novelty index when compared with the VPA mice fed with a standard diet [96].

6.2 Ketogenic diet and seizure associated with autism spectrum disorder

It is well established that individuals with ASD have higher prevalence of epilepsy and/or subclinical

epileptic discharges (SEDs), compared to healthy individuals [97]. Although the exact relationship to the

etiology of ASD remains to be further defined in many cases, epilepsy is associated with higher rates of

intellectual disability [98], more severe ASD symptoms [99], and higher rates of mortality [100], especially

if it continues into adulthood. The underlying causes of epilepsy are often related to genetic [101] and/or

metabolic abnormalities found in ASD individuals.

Among ASD population, it is then necessary to distinguish two subgroups: ASD children with SEDs and those

with ASD and epilepsy. Both groups share similar features including more frequent regression, neurological

and brain MRI abnormalities. Indeed, children with ASD and epilepsy have more severe intellectual

disability and more severe socialization and hyperactivity disorders, compared to those with SEDs only.

Furthermore, two neuropathological findings are shared by ASD and epilepsy: abnormalities in minicolumn

architecture and GABA neurotransmission [102], as reported in medical conditions associated with both
epilepsy and ASD, including specific genetic syndromes, specific metabolic disorders and immune

dysfunctions.

On the other hand, KD has a long and successful history for treating refractory epilepsy, showing an effect

comparable to AEDs [103]. In a retrospective case-control survey study [104], based on parental

perceptions of effectiveness, KD was rated as being the most favorable non-AEDs treatment in improving

seizures, and was also rated as providing favorable effects on other important clinical factors related to

ASD. More in detail, responses were obtained in 733 children with seizures. In general, AEDs (mainly VPA,

levetiracetam, lamotrigine and ethosuximide) were perceived to decrease seizure frequency, but worsened

other clinical factors. Conversely, some non-AEDs treatments such as KD, were reported to have favorable

effects both on seizures and on other clinical features as behaviour disorders. In particular, a single case

study [105] reports the administration of a gluten-free casein-free modified KD (1.5:1 lipid: non-lipid ratio;

medium- chain and polyunsaturated fatty acids) for a period of 14 months to a 12-year-old child with ASD,

seizures, medical comorbidities associated with a family history of metabolic and immune disturbances.

Because of improvements in seizure activity, electroencephalogram pattern, cognitive and social skills,

language function, and complete resolution of stereotypies, anticonvulsant medication doses were reduced

without worsening of seizures. Notably, the administration of the diet was accompanied by a wealth of

medications, a significant weight loss, and transitioning to puberty; for all these reasons, it is difficult to

evaluate the role of KD.

6.3 Ketogenic diet and core symptoms of autism spectrum disorder

Concerning the use of KD in the treatment of children with autistic behaviour, the literature remains largely

limited to a prospective pilot study [15], with a group of 30 children aged between 4 and 10 years, with

autistic behavior. The John Radcliffe diet (a modified medium-chain triglyceride diet with a caloric

distribution of 30% in medium-chain triglyceride oil, 30% fresh cream, 11% saturated fat, 19%

carbohydrates, and 10% proteins, with a ratio between fat /protein and CHO varying between 3:1 to 4:1)

was administered for 6 months, with intervals of 4 weeks interrupted by two diet-free weeks. Of the 30

children, 40% did not comply or did not tolerate the diet. From the remaining 60%, two children with
milder autistic behaviours showed the highest improvement (as judged by total Childhood Autism Rating

Scale score) in concentration and learning abilities, social behavior and inter- actions, while the others

showed mild to moderate improvement. Interestingly, the beneficial effects of KD persisted even after

termination of the trial. Six of the children enrolled in this study had a higher baseline ketonemia with no

apparent PDH and/or RCC deficiencies. Anyway, it is not clear if any of the other patients underwent this

screening, in addition to the lack of the inclusion of a control diet before administering the KD to the ASD

group or during the trial. Authors, therefore, stated that there was some evidence for KD to be a potential

alternative or additional treatment at least in a subset of children with ASD. Currently, no relationship can

be drawn between diet type and clinical findings. Another study [16] performed a detailed metabolic

screening in a Greek cohort of 187 of ASD patients revealing biomarkers such as urine 3-hydroxiisovaleric

acid and serum B-OH-B in 7% of patients for whom biotin supplementation or a KD prescription resulted in

mild to significant clinical improvement in autistic features. These preliminary data seem to suggest that at

least a subset of patients with ASD may benefit from dietary treatment with KD, showing improved learning

abilities and social skills. (All data are reported in Table 5).

7. Expert commentary

The use of KD for childhood neurological disorders other than epilepsy is constantly increasing. In the last

years, the particular metabolic state induced by KD has been widely studied; theoretical basis for the

efficacy of KD have been provided for many disorders. In particular, KD can be an effective therapeutic tool

for several mitochondrial-based diseases; according to this, there is a large evidence for KD to improve

mitochondrial functioning and induce mitochondriogenesis.

Mitochondrial dysfunction is nowadays recognized as central in many medical conditions, including

neurodegeneration, inflammation, cancer, etc. Among the large and heterogeneous spectrum of

mitochondriopathies, KD is still recommended as first line therapy for PDHD, in which the diet shows

efficacy in reducing epilepsy rate, but seems not to deeply modify the course of disease; single cases or
small case series support its beneficial employment also in some RCC defects and MELAS. In fact, thanks to

its capacity of neuromodulating and its stabilizing effect on neuronal membrane, KD is able to reduce

seizure activity in several and different conditions. This could led to a decrease not only in epilepsy rate in

various mitochondriopathies, including RCC defects, but also in children diagnosed with ASD, for whom

latest studies suggest that KD could even influence social and cognitive skills, including ASD core symptoms,

at least in a subset of patients.

Nonetheless, it should be emphasized that the few available studies are mostly experimental or based on

questionnaires to parents, while the effects of KD should be more properly evaluated, for example, by

means of semi-structured tests (eg. ADOS) for a more accurate assessment of changes on autism’s core

symptoms.

Data supporting any potential role of KD in improving migraine are available, but still based on small case

series. In this field, there is a strong need for KD to be further assessed in randomized controlled trials

(RCT).

Moreover, thanks to its anticancer, antiangiogenic and proapoptotic properties, KD could represent an

adjunctive or alternative option for the treatment of malignant brain tumors. In this topic, we probably are

at a very early stage; more accurate data on the potential benefit of KD can only come from RCT studies

(not easy for ethical reasons) in homogeneous populations by age, type of cancer, timing at diet onset (eg.

as early as diagnosis has been made), in addition to conventional treatments.

Finally, recent data suggest the potential role of KD in children diagnosed with AHC; in some of these

patients, KD seems to improve the clinical course of disease, especially thanks to its emerging capacity of

reducing paroxysmal activity. Anyway, at present, these data are still based on a few reported cases.

8. Five-year view

Among mitochondrial disease, KD is currently considered as first line therapy in PDHD. Nevertheless, its use

is based on reports of a few children affected by PDHD, who improved dramatically while on KD; in
addition, these reports did not provide detailed information about the caloric distribution of nutrient

components. For all these reasons, more detailed systematic studies are requested, in order to achieve a

better compliance of the patients to the diet, and to investigate the effect of both standard and less

restrictive KD on long-term outcomes. Also concerning the emerging role of KD in other

mitochondriopathies, including RCC defects, although some studies have suggested its efficacy as a

therapeutic tool, we believe that more clinical trials are needed in order to clarify pathophysiologic

mechanisms underlying these kinds of diseases and thus to determine which individuals are more likely to

benefit from KD. Actually, KD could be proposed cautiously with regard to its side effects and in the

absence of definitive evidence for its real efficacy. For some mitochondriopathies, the use of KD is still

based on animal models or in vitro experimental; further studies which would investigate KD efficacy in

vivo or among human population, are needed.

At the moment, the use of KD is being investigated with promising results, even in other previously

discussed neurological conditions: in patients affected by AHC, KD has shown positive effect in attenuating

paroxysmal activity and we expect an expanding use of the diet also in other similar and emerging

conditions; for which, further studies, including larger populations, are warranted. With regard to

malignant brain tumors, given the multitude of simultaneous variables that must be considered in this field,

KD could be proposed as a co adjuvant-therapy depending on the clinical pattern and the extent of the

disease; however, larger case series should be provided. The same for migraine and ASD, for which initial

data supporting the potential usefulness of KD, should be confirmed by, at least, well conducted open

studies.

Next years will probably witness an expanding investigation of KD role in emerging various medical

conditions, through more structured, human based studies.

 9. Key issues

• KD represents the treatment of choice for PDHD.

• Emerging data from literature suggest its potential role on reducing seizure activity and
achieving better clinical outcomes in various mitochondrial diseases, including RCC defects.
• Alternating hemiplegia could benefit from KD, especially concerning paroxysmal activity.
• In addition to its efficacy in decreasing epilepsy rate in children with ASD, KD could improve
cognitive and social skills in children being affected.
• Thanks to anticancer, antiangiogenic and proapoptotic properties, KD could represent an
adjunctive or alternative option for the treatment of brain tumors.
• KD could be effective in reducing intensity and frequency of migraine attacks in selected cases,
although available data are still few.
• In addition to its potential efficacy in decreasing seizure frequency in children with ASD, KD
looks promising in improving cognitive and social skills in autistic children, though well-
conducted clinical studies are currently missing.
• Before starting KD, inborn errors of metabolism should be carefully investigated and excluded.

Funding

This paper was not funded.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants
or patents received or pending, or royalties.

Table 1. Effect of Ketogenic diet in the treatment of mitochondriopathies.

Study Type of Type of KD Patients KD duration Outcome

Mithocondriopahies enrolled (n)

Wexler et al. (1997) PDHD KD with different 7 boys variable favorable (increased
degrees of CHO (ranging from 4 longevity and improved
restriction (3:1, 2:1, months to 14 mental development)
 1:1 ratio) years)

Falk et al. (1976) PDHD Less restrictive KD 2 boys not well defined favorable (increased rate
(<1:1 ratio) of growth, development,
strength, endurance)

Wijburg et al. (1992) Leigh disease associated KD (1:1 ratio) 1 boy 2 years favorable (clinical and
with PDHD biochemical amelioration,
striking improvement of
cerebral lesions)

El-Gharbawy et al. PDHD Classic KD (3:1 1 boy 6 months on favorable (seizures

(2011) ratio) and less classic KD, 1 cessation, cognitive and
restrictive KD year on less behavioural progress)
restrictive KD

Di Pisa et al. (2012) PDHD Classic KD 1 boy 6 months favorable (reduced

seizure frequency,
improvement in
psychomotor
development)

Kang et al. (2007) RCC defects Classic KD (4:1 14 children 6 months favorable ( 7 patients:
ratio) seizures free, 2 patients:
9: Complex I, reduction of seizures
1: complex II, frequency)

3: complex IV,

1: combined I not favorable (4 patients:

and IV complex not response to KD or not
defects able to complete KD)

Laugel et al. (2007) RCC I defect KD (3:1 ratio) 1 boy 2 years favorable (improvement
in ocular palsy)

Seo et al. (2010) Ohtahara Syndrome KD (2:1 ratio) 1 female infant Not specified favorable (partial seizure
associated with RCC I (at least 3 control)
defect months)

Joshi et al. (2009) Alpers-Huttenlocher Classic KD (4:1 1 girl 7 months favorable (seizure control,
Syndrome ratio) improvement in
psychomotor
development)

Steriade et al. (2014) MELAS Modified KD not 1 girl 1 year favorable (seizure
well defined cessation, decreased
frequency of stroke-like
episodes)
 KD: ketogenic diet; PDHD: Pyruvate dehydrogenase deficiency; RCC: Respiratory chain complex;

MELAS: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. CHO: Carbohydrates

Table 2. Effect of Ketogenic diet in the treatment of alternating hemiplegia of childhood.

Study Mutations involved Type of KD Patients KD duration Outcome

enrolled (n)

Vila-Pueyo et al. ATP1A3 (patients 1 and Not available 3 patients Variable (1-2 Favorable (reduction in
(2014) 2) years) the frequency and
severity of the attacks,
ATP1A3 + CACNA1A improvement in cognitive
(patient 3) functions)

Roubergue A et al. ATP1A3 MAD 1 girl 15 months Excellent (complete

(2015) disappearing of the
attacks)

Ulate-Campos et al. de novo mutation in the KD (ratio 4:1) 1 girl 4 years Favorable (reduction in
(2014) ATP1A3 gene with a the frequency and
duplication and insertion severity of the attacks,
in SLC2A1 gene improvement in motor
function)

AHC: alternating hemiplegia of childhood; KD: ketogenic diet; MAD: modified Atkins diet;
Table 3. Effect of ketogenic diet in the treatment of brain tumors.

Brain Tumors
Study Type of Type of KD Patients KD duration Outcome
tumor enrolled (n)

Nebeling et Advanced Classic KD 2 pediatric 8 weeks Favorable in 1 patient,

al. (1995) stage females free of disease
malignant progression up to 12
Astrocytoma months
tumors
Rieger J Recurrent carbohydrate 20 adults (13 F, 7 6 weeks Moderate at best: 3
(2014) glioblastoma intake to 60 M) patients, stable disease
g/day, highly up to 11, 12, 13 weeks,
fermented possible synergistic
yoghurt drinks effect with other
(500 ml per therapies
day) and two
different plant
oils (basic oil
and addition
oil)
Champ CE Glioblastoma Classic KD Retrospective Not available Favorable: 4 patients
et al. multiforme analyses of 53 alive at a median follow
(2014) patients, 6 of up of 14 months
whom received KD
Schwartz K Glioma Classic KD 2 12 weeks Unfavorable: both
et al. patients progressed
(2015) their tumor (one after 4
weeks, one after 12
weeks)

KD: ketogenic diet.

Table 4. Effect of Ketogenic diet in the treatment of migraine.

Migraine
Study Severity Type of Patients KD duration Outcome
of KD enrolled (n)
migraine
Di Lorenzo 5-6 attacks weight- 47 years old 4-week cycles Favorable: migraine
et al. per month loss KD twin sisters separated by two- disappeared during each
(2013) (up to 72 KD period (from day 3 of
month intervals
hours of KD start) and returned
duration) during the transitional
diet periods, albeit with
reduced frequency,
duration and intensity.

Di Lorenzo Not very-low- 45 (KD group), 4 weeks followed Favorable: migraine

et al specified calorie KD 51 (SD) by 5 months of SD improved in the KD
(2015) group (attack frequency,
days with headache,
tablet intake) during the
KD period and worsened
after the transition to SD
Kossof et 15 MAD 8 adolescents 12 weeks Indifferent: no effect on
al. (2010) headaches headache frequency
per week for
3 months

KD: ketogenic diet; MAD: Modified Atkins Diet; SD: standard diet.

Table 5. Effect of ketogenic diet in the treatment of Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD)

Study Assessment Patients Type of KD duration Outcome

enrolled (n) KD
Frye et al Seizures Survay of 733 Not Not reported Favorable: KD was
(2011) associated to parents of reported perceived to improve
ASD subjects with seizures as well as other
ASD symptoms

Herbert et Seizures 1 patient gluten- 14 months Favorable: seizure free,

al. (2013) associated to free improvement in mood
ASD casein- and behaviour,
free stereotyped behaviours,
ketogenic social skills and language
diet function

Evangeliou ASD symptoms 30 children John 6 months, with Significant improvement

et al. intervals of 4 (assessed with CARS) in 2
(2003) Radcliffe weeks patients, average
interrupted by improvement in 8
diet two diet-free patients, minor
improvement in 8
 weeks patients

Spilioti et ASD symptoms 6 children with Classic Not reported Favorable in 1 patient
al. (2013) pathologically KD with remarkable
increased beta- improvement in CARS
hydroxybutyrate score; 5 patients: subtle
and lactate improvement
following
glucose loading
test

KD: ketogenic diet. ASD Autism Spectrum Disorder; CARS: Childhood Autism Rating Scale

References

Reference annotations

* Of interest
** Of considerable interest

1. Branco AF, Ferreira A, Simões RF, et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J

Clin Invest. 2016;46:285-98

2. Neal EG, Chaffe H, Schwartz RH, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomized

controlled trial. Lancet Neurol 2008;7:500-6

3. Liu YM and Wang HS. Medium-chain triglyceride ketogenic diet, an effective treatment for drug-resistant epilepsy

and a comparison with other ketogenic diets. Biomed J 2013;36:9-15

4. ** Kossoff E, Zupec-Kania B, Amark P et al. Optimal clinical management of children receiving the ketogenic diet:

recommendations of the International Ketogenic Diet Study Group. Epilepsia 2009;50:304–17

A paper of great interest: the first attempt to create a consensus statement regarding the clinical management of

KD.

5. Wibisono C, Rowe N, Beavis E, et al. Ten-year single-center experience of the ketogenic diet: factors influencing

efficacy, tolerability, and compliance. J Pediatr 2015;166:1030-6 e1

6. * Kang HC, Chung DE, Kim DW, Kim HD. Early- and late-onset complications of the ketogenic diet for intractable

epilepsy. Epilepsia 2004;45:1116-23

A manuscript of high value regarding side effects of KD for intractable epilepsy.

7. Coppola G, Verrotti A, Ammendola E, et al. Ketogenic diet for the treatment of catastrophic epileptic

encephalopathies in childhood. Eur J Paediatr Neurol. 2010;14:229-34

8. Groomes LB, Pyzik PL, Turner Z, et al. Do patients with absence epilepsy respond to ketogenic diets? J Child Neurol

2011;26:160-5

9. Kossoff EH, Rowley H, Sinha SR and Vining EP. A prospective study of the modified Atkins diet for intractable

epilepsy in adults. Epilepsia 2008;49:316-9

10. ** Kim DY, Simeone KA, Simeone TA, et al. Ketone bodies mediate antiseizure effects through mitochondrial

permeability transition. Ann Neurol 2015;78:77–87

A study of notable interest investigating physiopathological mechanisms beyond anti-seizure effects of ketone

bodies.

11. ** Kang HC, Lee YM, Kim HD, et al. Safe and effective use of the ketogenic diet in children with epilepsy and

mitochondrial respiratory chain complex defects. Epilepsia 2007;48:82-8

A study assessing the safety and efficacy of KD in RCC defects, a new field of growing interest.

12. Vila-Pueyo M, Pons R, Raspall-Chaure M, et al. Clinical and genetic analysis in alternating hemiplegia of childhood:

Ten new patients from Southern Europe. J Neurol Sci 2014;344:37–42

13. Roubergue A, Philibert B, Gautier A, et al. Excellent response to a ketogenic diet in a patient with alternating

hemiplegia of childhood. JIMD Rep. 2015;15:7-12

14. Ulate-Campos A, Fons C, Artuch R, et al. Alternating hemiplegia of childhood with a de novo mutation in ATP1A3

and changes in SLC2A1 responsive to a ketogenic diet. Pediatr Neurol. 2014;50:377-9

15. Evangeliou A, Vlachonikolis I, Mihailidou H, et al. Application of a ketogenic diet in children with autistic behavior:

pilot study. J Child Neurol. 2003;18:113-8

16. Spilioti M, Evangeliou AE, Tramma D, et al. Evidence for treatable inborn errors of metabolism in a cohort of 187

Greek patients with autism spectrum disorder (ASD). Front Hum Neurosci 2013;7:858

17. Nebeling LC, Miraldi F, Shurin SB, Lerner E. Effects of a ketogenic diet on tumor metabolism and nutritional status

in pediatric oncology patients: two case reports. J Am Coll Nutr 1995;14:202–8

18. Kalamian M, Zupec-Kania B, Favara BE, Liepa GU. Ketogenic diet as adjunctive therapy for brain tumors. First

international symposium on the ketogenic diet for epilepsy and other neurological disorders Barrows Neurological

Institute, Phoenix Az 2008: Poster presentation

19. Rieger J, Bähr O, Maurer GD, et al. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol

2014; 44:1843-52

20. * Champ CE, Palmer JD, Volek JS, et al. Targeting metabolism with a ketogenic diet during the treatment of

glioblastoma multiforme. J Neurooncol 2014;117:125-31

A manuscript of great interest because of recent knowledges about KD and malignant brain tumors.

21. Schwartz K, Chang HT, Nikolai M, et al. Treatment of glioma patients with ketogenic diets: report of two cases

treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab

2015 25;3:3

22. Di Lorenzo C, Currà A, Sirianni G, et al. Diet transiently improves migraine in two twin sisters: possible role of

ketogenesis? Funct Neurol 2013;28:305-8

23. Di Lorenzo C, Coppola G, Sirianni G, et al. Migraine improvement during short lasting ketogenesis: a proof-of-

concept study. Eur J Neurol 2015;22:170-7

24. Kossoff EH, Huffman J, Turner Z, Gladstein J. Use of the modified Atkins diet for adolescents with chronic daily

headache. Cephalgia 2010;30:1014-6

25. Di Mauro S, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol.

2013;9:429-44.

26. Schaefer AM, McFarland R, Blakely EL, et al. Prevalence of mitochondrial DNA disease in adults. Ann Neurol.

2008;63:35–9.

27. Elliott HR, Samuels DC, Eden JA, et al. Pathogenic mitochondrial DNA mutations are common in the general

population. Am J Hum Genet. 2008;83:254–60.

28. Chinnery PF, Johnson MA, Wardell TM, et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann

Neurol. 2000;48:188–93

29. Kisler JE, Whittaker RG, McFarland R. Mitochondrial diseases in childhood: a clinical approach to investigation and

management. Dev Med Child Neurol. 2010;52:422–33

30. Govindaraj P, Khan NA, Gopalakrishna P, et al. Mitochondrial dysfunction and genetic heterogeneity in chronic

periodontitis. Mitochondrion 2011;11:504–12

31. Viscomi C, Bottami B, Zeviani M. Emerging concepts in the therapy of mitochondrial disease, Biochimica

Biophysica Acta, 2015

32. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell 2012;148:1145–59

33. Gilkerson RW, De Vries RL, Lebot P, et al. Mitochondrial autophagy in cells with mtDNA mutations results from the

synergistic loss of transmembrane potential and mRORC1 inhibition. Hum Mol Genet 2012;21:978-90

34. Danial, N.N., Hartman, et al. How does the ketogenic diet work? Four potential mechanisms. J Child Neurol

2013;28:1027–33

35. Hartman, A.L., Rho, J.M., 2012. The biochemical basis of dietary therapies for neurological disorders. In: Neal, EG

(Ed.), Dietary Treatment of Epilepsy: Practical Implementation of Ketogenic Therapy. Wiley-Blackwell, Oxford, UK, pp.

34–44

36. * Santra S, Gilkerson RW, Davidson M, Schon EA. Ketogenic treatment reduces deleted mitochondrial DNAs in

cultured human cells. Ann Neurol 2004;56:662–9

A manuscript of notable value for new fields of KD investigation in vitro.

37. Steriade C, Andrade DM, Faghfoury H, et al. Mitochondrial Encephalopathy With Lactic Acidosis and Stroke-like

Episodes (MELAS) May Respond to Adjunctive Ketogenic Diet. Pediatr Neurol 2014;50:498-502

38. Krebs P, Fan W, Chen YH, et al. Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is

ameliorated by ketogenic diet. Proc Natl Acad Sci U S A 2011;108:19678-82

39. Ahola-Erkkilä S, Carroll CJ, Peltola-Mjösund K, et al. Ketogenic diet slows down mitochondrial myopathy

progression in mice. Hum Mol Genet 2010;19:1974-84

40. Lissens W, Meirleir DL, Sebeca S, et al. Mutation in the X-linked pyruvatedehydrogenase (E1) a subunit gene

(PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 2000;15:209-19

41. Cederbaum SD, Blass JP, Minkoff N, et al. Sensitivity to carbohydrate in a patient with familial intermittent lactic

acidosis and pyruvate dehydrogenase deficiency. Pediatr Res 1976;10:713–20

42. Singhi P, De Meirleir L, Lissens W, et al. Pyruvate dehydrogenase-e1α deficiency presenting as recurrent

demyelination: an unusual presentation and a novel mutation. JIMD Rep. 2013;10:107-11

43. Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with

ketogenic diets. Studies in patients with identical mutations. Neurology 1997;49:1655–61

44. * Falk RE, Cederbaum SD, Blass JP, et al. Ketogenic diet in the management of pyruvate dehydrogenase deficiency.

Pediatrics 1976;58:713-21
A paper of high interest because providing useful information about the role of KD in the management of PDHD.

45. Wijburg FA, Barth PG, Bindoff LA, et al. Leigh syndrome associated with deficiency of the pyruvate dehydrogenase

complex: results of treatment with a ketogenic diet. Neuropediatrics 1992;23:147-52

46. El-Gharbawy AH, Boney A, Young SP, Kishnani PS. Follow-up of a child with pyruvate dehydrogenase deficiency on

a less restrictive ketogenic diet. Mol Genet Metab 2011;102:214-5

47. Di Pisa V, Cecconi I, Gentile V, et al. Case report of pyruvate dehydrogenase deficiency with unusual increase of

fats during ketogenic diet treatment. J Child Neurol 2012;27:1593-6

48. * Weber TA, Antognetti MR, Stacpoole PW. Caveats when considering ketogenic diets for the treatment of

pyruvate dehydrogenase complex deficiency. J Pediatr 2001;138:390-5

A critical analysis of the use of KD in PDHD, of interest.

49. Orfali KA, Fryer LGD, Holness MJ, Sugden MC. Long-term regulation of pyruvate dehydrogenase kinase by high fat

feeding. FEBS Lett 1997;336:501-5

50. Dietschy JM, Woollett LA, Spady DK. Dietary fatty acids and the regulation of plasma low-density lipoprotein

cholesterol levels. Artheroscler Rev 1991;23:7-18

51. Fryer LGD, Orfali KA, Holness MJ, et al. The longterm regulation of skeletal muscle pyruvate dehydrogenase kinase

by dietary lipid is dependent on fatty acid composition. Eur J Biochem 1995;229:741-8

52. Nordli DR, DeVivo DC. (2001) The ketogenic diet. In Wyllie E (Ed) The treatment of epilepsy, 3rd ed. Lippincott

Williams & Wilkins, Philadelphia pp. 1001–06

53. Kang HC, Kim YJ, Kim DW, Kim HD. Efficacy and safety of the ketogenic diet for intractable childhood epilepsy:

Korean multicentric experience. Epilepsia 2005;46:272–9

54. Laugel V, This-Bernd V, Cormier-Daire V, et al. Early-onset ophthalmoplegia in Leigh-like syndrome due to NDUFV1

mutations. Pediatr Neurol 2007;36:54-7

55. Seo JH, Lee YM, Lee JS, et al. A case of Ohtahara syndrome with mitochondrial respiratory chain complex I

deficiency. Brain & Development 2010;32:253–7

56. Joshi CN, Greenberg CR, Mhanni AA, Salman MS. Ketogenic diet in Alpers- Huttenlocher syndrome. Pediatr Neurol

2009;40:314-6

57. Bastin J. Regulation of mitochondrial fatty acid beta-oxidation in human: what can we learn from inborn fatty acid

beta-oxidation deficiencies? Biochimie 2014;96:113-20

58. Bennett MJ. Pathophysiology of fatty acid oxidation disorders. J Inherit Metab Dis 2010;33:533-7
59. Sperl W, Fleuren L, Freisinger P, et al. The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial

disorders. J Inherit Metab Dis 2015;38:391-403

60. Suman B, Kripamoy A. Pyruvate dehydrogenase complex deficiency and its relationship with epilepsy frequency.

Epilepsy Res 2015;116:40-52

61. Sweney MT, Silver K, Gerard-Blanluet M et al. Alternating hemiplegia of childhood: early characteristics and

evolution of a neurodevelopmental syndrome. Pediatrics 2009;123:534–41

62. Panagiotakaki E, Gobbi G, Neville B et al. Evidence of a non-progressive course of alternating hemiplegia of

childhood: study of a large cohort of children and adults. Brain 2010;133:3598–610

63. Heinzen EL, Swoboda KJ, Hitomi Y et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.

Nat Genet 2012;44:1030–4

64.Rosewich H, Thiele H, Ohlenbusch A et al. Heterozygous de-novo mutations in ATP1A3 in patients with alternating

hemiplegia of childhood: a whole-exome sequencing gene identification study. Lancet Neurol 2012;11:764–73

65. Ishii A, Saito Y, Mitsui J, et al. Identification of ATP1A3 mutations by exome sequencing as the cause of alternating

hemiplegia of childhood in Japanese patients. PLoS One 2013;8(2):e56120.

66. Mikati MA, Kramer U, Zupanc ML, Shanahan. Alternating hemiplegia of childhood: clinical manifestations and long-

term outcome. Pediatr Neurol 2000;23:134–41

67. Ito Y, Oguni H, Ito S, et al. A modified Atkins diet is promising as a treatment for glucose transporter type 1

deficiency syndrome. Dev Med Child Neurol 2011;53:658–63

68. Klepper J, Scheffer H, Leiendecker B, et al. Seizure control and acceptance of the ketogenic diet in GLUT1

deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics. 2005;36:302-308

69. De Giorgis V, Veggiotti P. GLUT1 deficiency syndrome 2013: Current state of the art. Seizure 2013;22:803-11

70. Sasaki M, Sakuma H, Fukushima A, et al. Abnormal cerebral glucose metabolism in alternating hemiplegia of

childhood. Brain Dev 2009;31:20-6

71. Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5--a

population-based study. Lancet Oncol 2014;15:35-47

72. Ostrom QT, Bauchet L, Davis FG, et al. The epidemiology of glioma in adults: a "state of the science" review. Neuro

Oncol 2014;16:896-913

73. Johnson KJ, Cullen J, Barnholtz-Sloan JS, et al. Childhood brain tumor epidemiology: a brain tumor epidemiology

consortium review. Cancer Epidemiol Biomarkers Prev 2014;23:2716-36

74. Kapelner A, Vorsanger M. Starvation of cancer via induced ketogenesis and severe hypoglycemia. Med Hypotheses

2015;84:162-8

75. Luna B, Bhatia S, Yoo C, et al. Proteomic and Mitochondrial Genomic Analyses of Pediatric Brain Tumors. Mol

Neurobiol. 2015;52:1341-63

76. Marsh J, Mukherjee P, Seyfried TN. Drug/diet synergy for managing malignant astrocytoma in mice: 2-deoxy-D-

glucose and the restricted ketogenic diet. Nutr Metab (Lond) 2008;25:5-33

77. Stafford P, Abdelwahab MG, Kim do Y, et al. The ketogenic diet reverses gene expression patterns and reduces

reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab (Lond) 2010;10:7-74

78. * Abdelwahab MG, Fenton KE, Preul MC, et al. The ketogenic diet is an effective adjuvant to radiation therapy for

the treatment of malignant glioma. PLoS One 2012;7:e36197

A study of great impact regarding new direction about the usefulness of KD in the management of brain tumors.

79. Dang MT, Wehrli S, Dang CV, Curran T. The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway

Medulloblastoma in Mice. PLoS One. 2015;10:e0133633

80. Woolf EC, Curley KL, Liu Q, et al. The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of

Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model. PLoS

One 2015;10:e0130357

81. Chu-Shore CJ, Thiele EA. Tumor growth in patients with tuberous sclerosis complex on the ketogenic diet. Brain

Dev 2010;32:318-22

82. Hershey AD. Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol 2010;

9:190-204

83. Headache Classification Committee of the International Headache Society (IHS) The International Classification of

Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629–808

84. Lampl C. Childhood-onset cluster headache. Pediatr Neurol 2002;27:138-40

85. Yorns WR Jr, Hardison HH. Mitochondrial dysfunction in migraine. Semin Pediatr Neurol. 2013;20:188-93

86. Ross-Araujo D, Stuart S, Lea RA, et al. Epigenetics and migraine; complex mitochondrial interactions contributing

to disease susceptibility. Gene. 2014;543:1-7

87. Wheless JW. History of the ketogenic diet. Epilepsia 2008;49:3-5

88. * Cullingford T. The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders.

Prostaglandins Leukot Essent Fatty Acids. 2004;70:253-64

A paper of remarkable value; it provides a detailed analysis of molecular mechanisms involved in the efficacy of KD

in neurological disorders.

89. Maalouf Sullivan PG, Davis L, Kim DY, Rho JM. Ketones inhibit mitochondrial production of reactive oxygen species

production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 2007;145:256-64

90. de Almeida Rabello Oliveira M, da Rocha Ataíde T, de Oliveira SL, et al. Effects of short-term and long-term

treatment with medium- and long-chain triglycerides ketogenic diet on cortical spreading depression in young rats.

Neurosci Lett 2008;434:66-70

91. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),

2013

92. Accordino RE, Kidd C, Politte LC, et al. Psychopharmacological interventions in autism spectrum disorder. Expert

Opin Pharmacother 2016;17:937-52

93. Longden E, Read J. Assessing and Reporting the Adverse Effects of Antipsychotic Medication: A Systematic Review

of Clinical Studies, and Prospective, Retrospective, and Cross-Sectional Research. Clin Neuropharmacol 2016;39:29-39

94. Mantis JG, Fritz CL, Marsh J, et al. Improvement in motor and exploratory behavior in Rett syndrome mice with

restricted ketogenic and standard diets. Epilepsy Behav 2009;15:133–41

95. Ruskin DN, Svedova J, CoteJ L, et al. Ketogenic diet improves core symptoms of autism in BTBR mice. PLoSOne

2013; 8:e65021

96. Castro K, Baronio D, Perry IS, Riesgo RD, Gottfried C. The effect of ketogenic diet in an animal model of autism

induced by prenatal exposure to valproic acid. Nutr Neurosci 2016 Feb 9

97. Hara H. Autism and epilepsy: a retrospective follow-up study. Brain Dev. 2007;29:486-90

98. Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol. 2002;1:352-8

99. El Achkar CM, Spence SJ. Clinical characteristics of children and young adults with co-occurring autism spectrum

disorder and epilepsy. Epilepsy Behav. 2015;47:183-90

100. Shavelle RM, Strauss DJ, Pickett J. Causes of death in autism. J Autism Dev Disord. 2001;31:569-76

101. Jabbari K, Nürnberg P. A genomic view on epilepsy and autism candidate genes. Genomics. 2016;108:31-6

102. Frye RE, Rossignol DA. Identification and Treatment of Pathophysiological Comorbidities of Autism Spectrum

Disorder to Achieve Optimal Outcomes. Clin Med Insights Pediatr. 2016;10:43-56

103. Levy RG, Cooper PN, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev

2012 Mar 14;3:CD001903

104. Frye RE, Sreenivasula S, Adams JB. Traditional and non-traditional treatments for autism spectrum disorder with

seizures: an on-line survey. BMC Pediatr 2011;11:37

105. Herbert MR, Buckley JA. Autism and dietary therapy: case report and review of the literature. J Child Neurol

2013;28:975–82