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Ketogenic Dietary Therapy Controversies for Its Second Century

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As the ketogenic diet approaches 100 years of continuous use, we reflect on its successes and consider new avenues of research for the next century. One controversial question is regarding whether ketogenic dietary therapies could be successful first-line treatments for epilepsy. Second, is it possible to mimic the mechanisms of action of ketogenic dietary therapy with a drug (eg, a tablet formulation)? A third controversy worthy of future study involves its expanded usage in adults with refractory epilepsy and its role in treating women of childbearing age. Finally, as flexible, alternative diets have recently become widely available, is it feasible and safe to have families and patients start ketogenic dietary therapy successfully on their own with limited medical supervision?
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Current Review
In Clinical Science
Ketogenic Dietary Therapy Controversies
for Its Second Century
Eric Kossoff, MD
1
* , and Mackenzie Cervenka, MD
1
1
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
*Correspondence: Eric Kossoff, Department of Neurology, Johns Hopkins University, 200 N Wolfe St Suite 2158, Baltimore, MD
21287, USA; e-mail: ekossoff@jhmi.edu
Abstract
As the ketogenic diet approaches 100 years of continuous use, we reflect on its successes and consider new avenues of research
for the next century. One controversial question is regarding whether ketogenic dietary therapies could be successful first-line
treatments for epilepsy. Second, is it possible to mimic the mechanisms of action of ketogenic dietary therapy with a drug (eg, a
tablet formulation)? A third controversy worthy of future study involves its expanded usage in adults with refractory epilepsy and
its role in treating women of childbearing age. Finally, as flexible, alternative diets have recently become widely available, is it
feasible and safe to have families and patients start ketogenic dietary therapy successfully on their own with limited medical
supervision?
Keywords
ketogenic, diet, fasting, ketosis, epilepsy
Introduction
It is perhaps the ultimate comeback story in the modern era for
the treatment of epilepsy. One hundred years ago, Dr Russell
Wilder at the Mayo Clinic in Rochester, Minnesota, theorized
that a low-carbohydrate, high-fat diet could mimic the benefi-
cial effects of fasting, which had been recognized as helpful in
suppressing seizures for over a decade.
1
He was partially cor-
rect —the “ketogenic” diet, as he named it, did reduce seizures,
but as recent research has demonstrated, its effects are vastly
different from fasting mechanistically.
2,3
For the next 20 to 30
years, the classic ketogenic diet was one of the most popular
epilepsy treatments for children and adults with few options
other than phenobarbital and bromides available. The period
from 1940 to 1980 saw a gradual, steady decline in ketogenic
diet use, likely due to a combination of new antiseizure drugs
such as phenytoin, carbamazepine, and valproate, but also an
abrupt drop-off in published clinical research for unclear rea-
sons. The ketogenic diet was relegated to status as a treatment
of last resort, only used for children with the most refractory
epilepsy syndromes at a handful of pediatric epilepsy centers.
The comeback started in 1994 with the creation of the Char-
lie Foundation patient support group (www.charliefoundation.
org), which helped fund and stimulate multicenter clinical
trials, the first edition of a ketogenic diet guidebook,
4
media
attention, and regional new ketogenic diet center trainings.
Today, as we near the 100-year anniversary from 1921, keto-
genic dietary therapy has returned to the mainstream of epi-
lepsy care. Most pediatric (and gradually more adult) epilepsy
centers offer ketogenic dietary therapies, and randomized con-
trolled trials to date have demonstrated efficacy,
5-9
several
expert consensus statements have been published to guide
care,
10-12
and biannual international ketogenic diet scientific
conferences, the seventh of which will be held later this year
in Brighton, United Kingdom. Finally, innovative strategies for
modifying the classic ketogenic diet have recently emerged
such as the medium chain triglyceride oil diet, the modified
Atkins diet, and the low glycemic index treatment, to address
issues of compliance and ease of initiation.
What does the future hold for the upcoming second century
of ketogenic dietary therapy? It has been demonstrated as
effective in all ages, with evidence documenting epilepsy
Epilepsy Currents
1-5
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EPILEPSY CURRENTS
etiologies with perhaps ideal use (Table 1),
10
and adverse
effects are now being screened for, identified, and even pre-
vented. However, there are still some very important questions
that hopefully will be answered by the next generation of
researchers in the years to come. In this review, 4 of the more
controversial questions are posed to stimulate discussion and
identify future research directions in ketogenic dietary
therapies.
1. Could ketogenic dietary therapy be used as a first-line
treatment?
One of the most common questions currently asked by neu-
rologists as well as patients and their families is “If ketogenic
dietary therapy works so well, why do we have to wait until
after we try 2 or more antiseizure drugs to use it?” Practically,
to justify early use, one would have to be able to identify one of
several epilepsy conditions shown to be highly responsive to
ketogenic dietary therapy within a few months; however, most
of the “indications” for ketogenic dietary therapy (Table 1) take
longer time periods to diagnose.
10
Some of these conditions do
have limited published evidence for early or first-line ketogenic
dietary therapy use, primarily for infantile spasms, epilepsy
with myoclonic–atonic seizures (Doose syndrome), and glu-
cose transporter type 1 (Glut1) deficiency syndrome.
13-15
Genetic testing, especially for SLC2A1 mutations for Glut1
deficiency, may in the future identify patients responsive to
ketogenic dietary therapy earlier than ever before, perhaps even
before seizures begin.
What about the vast majority of patients with idiopathic
epilepsy or other known causes? Patients with focal epilepsy,
idiopathic generalized epilepsies (eg, absence and juvenile
myoclonic epilepsy), and even with structural malformations
have been reported to benefit from ketogenic dietary thera-
pies.
10
In both adults and children, ketogenic dietary therapy
has been used as “monotherapy” replacing antiseizure drugs,
but this is not the norm.
16,17
Implementing outpatient, nonfast-
ing ketogenic diet starts or alternative diets (eg, modified
Atkins diet, low glycemic index treatment) is an attractive way
for these patients and families to start ketogenic dietary therapy
quickly without a hospital admission (and required insurance
approval).
10
Immediate, simple initiation removes a possible
barrier to first-line use when compared to the relative ease of
starting an antiseizure drug in clinic. There is more on this in
the final question of this review, but the ketogenic diet com-
munity should consider expanding the scope of rigorous and
systematic analyses to pave the way for future randomized
trials comparing ketogenic dietary therapy to an antiseizure
drug for new-onset epilepsies.
2. Can ketogenic dietary therapy ever be replicated in a
pill?
The ultimate “holy grail” question for basic scientists inves-
tigating the mechanisms of action of ketogenic dietary therapy
and for the pharmaceutical industry concerns whether or not
researchers could create a tablet (or solution) that replicates the
effects of this dietary change.
18
If this were possible, then the
lifestyle modification of ketogenic dietary therapy would be no
longer necessary. Patients with epilepsy would never have to
restrict their foods at home nor face stigma in school or at
social occasions. As studies investigate novel uses for keto-
genic dietary therapy in conditions other than epilepsy (eg,
cancer, autism, dementia, migraine), having a tablet as the
intervention versus a dietary change might certainly help with
trial enrolment and compliance.
Unfortunately, but perhaps predictably, ketogenic dietary
therapy has been shown in the past few decades to have mul-
tiple distinct mechanisms of action.
19
As a result, no single
compound mimicking all of its effects has been discovered or
created. However, several innovative researchers have identi-
fied new compounds which do appear to do part of what keto-
genic dietary therapy can accomplish. These include
triheptanoin,
20
2-deoxyglucose,
21
decanoate,
10
ketone salts,
and esters.
22
Recent studies have also demonstrated that altera-
tions in the gut microbiota that occur during use of ketogenic
dietary therapy may also lead to elevated GABA/glutamate
levels and improved seizure control in a mouse model.
23
As these new compounds are developed and tested in clin-
ical trials, will they prove to be substitutes for ketogenic dietary
therapy or perhaps more appropriately as supplements for a
patient already on this treatment? If a patient on ketogenic
dietary therapy is doing well, but not completely seizure-free,
would they benefit from the addition of one of these com-
pounds to act synergistically with? Would a patient struggling
with diet compliance be more motivated and successful with
the addition of one of these therapies? One thing is certain,
pharmaceutical companies are currently very interested in
ketogenic dietary therapy not as an alternative to their drugs,
but as a potential new “metabolic” class of drugs worthy of
investigation.
3. What is the role in treating women of childbearing age
with ketogenic diet therapies?
One of the fastest growing populations of patients starting
ketogenic dietary therapy today are adults with epilepsy. A
Table 1. Seizure Disorders and Epilepsy Syndromes (Listed Alphabe-
tically) in Which Ketogenic Dietary Therapy Has Been Consistently
Reported as 70% With >50% Seizure Reduction.
10
Angelman syndrome
Complex 1 mitochondrial disorders
Dravet syndrome
Epilepsy with myoclonic-atonic seizures (Doose syndrome)
Glucose transporter protein 1 (Glut-1) deficiency syndrome
Febrile infection-related epilepsy syndrome (FIRES)
Formula-fed (solely) children or infants
Infantile spasms
Ohtahara syndrome
Pyruvate dehydrogenase deficiency
Super-refractory status epilepticus
Tuberous sclerosis complex
2Epilepsy Currents
PubMed search revealed that 42 peer-reviewed manuscripts
have been published on the treatment of epilepsy or status
epilepticus in humans, containing “adult(s)” and “ketogenic
diet(s)” or “modified Atkins” or “low glycemic index” in the
title. Among these, 35 (83%) have been published in the last
decade and over half in the last 5 years alone. Studies have
demonstrated relatively equivalent efficacy for seizure control
between adults and children, which despite no data to the con-
trary, had been typically dismissed by most neurologists.
9,24
Adults with juvenile myoclonic epilepsy and super-refractory
status epilepticus may do particularly well.
25,26
Epilepsy cen-
ters worldwide are starting to offer dietary therapy for adults,
and an expert consensus guideline is in preparation (personal
communication, Dr Mackenzie Cervenka).
Among the adults starting ketogenic dietary therapy, women
of childbearing age are of particular interest to the ketogenic
diet community, especially recognizing the lack of demon-
strated safe antiseizure drugs due to known teratogenicity.
27
To date, there has been only one publication documenting
pregnancy outcomes of 2 women on ketogenic dietary ther-
apy.
28
With the growing interest in ketogenic dietary therapy
beyond epilepsy (for other neurologic disorders, cancer, obe-
sity, and diabetes specifically),
29
hopefully we will learn more
about the potential risks to a fetus as more women are treated,
but for now it is not clear. Information from a large multicenter
pregnancy registry similar to those designed to track terato-
genicity prevalence with antiseizure drugs and/or prospective
trial (if approved by an institutional review board) would help
tremendously to clarify the risks but will take many years to
complete and analyze. Additional information about potential
negative effects of ketogenic dietary therapy on bone density
and menstrual cycles
30,31
is also of paramount importance to
adult women and needs to be further explored.
4. Can ketogenic dietary therapy be started by a patient or
family on their own?
Nearly every article, chapter, review, or book written about
ketogenic dietary therapy for epilepsy will state in the first
paragraph that these therapeutic diets are medical treatments
that should never be started without medical supervision. How-
ever, with the current surge in ketogenic dietary therapy popu-
larity beyond epilepsy, widespread Internet resources, recipe
books, and even computer programs for calculating ketogenic
ratios and meal plans, most ketogenic diet centers like ours are
seeing a dramatic rise in “self-guided” ketogenic diet thera-
pies.
32
Of course these patients require guidance and advice
to keep them medically safe and free of adverse effects. Just as
with artisanal cannabadiol products and other nonprescription
“alternative” products, side effects do exist. Many of these
patients and families express surprise that vitamins and calcium
are required and routine laboratory studies are recommended.
10
However, a number of these self-starting patients have been
anecdotally successful in inducing ketosis and also reducing
seizures. In fact, the concept behind the modified Atkins diet
as a ketogenic dietary treatment began with a mother who read
a paperback Atkins book and started on her own in 2001 and is
one of the original published cases.
33,34
A pilot study of an
e-mail-based initiation protocol for adults with epilepsy proved
surprisingly feasible, although with overall results slightly
lower than starting adults in the outpatient clinic setting.
35
This simplified, patient-initiated approach provides advan-
tages during the expansion of use of ketogenic dietary therapy.
Developing countries with limited resources, and at times no
dietitian support, could still use alternative diets in this way.
36
A consensus guideline was created specifically for this poten-
tial usage.
37
Patients and families might consider a home-based
alternative diet as a “test” of feasibility and effectiveness, then
choose not to start ketogenic dietary therapy if neither prove to
be the case. Although disappointing perhaps, a negative trial
might avoid the time and expense of an unnecessary hospital
admission or ketogenic clinic visit. The emergence of teleme-
dicine may also allow for a more structured home-based
approach. Finally, centers with long waitlists for appointments
to start ketogenic dietary therapy may be unconsciously creat-
ing a barrier to increased use. Studies challenging the anecdotal
claim that ketogenic dietary therapy must be done under direct
supervision are warranted, but in the meantime, patients and
families who choose to start on their own should be supported
and assisted to achieve the best possible outcomes if possible.
Conclusions
Ketogenic dietary therapies for epilepsy, proposed as a treat-
ment 100 years ago, have reemerged from dormancy in the past
several decades and gained worldwide acceptance. Studies
have resolved questions regarding efficacy, patient populations
with specific seizure disorder and epilepsy syndrome types that
would benefit most, overall adverse effect profile and manage-
ment, and even incorporated flexibility in initiation and main-
tenance. Many important questions remain to be studied, and
this review highlights just four of these controversial issues.
Hopefully, further investigation will address these research
topics and stimulate further hypotheses to be explored in the
next century of use and beyond.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Dr Kossoff is a consultant for Atkins Nutritionals, Bloom
Science, and Nutricia. Dr Cervenka performs consulting with Nutricia
and Sage Therapeutics.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
Dr Kossoff has received royalties from Demos Health, Oxford Press,
and UpToDate. Dr. Cervenka has received grant support from Nutri-
cia, Vitaflo, Army Research Laboratory, The William and Ella
Owens Medical Research Foundation, and BrightFocus Foundation.
Dr. Cervenka receives speaking honoraria from LivaNova, Epigenix,
Kossoff and Cervenka 3
Nutricia and the Glut1 Deficiency Foundation and receives Royalties
from Demos Health.
ORCID iD
Eric Kossoff https://orcid.org/0000-0002-5260-5314
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Kossoff and Cervenka 5
... Ketogenic diets-which are based on strict carbohydrate restriction-have been used as a treatment for epilepsy since the 1920's (Kossoff and Cervenka, 2020), and are increasingly investigated in other neurological conditions, including Alzheimer's Disease (AD) (Stafstrom and Rho, 2012;Taylor et al., 2019). Induction of the metabolic state ketosis, characterized by increased circulating levels of the ketone body β-hydroxybutyrate (BHB), is a hallmark of ketogenic diets (Volek et al., 2015). ...
... The potential of using ketogenic supplements as a complemental strategy to carbohydrate restriction is discussed as ketogenic diet therapies are increasingly investigated in conditions beyond epilepsy (Kossoff and Cervenka, 2020), which include MCI/AD (Krikorian et al., 2012;Taylor et al., 2018;Brandt et al., 2019;Nagpal et al., 2019;Neth et al., 2020;Phillips et al., 2021). In a previous publication from the current clinical trial (Norgren et al., 2020b), we demonstrated that supplementation with kMCT and time-restricted feeding regarding carbohydrates provide twooptionally additive-strategies to induce transient ketosis in older adults following their normal diet. ...
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Background: β-hydroxybutyrate (BHB) can upregulate brain-derived neurotrophic factor (BDNF) in mice, but little is known about the associations between BHB and BDNF in humans. The primary aim here was to investigate whether ketosis (i.e., raised BHB levels), induced by a ketogenic supplement, influences serum levels of mature BDNF (mBDNF) and its precursor proBDNF in healthy older adults. A secondary aim was to determine the intra-individual stability (repeatability) of those biomarkers, measured as intra-class correlation coefficients (ICC). Method: Three of the arms in a 6-arm randomized cross-over trial were used for the current sub-study. Fifteen healthy volunteers, 65–75 y, 53% women, were tested once a week. Test oils, mixed in coffee and cream, were ingested after a 12-h fast. Labeled by their level of ketosis, the arms provided: sunflower oil (lowK); coconut oil (midK); caprylic acid + coconut oil (highK). Repeated blood samples were collected for 4 h after ingestion. Serum BDNF levels were analyzed for changes from baseline to 1, 2 and 4 h to compare the arms. Individual associations between BHB and BDNF were analyzed cross-sectionally and for a delayed response (changes in BHB 0–2 h to changes in BDNF at 0–4 h). ICC estimates were calculated from baseline levels from the three study days. Results: proBDNF increased more in highK vs. lowK between 0 and 4 h (z-score: β = 0.25, 95% CI 0.07–0.44; p = 0.007). Individual change in BHB 0–2 h, predicted change in proBDNF 0–4 h, (β = 0.40, CI 0.12–0.67; p = 0.006). Change in mBDNF was lower in highK vs. lowK at 0–2 h (β = −0.88, CI −1.37 to −0.40; p < 0.001) and cumulatively 0–4 h (β = −1.01, CI −1.75 to −0.27; p = 0.01), but this could not be predicted by BHB levels. ICC was 0.96 (95% CI 0.92–0.99) for proBDNF, and 0.72 (CI 0.47–0.89) for mBDNF. Conclusions: The findings support a link between changes in peripheral BHB and proBDNF in healthy older adults. For mBDNF, changes differed between arms but independent to BHB levels. Replication is warranted due to the small sample. Excellent repeatability encourages future investigations on proBDNF as a predictor of brain health. Clinical Trial Registration: ClinicalTrials.gov , NCT03904433.
... In summary, over the past few decades, ketogenic nutritional therapy has become newly popular and has gained worldwide acceptance as an effective non-pharmacologic treatment for epilepsy. Several expert consensus guidelines on patient care have been published that attempt to define the mechanisms of action of this form of therapy and resolve doubts regarding its efficacy [154][155][156][157]. The researchers recommend implementing ketogenic diet therapies when two anticonvulsant drugs have been ineffective, and even earlier in certain syndromes, including GLUT1 deficiency syndrome, pyruvate dehydrogenase deficiency, epilepsy with myoclonic-atonic seizures, infantile spasms, tuberous sclerosis complex, children with gastrostomy tubes and Dravet syndrome [155]. ...
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The ketogenic diet (KD) is a high-fat, low-carbohydrate and adequate-protein diet that has gained popularity in recent years in the context of neurological diseases (NDs). The complexity of the pathogenesis of these diseases means that effective forms of treatment are still lacking. Conventional therapy is often associated with increasing tolerance and/or drug resistance. Consequently, more effective therapeutic strategies are being sought to increase the effectiveness of available forms of therapy and improve the quality of life of patients. For the moment, it seems that KD can provide therapeutic benefits in patients with neurological problems by effectively controlling the balance between pro- and antioxidant processes and pro-excitatory and inhibitory neurotransmitters, and modulating inflammation or changing the composition of the gut microbiome. In this review we evaluated the potential therapeutic efficacy of KD in epilepsy, depression, migraine, Alzheimer’s disease and Parkinson’s disease. In our opinion, KD should be considered as an adjuvant therapeutic option for some neurological diseases.
... In addition, recent studies have alerted of potential side effects (Cai et al., 2017), including an increase in serum lipidemia with concomitant increased risk of cardiovascular alterations (Zamani et al., 2016), higher risk of bone mass reduction (Simm et al., 2017), long-term alterations in the immune system (Goldberg et al., 2020), or increased probabilities for cardiac fibrosis (Xu et al., 2021). Because of these potential adverse effects, and the difficulty to adhere to the diet, different dietary formulations are being proposed to achieve a therapeutic effect with a more tolerable nutritional intervention (Dallérac et al., 2017;Kossoff and Cervenka, 2020). Furthermore, the anti-seizure efficacy in patients treated with ketogenic diets is not always replicated in experimental rodent models, which hampers research on the underlying molecular mechanisms (Holmes, 2008), This is probably due to biological differences in metabolic rates and in cellular responses to KBs between humans and rodents, as well as to the fact that ketosis is tightly controlled in humans to avoid dangerous situations, whereas mice and rats fed a ketogenic diet are allowed to eat ad libitum. ...
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Ketone bodies are metabolites that replace glucose as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting, extenuating exercise, or pathological conditions such as diabetes. Beyond their role as an alternative fuel for the brain, the impact of ketone bodies on neuronal physiology has been highlighted by the use of the so-called “ketogenic diets,” which were proposed about a century ago to treat infantile seizures. These diets mimic fasting by reducing drastically the intake of carbohydrates and proteins and replacing them with fat, thus promoting ketogenesis. The fact that ketogenic diets have such a profound effect on epileptic seizures points to complex biological effects of ketone bodies in addition to their role as a source of ATP. In this review, we specifically focus on the ability of ketone bodies to regulate neuronal excitability and their effects on gene expression to respond to oxidative stress. Finally, we also discuss their capacity as signaling molecules in brain cells.
... When conducted properly, a ketogenic diet is tolerated [27] and it can induce an increased number of patients achieving seizure freedom over time [14,28]. Then, a correct management of the ketogenic diet is also important to avoid side effects [16,17,19], controversies [29], and, in some cases, a phenomenon known as the rebound effect [30], which is characterised by a paradoxical seizure worsening [31]. Thus, the initiation and maintenance of the dietary treatment are the result of concomitant efforts of paediatric neurologists/epileptologists, dieticians, families and other patients' caregivers [32]. ...
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E-health technologies improve healthcare quality and disease management. The aim of this study was to develop a ketogenic diet management app as well as a website about this dietary treatment and to evaluate the benefits of giving caregivers access to various web materials designed for paediatric patients with refractory epilepsy. Forty families participated in the questionnaire survey, from January 2016 to March 2016. All caregivers were exposed to paper-based materials about the ketogenic diet, whereas only 22 received the app, called KetApp, and videos produced by dieticians. Caregivers with free access to web materials were more satisfied than the others with the informative material provided by the centre (p < 0.001, Mann–Whitney test). Indeed, they showed a better attitude towards treatment, and they became more aware of dietary management in comparison to the control group (p < 0.001). Moreover, caregivers provided with web materials were stimulated to pursue the treatment (p = 0.002) and to introduce it to their children and other people (p = 0.001). Additionally, caregivers supplied with web materials were more willing to help other families in choosing the ketogenic diet (p = 0.004). Overall, these findings indicate that web materials are beneficial for caregivers of paediatric patients with refractory epilepsy in our centres. Thus, the use of e-health applications could be a promising tool in the daily aspects of ketogenic diet management, and it is especially of value in the attempt to start or maintain the diet during the ongoing COVID-19 pandemic crisis.
... Additionally, greater flexibility in the use of the diet will make patients less dependent on the medical team. (Kossoff and Cervenka, 2019) Further research, especially in the field of genetics, will be necessary for a better selection of candidates for the diet. (Ko et al., 2018;Caraballo, 2018) Another interesting topic to evaluate in the future are the patients with particular types of epileptic encephalopathies with a genetic etiology who may have an excellent response to KDTs. ...
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Several studies have already explored the role of ketone bodies on the physiological processes involved in the onset of seizures and ketogenic diet is a common treatment option in drug-resistant epilepsy either in children, adolescents or adults. This narrative review aims to summarize the available evidence on the possible mechanisms of action, and on the efficacy of the ketogenic diet and its variants on the treatment of epilepsy from infants to adults. Even though there is a robust biologic plausibility and either mechanistic studies and randomized controlled trials supporting ketogenic diet as a valid approach to reduce seizures in drug-resistant childhood epilepsy, the level of evidence is not as strong for the treatment of drug-resistant epilepsy in adults.
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Aim: To give evidence-based recommendations on the application of ketogenic diet parenteral nutrition (KD-PN) in emergency situations. Method: An international group of experts (n=14) researched the literature and distributed a survey among 150 expert centers. International accepted guidelines (European Society for Clinical Nutrition and Metabolism/European Society for Paediatric Gastroenterology Hepatology and Nutrition and the American Society for Parenteral and Enteral Nutrition) and handbooks for parenteral nutrition were considered general standards of care. Results: In the literature, we identified 35 reports of patients treated by KD-PN. International guidelines and handbooks provided some conflicting information. Twenty-four expert teams from nine countries responded to the survey, reflecting the limited clinical experience. Interpretation: This paper highlights 23 consensus-based recommendations for safe and effective KD-PN (e.g. diet initiation, calculation, application, monitoring, and evaluation) based on the best evidence available and expert opinions. What this paper adds: In acute settings, ketogenic diet therapy (KDT) can be administered parenterally. Parenteral administration of KDT should be started only at the intensive care unit. Initiate ketogenic parenteral nutrition stepwise to the highest ratio possible with the lowest level of complications. Evaluate the risk-benefit ratio of parenteral administration continuously. Restart enteral feeding as soon as appropriate.
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Current anti-seizure drugs (ASDs) are believed to reduce neuronal excitability through modulation of ion channels and transporters that regulate excitability at the synaptic level. While most patients with epilepsy respond to ASDs, many remain refractory to medical treatment but respond favorably to a high-fat, low-carbohydrate metabolism-based therapy known as the ketogenic diet (KD). The clinical effectiveness of the KD has increasingly underscored the thesis that metabolic factors also play a crucial role in the dampening neuronal hyperexcitability that is a hallmark feature of epilepsy. This notion is further amplified by the clinical utility of other related metabolism-based diets such as the modified Atkins diet and the low-glycemic index treatment (LGIT). Traditional high-fat diets are characterized by enhanced fatty acid oxidation (which produces ketone bodies such as beta-hydroxybutyrate) and a reduction in glycolytic flux, whereas the LGIT is predicated mainly on the latter observation of reduced blood glucose levels. As dietary implementation is not without challenges regarding clinical administration and patient compliance, there is an inherent desire and need to determine whether specific metabolic substrates and/or enzymes might afford similar clinical benefits, hence validating the concept of a “diet in a pill.” Here, we discuss the evidence for one glycolytic inhibitor, 2-deoxyglucose (2DG) and one metabolic substrate, β-hydroxybutyrate (BHB) exerting direct effects on neuronal excitability, highlight their mechanistic differences, and provide the strengthening scientific rationale for their individual or possibly combined use in the clinical arena of seizure management.
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Objective To compare the efficacy and safety of the ketogenic diet (KD) with standard adrenocorticotropic hormone (ACTH) treatment in infants with West syndrome. Methods In this parallel‐cohort (PC) randomized controlled trial (RCT), infants were randomly allocated to KD or high‐dose ACTH. Those who could not be randomized were followed in a PC. Primary end point was electroclinical remission at day 28. Secondary end points were time to electroclinical remission, relapse after initial response, seizure freedom at last follow‐up, adverse effects, and developmental progress. Results One hundred one infants were included: 32 in the RCT (16 KD; 16 ACTH) and 69 in the PC (37 KD; 32 ACTH). Electroclinical remission at day 28 was similar between KD and ACTH (RCT: 62% vs 69%; PC: 41% vs 38%; combined cohort: 47% vs 48%; KD vs ACTH, respectively). In the combined cohort, time to electroclinical remission was similar between both treatments (14 days for KD, 16 days for ACTH). However, relapse rates were 16% (KD) and 43% (ACTH, P = 0.09), and seizure freedom at last follow‐up was 40% (KD) and 27% (ACTH, P = 0.18). Adverse effects needing acute medical intervention occurred more often with ACTH (30% with KD, 94% with ACTH, P < 0.001). Age‐appropriate psychomotor development and adaptive behavior were similar. Without prior vigabatrin (VGB) treatment, remission at day 28 was 47% (KD) and 80% (ACTH, P = 0.02); relapse rates were 29% (KD) and 56% (ACTH, P = 0.13). Consequently, seizure freedom at last follow‐up was similar. In infants with prior VGB, seizure freedom at last follow‐up was 48% (KD) and 21% (ACTH, P = 0.05). Significance The study is underpowered; therefore, its results should be interpreted with caution. KD is as effective as ACTH in the long term but is better tolerated. Without prior VGB treatment, ACTH remains the first choice to achieve short‐term remission. However, with prior VGB, KD was at least as effective as ACTH in the short term and was associated with lower relapse rates in the long term; therefore, it represents an appropriate second‐line treatment after VGB.
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Objective Ketogenic diets reduce seizures in children with drug‐resistant epilepsy. Whether adults benefit from similar treatment has not been clarified. We therefore examined the efficacy of the modified Atkins diet in adults with drug‐resistant focal epilepsy. Methods We performed a randomized clinical trial (RCT) with patients >16 years who had at least 3 seizures per month despite having tried at least 3 antiepileptic drugs. They were randomized to either 12 weeks on the modified Atkins diet (diet group) or habitual diet (control group). Primary endpoint was a change in seizure frequency from baseline to the intervention period, comparing those on diet with controls. Results We assigned 37 patients to the diet group and 38 to the control group. Nine of the patients in the diet group and 4 controls were excluded. Of those who completed the dietary intervention (n = 24), median seizure change was −1.0 (interquartile range [IQR] −13.7‐8.8), while in the control group (n = 32) the median change was 4.5 (IQR −4.8‐33.5). The median difference between the groups was −7.0 (95% confidence interval [CI] −37.0‐3.0; P = .21). In the intention‐to‐treat analysis, the relative risk (RR) for achieving >50% seizure reduction was 1.8 (95% CI 0.3‐10.2; P = .65), while for achieving >25% seizure reduction RR was 2.43 (95% CI 0.94‐6.28; P = .06). We observed no serious adverse events. Significance In this RCT investigating the effect of an adjunctive modified Atkins diet on seizure frequency in adults with difficult‐to‐treat focal epilepsy, we found a significant reduction in seizure frequency in the diet group compared to the controls, but only for moderate benefit (>25% seizure reduction) among those who completed the intervention. However, seizure response varied considerably between individuals, perhaps negatively influenced by a drop in serum concentrations of antiepileptic drugs.
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Ketogenic dietary therapies (KDT) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDT were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre‐KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow‐up, side events, and KDT discontinuation. It has been helpful in outlining a state‐of‐the‐art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. Additionally, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last ten years. This article is protected by copyright. All rights reserved.
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The ketogenic diet has recently received much attention for its promise of treating obesity and type 2 diabetes. However, the enthusiasm for its potential benefits exceeds the current evidence supporting its use for these conditions. Although the temptation is great to recommend a potentially novel approach for otherwise difficult-to-treat diseases, it is important to remain grounded in our appraisal of the risks, benefits, and applicability of the diet to avoid unnecessary harm and costs to patients.
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The ketogenic diet (KD) is often started not only for seizure reduction but also to potentially wean antiseizure drugs (ASDs) in children with epilepsy. Although there have been several publications regarding ASD reduction on the KD, it is unknown how often complete medication withdrawal occurs. We reviewed the charts of all children started on the KD at Johns Hopkins Hospital and Johns Hopkins All Children's Hospital from 1/11 to 4/18. Children were defined as achieving drug-free diet (DFD) status if they started the KD on at least 1 ASD and achieved a period of time where they were on the KD alone. Over the time period, 232 children were evaluated; DFD status occurred in 43 (18.5%), of which 32 (13.8% of the full cohort) remained off ASDs for the remainder of their KD treatment course. Eleven children restarted ASD after a mean of 7 months. Children achieving DFD therapy were more likely to be younger, have fewer ASDs at KD onset, have Glut1 deficiency or epilepsy with myoclonic-atonic seizures, but were less likely to have Lennox-Gastaut syndrome or a gastrostomy tube.
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Aim: Despite antiepileptic medication and dietary treatment options available about 45% of children with epilepsy still suffer from uncontrolled seizures. Triheptanoin is an anaplerotic treatment designed to improve energy generation via the Krebs cycle. Method: For the first time, we evaluated the feasibility, tolerability and efficacy of add-on triheptanoin in 12 patients with medically refractory epilepsy (seven males, five females; min-max: 3-18yr, median 13.5 yr). Results: Eight out of a total of 12 children (67%), who tested the treatment, finished the trial and tolerated between 30 and 100 ml of triheptanoin per day for >12 weeks (median 55 ml, 20.5% caloric intake). The most common adverse effects were diarrhea and other gastro-intestinal effects in seven kids. One child experienced leaking and another child had an infected percutaneous endoscopic gastrostomy button. Five children (62.5%), who all had been on the ketogenic diet previously, showed sustained >50% reductions in seizure frequency, including one patient who became seizure free for 30 weeks. Four patients extended their treatment to a total of 201-909 days, until seizure frequency or severity increased. Interpretation: In this small trial, triheptanoin was safe and tolerable in children with epilepsy. As some children showed reductions in seizure numbers and/or severity, larger randomized controlled studies are now needed for further evaluation of safety and efficacy.
Article
The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.