Special Meeting: Controversies in Epilepsy
The Ketogenic Diet
Taken from "Epilepsy Update" Issue #6 1996
The following presentations are highlights from a session organized by Gregory
Homes, M.D. (Harvard Medical School, Boston). Included are presentations by Edwin
Trevathan, M.D., MPH (University of Kentucky), Marcio Vasconcelos, M.D. (Childrens
National Medical Center, Washington, DC), Carl Stafstrom, M.D., Ph.D. (Tufts
University School of Medicine and New England Medical Center, Boston), and James
Wheless, M.D. (University of Texas Medical School, Houston).
As most people who work in the field of epilepsy treatment are aware, there has
been a great deal of interest recently in the use of the ketogenic diet to reduce
the severity of seizures in patients with epilepsy, particularly younger patients
with very severe disease. The controversy surrounds the reported efficacy of
the diet, its unknown mechanism of action, and the difficulty of maintaining
it - in the context that its value has not been proven in large-scale controlled
clinical trials. Also, although administration of the diet requires the full
participation of a dietitian or nutritionist, many dietitians are not trained
to provide this high-fat and very-low- carbohydrate diet.
Description: The ketogenic diet gets its name because the high fat content of
the diet results in conversion of fat-to-ketones that are utilized as an energy
source in place of glucose. If carbohydrates (which are composed of sugars) are
eliminated from the diet, and a diet very high in fat is substituted, the body
has no dietary sources of glucose. As a result, ketones are made from the available
sources and these are used as fuel instead. It is necessary to be scrupulous
in the restriction of carbohydrates because even a very small amount of sugar
can cause the body to shift to glucose production and use, which it prefers to
ketones. For example, this restriction is such that children on the diet have
to be careful to take sugarless daily multivitamins.
Background: Ketosis, or the physiologic state in which there are elevated levels
of ketones in the blood, usually occurs in people in the fasting state. A state
similar to fasting can be induced by a very high fat diet. Hence the ketogenic
diet. A beneficial effect of ketosis on seizure activity was observed during
the last century, and systematic efforts to use this effect to treat epilepsy
date back to the 1920s before many of the current antiepileptic medications were
available.
In "The Ketogenic Diet - Does it Work in Children?" Edwin Trevathan,
M.D., MPH, who is director of the Comprehensive Epilepsy Program at the University
of Kentucky, presented a review of the history of the clinical use of the ketogenic
diet. He defined it as a "rigidly calculated high-fat diet, with adequate
protein and carbohydrate for growth, designed to maintain ketosis". Clinical
reports of the ketogenic diet may be classified as pre-1980 and post-1980. Prior
to 1980, the studies were mostly retrospective or anecdotal, had mixed patient
populations, did not include carbamazepine and valproate (which were unavailable
for antiepileptic treatment), and used the "classic" ketogenic diet.
Studies subsequent to 1980 also were mostly retrospective and small in scale,
but generally used the medium-chain triglyceride (MCT) ketogenic diet and usually
involved patients with severe intractable epilepsy. The MCT diet was designed
to be more palatable, with 60% of total calories coming from MCT oil; it allows
more protein and carbohydrate than the classic ketogenic diet. However, recent
experience suggests that the classic ketogenic diet may be better tolerated than
the MCT diet. Although it is difficult to interpret the results because of many
of the factors mentioned above, clinical series from the 1960s and 1970s generally
reported good results with the ketogenic diet. In a 1977 report of 1,000 patients,
792 of whom had intractable disease, seizures were controlled in 54% and marked
improvement was seen in 26%. Nevertheless, Dr. Trevathan emphasized, it is difficult
to interpret these results in a modern context when talking about a different
patient population with different additional treatment options available. Unfortunately,
one of the major drawbacks has been the difficulty of remaining on this rigidly
calculated diet. (A child on this diet cannot even accept a cookie or candy from
another child or have a special treat at a celebration or holiday gathering).
This is unfortunate because the probability of sustaining an improvement in seizure
activity appears to be correlated with remaining on the diet; this also may be
interpreted to mean that the ability to remain on the diet influences the ability
to sustain control of seizures.
While it is clear that some children with refractory epilepsy may be helped by
the ketogenic diet, the absence of good long-term data on risk and efficacy make
its use appropriate only in intractable patients. Further clinical studies are
needed to define the proper role of the ketogenic diet in clinical epilepsy practice.
Results of a Clinical Trial
Marcio Vasconcelos, M.D., who is a fellow at the Children's National Medical
Center in Washington, DC, presented the results of a clinical trial of the ketogenic
diet in his talk titled "Efficacy and Toxicity of the Ketogenic Diet in
Children With Intractable Epilepsy". He identified three objectives: 1)
to assess retrospectively the efficacy of the ketogenic diet in patients between
1992 and 1995, 2) to identify which factors influence its efficacy, and 3) to
study the incidence and severity of its toxicity. The diet was started during
hospitalization. Of the 29 patients, 12 received a ketogenic diet in a 3:1 ratio,
meaning that the diet was 3 parts fat to 1 part protein/carbohydrate, 14 received
a diet with a 4:1 ratio, 2 patients received a 5:1 ratio, and one patient received
an MCT diet. Six patients discontinued the diet during the first week, 16 discontinued
after the first week, and 7 remained on it for periods up to 12 months. Of the
16 who discontinued after the first week, 6 did so because of no improvement,
5 because of seizure recurrence, and 2 because of refusal to keep the diet. Results
were evaluated in 23 of the patients (ie, those who did not discontinue during
the first week). Of these 23, 5 (22%) became seizure-free, 7 (31%) had a 50%
or greater reduction in seizures, 1 had a less-than-50% improvement, and 10 (43%)
had no change. Of the 23, 11 displayed better mood or an increased level of activity,
8 had no change, and 2 were worse (irritable or aggressive).
Based on these results, Dr. Vasconcelos was able to reach the following conclusions:
&Ma The ketogenic diet was effective in 12 of 23 patients (53%).
&Ma The seizure types most responsive were generalized tonic-clonic, akinetic,
and myoclonic seizures; partial seizures were the least responsive.
&Ma Eleven of 21 patients exhibited improved mood and/or level of activity while
on the diet.
&Ma Side effects required withdrawal in 6 of 29 patients; the most severe side
effect was acidosis in 1 patient.
&Ma The following variables DID NOT seem to predict outcome:
1. Age
2. Diet ratio
3. Number of different seizure types
4. Presence of a structural lesion
&Ma The following variables DID seem to influence outcome:
1. Seizure type
2. Number of previous antiepileptic drugs
A Therapy in Search of an Explanation
Calling the ketogenic diet a "therapy in search of an explanation",
Carl E. Stafstrom, M.D., Ph.D., associate professor at Tufts University School
of Medicine and the New England Medical Center in Boston described research in
animal models to investigate the mechanisms of action through which the ketogenic
diet confers its apparent beneficial effect. Animal models are useful because
it is possible to control and evaluate precisely factors such as components of
the diet, types of seizures, and various bio-chemical and neurologic parameters.
Although cautioning the audience that a wide variety of experimental designs
makes broad conclusions difficult, Dr. Stafstrom indicated that we have learned
the following from animal models: 1) the ketogenic diet appears to afford protection
against acute seizures in some models, 2) the mechanism of anticonvulsant action
may be related to the ketosis itself, rather than to the associated acidosis
or other metabolic effects, and 3) several features of experimental responses
parallel those observed clinically. For example, the diet seems to be more effective
in younger animals just as it seems to be more effective in children than in
adults. Also, although the onset of action is gradual, the reversal of the effect
occurs rapidly. We see this clinically when it may take several days after beginning
the diet for the effect to build up, but, if ketosis is interrupted by the consumption
of carbohydrates, the anticonvulsant effect can reverse within hours. This is
why it is so important to maintain the diet strictly, and why it is so easy to
undo its effects: weeks of hard work can be undone if the child eats a couple
of cookies or candies because they contain enough glucose to switch the body
over to using glucose for fuel rather than the ketone bodies. (Remember that
the body only uses the ketones when sugar is unavailable; as soon as the slightest
amount of sugar is made available the body immediately converts it to glucose
to use for fuel).
Dr. Stafstrom described several experiments in which rats given ketogenic diets
were compared with rats on normal diets as various parameters of cognition and
behavior were tested. In general, the rats on the ketogenic diet did better in
several tests, such as the "water maze", which measures the ability
to learn and remember the location of food on a platform in a pool of water through
which the rat has to swim to reach the food. "I am not willing to say that
the ketogenic diet makes rats smarter, but at least it's clear that it doesn't
make them any dumber", said Dr. Stafstrom, and this observed effect correlates
with observations in children with severe epilepsy on the ketogenic diet who
experience improvements in mood, behavior, and cognition. Unfortunately, this
improvement carries with it an increase in activity, possibly hyperactivity,
in terms of awareness and exploration of the surroundings; this may correlate
with observations of increased irritability in some children on the diet.
A Practical Approach
In his presentation titled "The Ketogenic Diet - Is It Worth The Trouble?" James
Wheless, M.D., associate professor at the Texas Comprehensive Epilepsy Program,
the University of Texas Medical School in Houston, described the complex approach
he uses at this medical center to implement the ketogenic diet. He emphasized
that two factors are extremely important: the integration of a team approach
and education of the parents and the child. The team should include the epileptologist's
nursing staff and other office personnel (for training and to answer questions)
and a dietitian trained in the implementation of this diet. The Table shows the
John Hopkins Hospital multicenter protocol used by Dr. Wheless and his group
for administration of the ketogenic diet.
Dr. Wheless commented on several of the practical issues involved in implementing
the ketogenic diet. "Nutritional labeling of food has made all of this much
easier", was one of his points. Parents undergo an extensive training procedure
with a specially trained dietitian on how to prepare ketogenic diet meals and
how to shop in supermarkets. The team approach is very important, with the dietitian
perhaps being the most important member. One problem is that most dietitians
have not been trained to handle this sort of high-fat, low-carbohydrate diet.
In terms of education of the parents, Dr. Wheless said he has found it helpful
to refer to this whole process as "Ketosis therapy" because if it's
thought of as a medical therapy people have appropriate expectations about its
outcome, whereas if it's thought of as a diet people expect it to be foolproof
and without adverse effects. "This is a medical therapy, and like any medical
therapy, it can have adverse effects, but we try to balance them against the
potential benefit," said Dr. Wheless.
TABLE
A protocol for administration of the ketogenic diet. Developed as a multicentered
research protocol at the Johns Hopkins Hospital, Dr. James Wheless and his group
at the University of Texas Medical School in Houston participated in the development
of this protocol
&Ma Hospitalization for 3 to 5 days
Initial fast
Fluids 67% - 75% maintenance
Check urine ketones
Check blood glucose every 6 hours
Initial EEG
Education
Simplify AED regimen
Days 2 - 3 (urine ketones 160 mg/dL)
Start ketogenic diet 4:1 ratio (one-third total calories using eggnog for 2 -
3 meals)
Stop Dextrostix
Then two-thirds total calories using eggnog per meal for 2 - 3 meals
Days 3 - 5
First regular meal on 4:1 ratio diet
Discharge with vitamin B and calcium supplementation
AED regimen
&Ma At 1 month
Neurologist, nurse, dietitian
Adjust diet if needed
SMA-20, CBC, platelets
Lipoprotein electrophoresis
AED level(s) if needed
&Ma 3, 6, 12 months
Neurologist, nurse, dietitian
SMA-20, CBC, platelets
Lipoprotein electrophoresis
AED level(s) if needed
&Ma Maintain for 2 years
&Ma Wean over 1 year
Many questions remain regarding the use of this diet. First, although partial
fluid restriction is still part of most protocols, there does not seem to be
a current rationale for its inclusion; in general, its use is based on long-standing
tradition. Because very little is understood about the mechanism of the diet,
it is hard to evaluate the role, if any, played by the level of fluid intake.
Dr. Wheless said he hopes answers about this will come from ongoing and future
clinical trials of the diet.
In addition to the overwhelming questions about its mechanism of action, there
are many questions remaining about the practical application of the ketogenic
diet:
&Ma When to initiate? (ie, after how many antiepileptic drug (AED) failures?)
&Ma How long can it be maintained, or should it be maintained?
&Ma What are the side effects, and how can we monitor and reduce them?
&Ma What are the psychosocial effects of the diet on the child and on his or
her siblings and family structure?
These questions highlight the need for additional research. Problems with current
implementation include dietitians' unfamiliarity with the diet, parents' guilt
when these children's seizures do not improve while on the diet, parents' expectations
for cognitive/behavioral improvement, and management of side effects. This places
us in a unique and uncomfortable position, suggesting a treatment regimen that
appears to be effective in patients with severe disease who do not respond to
conventional therapy, but one that is difficult to implement and to explain.
Future clinical studies should clear up many of the urgent questions concerning
the ketogenic diet, and more clinical experience should enlighten us on its practical
daily use in our patients with severe and intractable epilepsy.
Page last updated: May 5, 2008
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