https://www.charliefoundation.org/who-we-are/who-2/about-the-foundation
https://ketocook.com/
https://web.archive.org/web/20080213122107/http://www.charliefoundation.org/noframes/whoweare/essay.php
'In: THE KETOGENIC DIET IN EPILEPSY: CLINICAL PRACTICE AND SCIENTIFIC
BASIS, C.E. Stafstrom, J. M. Rho (Editors), Humana Press 2004, Totowa, NJ
*AFTERWORD
"Things I Wish They Had Told Us: A Parent's Perspective on Childhood
Epilepsy"
*Jim Abrahams
The Charlie Foundation
/"IMPRESSION: It is my impression that Charlie has a mixed seizure disorder, mostly likely a variation of Lennox-Gastaut syndrome. Parents are full aware of the ramifications of this diagnosis. Although there are many traditional combinations and permutations of drugs that could be used here, I agree with the current approach. It is my understandin that the next drug to be tried is a combination of Felbamate and Tegretol with which I have no problem. I would also consider the combination of Felbamate with Valproate with perhaps a benzodiazepine. In addition, one wonders if the Felbamate could be pushed to an eve higher dose than it is now, since we really do not know what the maximum dose of Felbamate is in young children. Another possibility is high-dose Valproate monotherapy. One other alternative therapy which I have mentioned to the family, but only reluctantly because of the high
incidence of side-effects is high-dose ACTH. The problem is that while high-dose ACTH may be effective in stopping the seizures, they almost
always recur as the dose is tapered. This makes one wonder if the risk-benefit ratio justifies the use of this somewhat dangerous mode of therapy. Finally think that if all pharmacological or theraputic modalities fail, I would seriously consider a corpus callosotomy on this child. A corpus callosotomy would not be curative of all the seizure types, but may help the most troublesome part of his seizure complex, i.e. the "drops.”
I excerpted the above from a medical report we received on our son, Charlie. It’s not really necessary to mention the name of the doctor who wrote it. Suffice it to say he was the fifth pediatric neurologist my wife and I had taken Charlie to see in the year he had been experiencing seizures -- four of whom ran pediatric neurology departments at esteemed university hospitals around the United States. They all concurred. Yes, there were some variations in drug
combinations suggested, and I’m sure that to a certain extent this report dates itself in that there are new drugs available today. But the reason I begin with this “impression” is not so much for what it says, but rather for what it doesn’t -- what it and all the doctors who examined Charlie never told us.
Today, nine years later, I think back to those days, and realize how much time was lost, how much unnecessary damage was done to Charlie’s life, and as a result, how much needless pain was, and continues to be, experienced by Charlie and all of us who love him -- all because information was not shared. I know the value of “ifs,” but sometimes I can’t help myself: If only the first time we walked into a neurologist’s office someone had handed us a pamphlet, recommended a book or taken the time to tell us just some of the following information we have learned since then...
Treating kids with difficult to control seizures is 20% science and 80% art. It was not long after we received the above doctor’s report that I was watching a CNN report on childhood epilepsy and there was one of the doctors who had seen Charlie making that statement. (Actually the statistic he used was “10 % science and 90% art,” but since then I’ve put the art versus science question to many neurologists and none peg it lower than 75% art, so I’ve rounded the number down). “Hold on a second,” I thought when I heard the CNN broadcast. Those were lab coats Charlie’s doctors were wearing, not smocks to protect them from splattering paint! They were scientists! Interior decorating is an art form -- not pediatric neurology. In discussing the subject with me, a world-renowned pediatric neurologist likened treating difficult cases to fishing. Just as you return to one fishing hole time and again after you’ve had luck once, so too a neurologist will return to the same drug combination time and again after one success. To a parent, this is a big deal. Clearly it puts the onus on the parent of the sick child to ask a key question, “Based on what?” “Based on what information are you telling me this, doctor?” Similarly I believe it puts a duty on the doctor to advise a patient if he is basing a statement on anecdote, experience, or science. An example: Lennox Gasteau Syndrome features the full gamut of seizure types. Charlie suffered most of them -- including tonic-clonic seizures. We were instructed at the time by his doctors that a tonic-clonic seizure, if allowed to continue for over thirty minutes, could damage his young brain. Therefore, at thirty minutes, drug intervention with Valium or Ativan would be necessary. We lived ten minutes from a hospital. So,whenever Charlie would begin one of his many tonic-clonic seizures, the first thing we did was to make note of the time. Twenty minutes into the seizure we’d get into the car and take off for the hospital. Certainly, as we sat there trying to comfort him during his many tonic-clonic seizures, every parental instinct in us told us that these prolonged
misfirings of his brain had to be damaging and we should put a stop to them earlier if possible. But we were typical, terrified parents and never questioned from whence the magical thirty minutes came. We never asked, “Based on what?” Several years later, after Charlie’s seizures were controlled by the ketogenic diet, and when both his physical and mental delays were apparent, I attended an epilepsy conference and learned the
thirty-minute rule had been shortened to five minutes. Now tonic-clonic seizures could damage the brain in five minutes. All those hours of
holding him when we could have stopped his seizures had in fact been detrimental to Charlie. The thirty-minute rule was not scientific.
There were no blinded studies documenting the long-term effects oftonic-clonic seizures of more or less than thirty minutes. At best, the
thirty-minute rule was based on anecdote, and at worst it was based on lore. I wish that someone had told us. I wish we had known the art versus science percentage. I wish we had asked, “Based on what?” There’s no science behind it. This was an argument selectively used by several physicians who saw Charlie. Monotherapy, then multiple drugs, and finally a surgery failed to slow his seizures. He started to lose abilities he once had and, like most parents, we became more desperate. Holistic approaches, Chinese herbs, neck re-alignment and a host of non-Western approaches were suggested. The medical argument against them was: no science. I’d have no problem with that notion were it spread evenly across the playing field. But it’s not. From the naive patient’s point of view, when that argument is used to overrule “non-traditional” therapies, but omitted from Western recommendations, there is the assumption that Western approaches are backed by science. So, for example, when Dilantin was added to Charlie’s daily Felbatol, Tegretol, and benzodiazapine, in the absence of any cautionary thought regarding “no science,” I wrongly assumed (and probably never questioned) that modern science was at work. Nancy and I dutifully coerced Charlie into swallowing all that stuff around the clock and watched the terrible side-effects. Far from our minds was the notion he might be a guinea pig. If not a “crap shoot,” the chance of this drug combo stopping even some of his seizures and leaving him with any acceptable quality of life was beyond remote. What’s more, the effects of the simultaneous use of these potent drugs on his one year-old brain was and is completely without scientific documentation. We assumed naively that if there were no medical books
on the interactions and efficacy of that combination of drugs, certainly there were articles. As a matter of fact, I came to learn, there is no hard science regarding efficacy or side- effects behind any multiple drug combinations in the treatment of pediatric epilepsy. Again, my problem is more than trying multiple drug combinations. What I wish they had told us is that the “there’s no science behind it” argument is used to dissuade us from some approaches and omitted from others at the doctor's discretion. Seventy percent of new epilepsy patients have their seizures controlled with the first anti-epileptic drug they try -- almost irrespective of which drug it is. After the first drug fails, there is a 10% to 15% chance the second drug will work and only a 20 % chance drugs will ever control a child’s seizures. In other words, after a second anti-epileptic drug fails, four out of five children will not achieve seizure control with drugs alone. I’ve been told by some that this fact, were it known by many parents, would rob them of hope. I disagree. If someone had told us, it would have robbed us of complacency.
_A Couple of Drug Facts
1) The minimum criterion for the FDA to approve a new anti-epileptic drug, assuming the drug’s side-effects are not prohibitive, is that the drug stops 50% of the seizures in at least 50% of the children (who do not drop out of the study because of intolerance, noncompliance, or other reasons). In other words, if one hundred kids test a new drug and twenty-five drop out of the study, thirty-eight must have at least a fifty percent reduction in seizures. There is no requirement for a new drug to stop seizures to be approved by the FDA. For parent of a child with difficult-to-control seizures, there is always the "buzz," the promise about the next drug -- the next "great White hope" -- to arrive on the market. Very few of us know this liberal criterion for FDA approval.
2) In 1993, a new drug, Felbatol, met those requirements and was approved by the FDA for children with difficult-to-control seizures. It was produced by a company named Carter-Wallace. I wrote to Carter-Wallace to get their annual stock holders report. From this report, it was clear that in the two years prior to the release of Felbatol, the company spent $20,000,000 -- not on research and development, but on marketing the drug. In 1993, there were about twelve hundred pediatric neurologists in the U.S. to whom their advertising campaign was aimed. I’ll let you do the math. Twenty million dollars to convince twelve hundred folks to prescribe a drug! I certainly wish someone had told us that bit of information before we allowed Charlie to spend all those sleepless nights while he was on Felbatol, without helping his seizure control.
Legal Standard of Care Regarding Provision of Information
The legal standard of care in America today, with regard to a physician sharing information with a patient, is that the physician isrequired to tell his patient, in general, the same information his colleagues would share with their patients under similar circumstances. Practically speaking, that means that if, in a court of law, a doctor can get several other doctors to testify that they would have informed their patients similarly to the way he informed his patient, he has
conformed to the standard of care. This is not to suggest that legalities were ever a consideration regarding Charlie’s case; it is only to provide information I wish I had had, the bottom line regarding information-sharing by a physician. As his dad, especially in a case like Charlie’s where his seizures were difficult-to-control and the art versus science thing was clearly applicable, I always assumed our doctors would lay out a range of treatments and together we would decide on the correct course of action -- in essence, a doctor/patient partnership. I assumed an informed joint decision-making process. I was wrong. Certainly we didn’t pretend to have the medical expertise, but then
of course the doctors didn’t live with Charlie, and had no real knowledge of his family, its agony, and his living circumstances. And of course none of the doctors we saw had ever held their own child during a seizure. Unfortunately, informed joint decision-making turned out to be wishful thinking. Information was always provided on a need-to-know basis and then in a seemingly reluctant manner. In fact, there was almost a physical chill when more than limited probing and suggesting occurred.
The Ketogenic Diet
Throughout Charlie's epilepsy, I remember crying hardest with Nancy when we received the copy of the above report. It seemed so hopeless. And yes, we were “fully aware of the ramifications” of Charlie’s diagnosis. So, as a way to prepare Charlie and the rest of us for what seemed to be many more years of seizures drugs and “progressive retardation,” I started doing some research. To my surprise, in epilepsy texts dating back to the 1920’s (and in every decade from the 20’s through the present) from Hopkins, the Mayo Clinic and many other highly regarded institutions, there was consistent anecdotal documentation regarding the ketogenic diet and its efficacy (roughly one-third of the kids who tried it became seizure-free, one-third were
significantly improved and for one-third it was ineffective). The documentation totaled literally thousands of children with epilepsy. In addition, the diet’s side-effects were minimal compared to many of those that Charlie had experienced. I learned that there was still a dietician at Johns Hopkins who had forty plus years of experience with the diet. So, one month after receiving that gloomy report, we took Charlie to Johns Hopkins. They put him on the diet. His seizures dropped from dozens a day to zero within forty-eight hours of its initiation, and he was off all medication in another month.
I don’t want to minimize the difficulty of the diet, but it was a walk on the beach next to the drugs and continued seizure activity. More importantly, we had our son back! Today Charlie is eleven years old, off the diet, and has been seizure- and drug-free for years. I asked his doctors why they left it to us to learn about the diet they all had heard of. Their answers: 1) it was too difficult; 2) being high in fat, it may be unhealthy; and 3) there was no science behind the diet. Too difficult? What could be more difficult than watching your child than watching your child slip into retardation via drugs and
seizures? Unhealthy? Compared to what? No science? No need to deal
with that subject again. The medical destiny of each of us and our children is largely up to the patient and his/her family. To think otherwise can be damaging. There is a tendency when we walk into a doctor’s office to want to hand over our problem to the doctor and say, “Here it is, please fix it.” It’s comfortable, it’s easy, and more often than not, it works. Just as we take comfort in deferring to them, many doctors are unwilling to
confide in us that we may have stepped into one of Western medicine’s black holes. There are
many and they are deep, and kids with difficult-to-control seizures are among them. So what does that mean? It means that our medical problems and our
childrens’ medical problems are precisely that -- OURS. At first, that’s a pretty
intimidating and perhaps a seemingly foolish concept, both to us and to some physicians. After all, they went through years of education. They’ve seen countless patients in their practices. And then we walk into their offices with a disease we probably don’t even know how to spell. How presumptuous and perhaps foolish of us, the patients, to ask and then pursue the hard questions, learn the side-effects, get the second opinions, do the research, and participate in the cure -- in short, become proactive. Ironically, the "side-effect" of participating in our medical destinies may not only lead to getting better sooner. It is empowering. Though I would do almost anything to go back and have Charlie not suffer epilepsy, the experience has been empowering. Whether or not responsibility for informing ourselves confirms the information we learn from our physicians, it’s nevertheless empowering. As fate would have it, I am writing this afterword from a hospital bed where I am fighting leukemia. But the bed I am lying in, the treatment I am undergoing and the doctor who is helping me are not arbitrary. Though my diagnosis was shocking and treatment was needed immediately, there was time to find information, interview oncologists and even visit hospitals before setting sail on a course. Mercifully, I found a doctor who is bright, compassionate and believes in informed joint decision-making. We take control of so many lesser issues in our families’ lives -- meals, bedtimes, TV hours -- why not have that same attitude with the most important issue - our families’ health? In the worst case, we have learned something new; in the best case, we have improved either our lives or the lives of our children. There is no downside.'
https://web.archive.org/web/20080123063544/http://www.charliefoundation.org:80/noframes/diet/overview.php
'
'The Ketogenic Diet in Pediatric Epilepsy
Jong M. Rho, M.D.
Key Points
--Ketogenic diet helps control seizures in up to two-thirds of children refractory to anticonvulsant drugs
-- Children with partial seizures may not respond as well to the diet
-- The role of ketone bodies as markers of seizure control is imprecisely defined
-- Their role as direct anticonvulsant agents is also unknown
-- Tests for transporter defects and enzyme deficiencies help screen diet candidates
-- Important clinical questions about the ketogenic diet remain unanswered
Most practicing child neurologists possess a basic understanding of the ketogenic diet---the highfat, low-protein, and low-carbohydrate diet for treating children with epilepsy who do not respond to or cannot tolerate drugs. This diet mimics the biochemical changes associated with starvation and induces, among other changes, production of ketone bodies (mainly beta hydroxybutyrate, and to lesser extent, acetoacetate and acetone), which has been implicated in the mechanisms of seizure control.
Before the historic first announcement of results with the ketogenic diet by the Mayo Clinic [Wilder 1921], bromides and Phenobarbital were the only effective options for antiepileptic therapy. Fasting as a method for controlling epilepsy had been reported sporadically long before this time. However, it was only with such reports in the clinical journals did other
medical centers begin adopting the ketogenic diet as an effective treatment for intractable cases of epilepsy.
Still, the diet remained generally under-utilized, being utilized mainly at institutions such as the Mayo Clinic and Johns Hopkins, until the 1990s when a national television program aired a report on a child whose epilepsy was cured by the ketogenic diet. Later, the Charlie Foundation (named after the young patient) was formed and a television movie recounting Charlie’s success with the ketogenic diet was produced. It also prompted a flood of inquiries to pediatric neurologists and epileptologists about this treatment option.
Even today, however, after a long history of clinical use and the recent surge of professional interest and research, many questions remain unanswered about the ketogenic diet. The purpose of this review is to update neurologists by highlighting key issues and controversies pertaining to this important diet-based therapy for epilepsy. In particular, the review will focus on the potential role of ketone bodies in energy metabolism and in seizure control, the indications and contraindications for the ketogenic diet in pediatrics, and other practical clinical questions involving efficacy, patient selection, monitoring, and side effects.
Diet Overview
The classic ketogenic diet starts with a period of fasting and relative dehydration aimed at achieving ketosis, which is reflected by elevated ketone levels in the urine. There are several variations on this theme (e.g., the medium-chain triglyceride or MCT diet), all based on the principle that one can “force” the organism to use fatty acids and ketones as the main sources of energy, while decreasing the utilization of carbohydrates [Freeman et al, 2000]. This important diet initiation is usually accomplished in a hospital or specialized outpatient setting. An example of the dietary regimen after this introductory phase is listed as follows:
-- Restrict total calories to 75% of the recommended daily allowance, with 90% of the calories coming from fat
--Restrict protein to 1 gm/kg
--Provide a very small amount of carbohydrate
--Restrict fluid intake to 60-70 cc/kg/d
--Supplement this diet with vitamins and minerals
The target for the overall ratio by weight of ketogenic foods (i.e., fats) to anti-ketogenic foods (carbohydrates and proteins) is usually 4:1 or 3:1. Maintaining such a high ketogenic potential usually entails a diet of fatty oods, creams, and special oils. A dietitian or a nurse with special
nutrition training is required to tailor ketogenic diets for children and to help families adhere to exacting strict regimen. Also, before being placed on the diet, the child with intractable epilepsy should always be evaluated within the context of a childhood epilepsy center. Only a thorough evaluation in such a setting will ensure that surgical or pharmacological treatments with potentially greater success rates are not overlooked.
Most treatment centers leave the child on the diet for 2 to 6 months to assess potential efficacy. If the patient is seizure-free, as with anticonvulsant therapy, the therapy continues indefinitely for at least a two-year period. With such success, the patient can be weaned from the diet. There is clinical evidence to suggest that early intervention with the diet may even alter the processes of epileptogenesis and render a permanent cure. However, if a patient is taken off the diet (thus breaking ketosis) and seizures recur, it may be difficult to regain control after reinitiation of the diet due to a persistent of high insulin levels in the face of lowered glucagons. Therefore caution is recommended in prematurely removing patients who have been successfully controlled.
Intermediary Metabolism and Ketone Bodies
Elevated levels of ketone bodies have been strongly associated with seizure control and seizure freedom, and all practicing neurologists employ them as biochemical markers of treatment. However, the ketosis produced by the ketogenic diet may not be the main factor in controlling epileptic seizures in children [Schwartzkroin 1999]. Nevertheless, the clinical goal has historically been to achieve high urine ketone levels, and the importance of this time-honored practice can only be appreciated through an understanding of intermediary metabolism.
When the glycolytic pathway is deprived of glucose, as during starvation or the ketogenic diet, free fatty acids are mobilized as substrates for mitochondrial oxidation (Figure 1). In addition, certain amino acids may be converted to ketoacids that can provide other substrates (e.g., alanine to pyruvate) for Krebs cycle activity. The hepatic microsomal system can also convert fatty acids to dicarboxylic acids (via omega oxidation). These dicarboxylic acids require carnitineesterification for urinary secretion [Sankar & Sotero de Menezes, 1999].
Free fatty acids are not readily available to the neuron itself. However, fatty acids can undergo aseries of conversions and translocations to produce acetate substrates for ketone body production. These ketone bodies are carried across the blood-brain barrier (by a fasting-inducible transporter called the monocarboxylic acid transporter) and into the neuron where they are available as an energy substrate for cerebral metabolism.
Thus, one major physiologic role for ketone bodies is to provide an alternative energy substrate for brain and muscle under conditions of fasting or a high-fat diet. In a classic study of fasting obese volunteers, for example, glucose utilization accounted for only 29% of the brain’s oxygen
consumption while ketones extraction accounted for 52% [Cahill 1966]. Playing another major physiological role, ketone bodies act as the principle source of energy during early postnatal development. Furhter, they are the substrates for the carbon skeleton of lipids that comprise the cell membranes of growing brains and organs. Thus, ketones are involved in both the energy supply and lipid biosynthesis of the embryonic central nervous system (CNS).
But do ketone bodies exert a direct antiepileptic effect? Can they modulate neuronal excitability? Several clinical studies have now shown that diet-induced ketosis (especially at very high concentrations) seems to correlates with the level of seizure control. (The most recent studies will be discussed later.) Also, abrupt loss of seizure control has long been known to occur within hours after ketosis is broken [Huttenlocher, 1976].
Thus the compelling question remains: are ketones directly responsible for anticonvulsant activity? Or are they just an epiphenomenon of some other diet-induced physiological change? These questions have been explored in varied experimental settings.
&Mac183; ß One recent animal study, for example, showed that ketone bodies do not directly alter the excitatory or inhibitory hippocampal synaptic transmission. [Thio 2000] Neither beta-hydroxybutyrate nor acetoacetate affected whole cell currents evoked by glutamate, kainite, or gamma aminobutyric acid (GABA) in cultured hippocampal neurons. The ketone bodies also failed to prevent spontaneous epileptiform activity in the hippocampal-enterorhinal cortex slide seizure model.
&Mac183; Results from our laboratory in cultured mouse neocortical neurons were similar, with no effects of the ketone bodies on the classic neuronal targets of anticonvulsants. Investigators should also be aware that beta-hydroxybutyrate is a stereoisomer, with the D-isomer being the biologically relevant species. The non-physiologic L-isomer possesses anticonvulsant activity both in vivo and in vitro, and is due to the presence of a contaminant, dibenzylamine.
&Mac183; Similarities in the chemical structures of beta-hydroxybutyrate and GABA have led to speculation about GABAergic inhibition induced by the ketogenic diet. Results from studies are conflicting, with one showing no changes in whole brain GABA [Al-Mudallal 1996] and another demonstrating that ketonescan increase GABA in synaptosomes. [Erecinska 1996].
&Mac183; Finally, magnetic resonance spectrophotometric techniques have shown elevated levels of cerebral ketones in patients who are successfully controlled by the ketogenic diet [Pan et al., 1999].
Overall, the experimental evidence supporting a direct link between ketone and seizures is far from convincing. Indeed, as with the underlying causes of the seizures themselves, the ameliorating actions of the ketogenic diet may be multiple, with a host of diet-influenced metabolic changes acting in concert to decrease membrane excitability.
But even as research continues, the clinical connection between peripheral ketone levels and seizure control still impels clinicians to confront more practical questions. For example, what assay method should be employed to monitor diet efficacy? Urine dipsticks are commonly used for this purpose but these measure acetoacetate, the less prominent ketone body. Which ketone body actually correlates best with seizure control is unknown. If beta-hydroxybutyrate ketone is actually the preferred marker, a new reflectance meter (Keto-Site™, GDS Diagnostics) will assay the D-isomer from a small drop of blood. But then, what is the “therapeutic concentration”
for either of these ketones? And what does the peripheral level predict about the brain level?
Clearly, many questions remain about the physiological relevance and the practical utility of monitoring ketone bodies in the ketogenic diet.
Special Indications and Contraindications
Several specific inborn errors of metabolism can upset mitochondrial function and lead to dysfunctional glycolysis. Children with these special conditions may be strong candidates for the ketogenic diet, which will provide an important alternative energy source capable of crossing the blood-brain barrier (BBB) and sustaining cerebral energy metabolism.
The best example of such a condition is the family of glucose transporter defects (e.g., GLUT-1 deficiency) where glucose cannot penetrate the BBB [DeVivo 1991]. Two other conditions with less clear indications for special diet are pyruvate dehydrogenase complex deficiency where acetyl CoA production is blocked [Wexler 1997] and glycolysis-upsetting phosphofrucokinase deficiency [Swoboda 1997]. The benefit of the ketogenic diet is even less certain in mitochondrial cytopathies due to Complex I deficiency, which presents in infancy with hypoketogenic hypoglycemia and hepatomegaly [Sankar & Sotero de Menezes, 1999].
_______________________________________________________________________
Insight“In difficult-to-control seizures in infants, especially myoclonic seizures, it’s important to consider an early look at glucose in the spinal fluid even if the child is afebrile. With glucose transporter defects, the ketogenic diet is the treatment of choice.”
Dr. Riviello
_______________________________________________________________________
Most inborn errors of metabolism involving mitochondrial transport of fatty acid oxidation are absolute contraindications for the ketogenic diet. These include, for example, deficiencies in carnitine (primary or secondary), carnitine palmitoyltransferase I or II, and translocase. The most common fatty acid disorder to be vigilant for is the medium-chain acyl dehydrogenase deficiency (MCAD). Other such deficiencies include those of long-chain acyl dehydrogenase, short-chain acetyl CoA dehydrogenase, long-chain 3-hydroxyacyl-CoA, and medium-chain 3-hydroxyacyl-CoA.
Clues to an inborn error of metabolism include developmental delay, hypotonia, exercise intolerance, and easy fatigability. In children with these presenting symptoms, several tests can determine if the child is suitable for the ketogenic diet. The recommended biochemical screening tests (in addition to the routine laboratory studies such as liver function tests, complete blood count, etc.) are for urine organic acids, serum amino acids, and serum lactate and pyruvate. As implied in Figure 1, findings of highly elevated dicarboxylic acids in the urine signal a problem with the normal pathway of intermediary metabolism (either mitochondrial cytopathy or a fatty acid oxidation defect) and this warrants further investigation.
Clinical Question
The ketogenic diet is highly effective in some children, but efficacy rates have varied depending on the study. Results from large prospective multicenter trials using either the classic Hopkins diet or the modified medium chain triglyceride (MCT) oil-diet are listed in Table 1. In general, more recent studies have reported lower rates of seizure control, probably due to better tracking of drop-outs (i.e., intention-to-treat analysis) and longer follow-up periods. Overall, about one-third of children come close to seizure freedom on the ketogenic diet, one third have reductions in seizure frequency, and one third do not respond. In recent prospective, multicenter studies, only 10% actually become seizure-free [Vining 1998; Freeman 1998].
Despite generally high efficacy rates in these children who are unresponsive to drugs, many questions about the ketogenic diet require further study. Determining which seizure types respond best to the diet, for example, has been a subject of debate for decades. The early controversy centered on cryptogenic versus idiopathic efficacy [Keith 1963, Livingston 1972]. And more recently, despite some reports of efficacy in both partial and generalized seizures [Schwartz 1989, Freeman 1998] many patient type- for example, those with partial seizures arising from temporal lobe pathology-still appear relatively resistant to the diet’s effects. In fact, patients with partial seizures have been excluded from most studies assessing the clinical efficacy of the ketogenic diet.
Other remaining points of controversy include the benefits of the classic diet versus the modified MCT oil diet, the potential of vagal nerve stimulation as a therapeutic alternative in these drug refractory patients, the long-term developmental effects of restricted protein and calories, and the effect of age on efficacy. On this last point, note that the diet has historically been considered more effective in infants and children because ketone extraction from periphery to brain is more efficient in the developing brain. The clinical data with the ketogenic diet in the adults is sparse, with approximately half the patients responding with greater than 50 % seizure reduction [Sirven et al., 1999].
The potential adverse effects of the ketogenic diet are well known (Table 2). In recent years, the clinical literature has focused on nephrolithiasis, growth retardation, and the potential for cardiac disease. Some of the acute toxic effects can be serious and careful monitoring is required.
Because many children with intractable epilepsy are on valproic acid, the special issue of potential exacerbation of drug side effects by the diet becomes another key issue. In particular, because carnitine deficiency is well documented with valproic acid use, supplementation is recommended in documented cases of deficiency (e.g., plasma free carnitine < 20 _mol/L after the first week of life or an esterifed to free ratio of > 0.4).
The ketogenic diet also increases the risk of nephrolithiasis, a risk that may increase in patients taking carbonic anhydrase inhibitors such as acetazolamide or, potentially, with newer broad-spectrum anticonvulsants that act (in part) at this same enzyme (e.g., topiramate and zonisamide). Preliminary experience indicates that children can be treated safely with such agents combined with the ketogenic diet.
In summary, although its mechanism of seizure control is imprecisely defined and severalpractical details of therapy (e.g., patient selection) require further study, the ketogenic dietremains a valuable option for therapy in the most drug-resistant cases of pediatric epilepsy. Before initiating a trial of the ketogenic diet, the clinician must ensure that the patient has had adequate trials of at least 2-3 anticonvulsants, and has been carefully considered for potential epilepsy surgery or vagus nerve stimulation. A thorough diagnostic metabolic work-up and a frank evaluation of the family’s potential to comply with the diet are also mandatory. In carefully selected patients without other options, the ketogenic diet can provide major benefits, both in terms of seizure control and quality of life.
Q&A
Q1 Why not just use the Atkins diet? Isn’t that ketogenic?
Dr. Rho: Many different diets are variations on the ketogenic theme but we
simply don’t have the clinical data to say which works best.Dr. Morton: We also need to counsel patients who have initiated this diet on
their own. Just because the do-it-yourself Atkins book is available at Barnes and Noble and it’s talked about in a keto chat room doesn’t make it safe. I had one patient who became hypokalemic on the diet.
Q2 Is he vagal nerve stimulator replacing the ketogenic diet as an option for children who are not traditional surgical candidates?
Dr. Rho: To some degree, that was our experience at the University of Washington in Seattle. The overall use of the ketogenic diet at several major centers has fallen somewhat in the past few years.
Dr. Bourgeois: It depends on the seizure type. At Children’s Hospital in Boston we still prefer the ketogenic diet for those with Lennox-Gastaut and similar epilepsies. The VNS might be considered for those few children with partial seizures who are not surgical candidates, but overall our use of the ketogenic diet has stayed about the same.
Q3 What is the role of the family in success of the ketogenic diet?
Dr. Rho: The diet involves an exacting formulation and regimen and the family and social structure of the patient is critical to its success. If the family cannot help maintain complete compliance, ketosis cannot be achieved. Even small lapses such as not eating the whole meal (to maintain the proper ratio) or eating substances that contain sugar (whether a candy bar or even certain anticonvulsants) can undermine the diet. Family support is critical in maintaining a child on this diet.
Table 1. Clinical Efficacy of the Ketogenic Diet
Study Diet Seizure-Free Seizures_ Follow-up
By&Mac179; 90%
Livingston 1954 Classic 43% 3 months
(n= 304) (“controlled”)
Schwartz 1989 Classic 46% 3 months
(n=59) MCT 37% 3 months
Mod MCT 41% 3 months
Kinsman 1992 Classic 29% 38% 31 months
(n=58) (50-99%)
Swink 1996 Classic 22% 22% 12 months
(n=22)
Freeman 1998 Classic 7% 20% 12 months
(n= 150, intent to treat)
Vining 1998 Classic 10% 20% 12 months
(n=51, intent to treat)
MCT: Medium chain triglyceride
Table 2. Side Effects of the Ketogenic Diet
Possible long-term effects of high fats (cholesterol, triglycerides)
Growth retardation due to protein deficiency
Vitamin and mineral deficiencies
Constipation
Kidney stones
Elevated uric acid production
Impaired immune defenses (possibly related to neutrophils)
Metabolic acidosis
Liver failure
Figure 1. Taking the Alternative Route to Cerebral Energy Generation:
Metabolic Shifting with Ketogenic Diet'
Fall 2003
Volume 16, Number 2
Volume 16, Number 2
A Talk with John Freeman:
Tending the Flame.
Freeman's route with the ketogenic diet calls to mind Gandhi's comment: First they ignore you; then they laugh at you; then they fight you; then you win.
 |
In the 1920s, when bromides and phenobarbital led approaches to epilepsy, the alternative-a high-fat, very low-carbohydrate and protein regimen-gave about a third of child patients excellent to complete control of their seizures. The rest on "the ketogenic" had at least 50 percent control or better. In part because the diet was so unusual-it mimics seizure-quelling metabolic changes that come, oddly enough, after days of fasting-and in part because nobody had a clue to how it worked, the ketogenic route seemed magical.
"All that, for the most part, hasn't changed," says Freeman. Today, parents of the nearly 500 children he and his team have treated still shake their heads that such an approach can work. "And what we don't know about the diet still exceeds what we do,"Freeman says. What's different, however, is that he and colleagues Patti Vining, M.D., and Eric Kossoff, M.D., have worn down naysayers-and there've been some-with sound research.
They've shown, for example, that diet advantages extend to teenagers, that children's growth is only mildly slowed and that side effects like kidney stones are manageable. They've correlated blood levels of one ketone body-a metabolic byproduct-with efficacy in stopping seizures and have published protocols on keeping patients on the dietary straight and narrow.
Q. There's no denying the obvious about the ketogenic diet: it's loaded with fat.
A. That's true. The version we use is 90 percent fat, with 4 to 8 grams of carbohydrate and 1 gram per kilogram weight of protein daily. Most people's first reaction is "yuk." Yes, patients drink heavy cream. But the diet's palatable: Mushroom omelets with bacon. Broccoli with cheese. There's variety.
Q. And you certainly need the fat...
A. … because it gives the desired effect. Normally, fat is burned to carbon dioxide and water. But that's in the presence of carbohydrate. Without the Mars bars, fat's incompletely oxidized. Then blood levels of ketones-specifically beta-hydroxybutyric acid (HBA) and acetone-begin to rise. We think ketones are largely responsible for the diet's effects. One of our studies shows seizure rates drop as levels of HBA rise.
Q. How would anyone think up such a diet for epilepsy?
A. What you're doing is mimicking the effect of starvation. In the 1920s, people discovered that fasting 10 to 20 days might control seizures for weeks or even years. The fellow who developed the ketogenic diet-not me-knew that rigorous fasting prompts ketosis. In 1922, after trying the diet on patients, he saw their seizures decrease rapidly.
Q. But then the diet went out of favor?
A. Yes. In 1938, Houston Merritt discovered Dilantin, a wonderful anticonvulsant but a setback to our understanding the ketogenic diet and epilepsy in general. It's easier to take a pill than to fast for 18 to 25 days and stick to a diet. So most people switched. Only a few places like Hopkins continued the diet for small numbers of patients.
Q. Yet, there's been a resurgence of interest?
A. There has. In 1993, a Hollywood producer, Jim Abrahams, called me. His young son Charlie had suffered thousands of seizures. He'd been through all the medications, had seen five different pediatric neurologists, had had a fruitless surgery and still lived with hundreds of seizures a day. Then Jim came across a chapter on the ketogenic diet in a library book. He called us; we put Charlie on the diet. The boy's seizures were completely controlled.
Jim was outraged that nobody'd informed him of the diet! So he began to publicize it. Then came The Deluge. After Charlie's story appeared on "Dateline," we got 5,000 phone calls. Now, years later, interest is still steady.
There've always been patients with uncontrollable seizures. Their desperation is real and the diet offers a valid option.
Q. How's the diet sit with most clinicians?
A. When we started publishing studies in 1996, nobody believed us. When we held a press conference after our first multicenter trial, the president of the American Epilepsy Society stood up and said, "it's never been studied in a blinded fashion." That really stuck in my craw. So we've steadily ticked off studies, all of which support the diet's efficacy and safety when done properly. And we've just finished the double-blind, crossover study and are analyzing data.
Many epileptologists don't use the diet. They believe it works-our studies show-but they lack staff. The secret to the ketogenic diet is the dietitian. There's a lot of interaction with the dietitian, a lot of education because the diet's not easy. Actually, it takes a team, and we have an excellent one.
Q. Why don't you see adults on the diet?
A. A good question. As far as we know, no biology lies behind its not working for them. At the least, it might help adults leave or lower medications. But I'm a pediatric neurologist.
Q. You say the diet may have other uses?
A. Possibly. We know ketones preserve heart muscle up to a point after heart attack, probably because an oxygen and glucose-starved heart can use them as an alternate energy source. Would a keto diet be helpful? What about strokes? The brain can metabolize ketones. Would it help stroke victims to go on a short keto diet?
Q. And the future for epilepsy patients?
A. Sooner or later, we'll understand how the diet works. Why, for example, does the diet control seizures in some children who've failed six drugs-not only while they're on it, but apparently forever after they've stopped?
Something has fundamentally changed epilepsy's "on" switch. We hope the diet will lead us to that switch, and to a therapy that doesn't involve whipping cream.
https://www.charliefoundation.org/blog/entry/mrs-kelly
Mrs. Kelly
Mrs. Kelly
Ironically, though the Ketogenic Diet is underutilized due largely to a dearth of keto dietitians, the argument could well be made that none of us would be reading this blog, and perhaps today the diet itself may have faded into extinction, were it not for one particular dietitian, Millicent Kelly RD. Along with Dr. John Freeman and Dr. Samuel Livingston, she became the dietitian at Johns Hopkins that quietly put so many hundreds of children on the ketogenic diet and kept the diet afloat while fighting a near perfect Western medicine storm of modern drugs, their simplicity of use, and their enormous profit margins.
Mrs. Kelly, as her patients came to call her, enrolled at Johns Hopkins after college graduation in 1948 to take a one-year course as a student dietitian. She formally retired in 1999. She learned the diet from Dr. Samuel Livingston, a Johns Hopkins pediatrician and a passionate advocate for the diet. In 1953 he published that of 304 patents he had put on the diet, 43% had complete seizure control and another 34% were markedly improved. (As a measure of how times have changed, Livingston not only would make follow-up house calls on his keto patients, he would frequently take a week at a time and travel from Baltimore to Texas, Florida, or Wyoming to see how they were doing). It was in this positive environment that Mrs. Kelly learned and then helped perfect the diet, one child at a time.
Two decades later, in 1973, though the keto dietary staff at Hopkins had shrunk to Mrs. Kelly and just a few other dietitians, Livingston wrote, “Since 1958 we have treated an additional 575 patients with the ketogenic diet regimen and the results with regard to seizure control were essentially the same as those reported earlier.” Yet the patient lists dwindled as new, easily prescribed drugs came along and overwhelmed the work intensive ketogenic diet.
It was about this time that Livingston retired and handed over the reins of the ketogenic diet program to John Freeman who, equally impressed with the diet’s success and challenged by the absence of medical acceptance in the face of modern drugs, found a way to keep the diet afloat--found a way within the Hopkins machinations to keep Mrs. Kelly helping fifteen to twenty sick kids per year stop having seizures with a diet and her gentle tenacity.
Decades passed. More new drugs were introduced. Other ketogenic diet centers began to fall by the wayside. One by one, the dietitians dropped out of the keto program leaving Dr. Freeman and Mrs. Kelly, along with Diana Pillas coordinator-counselor at Hopkins Pediatric Epilepsy Center, the lone slender threads that kept the ketogenic diet helping kids at Hopkins. By 1990, contract food services took over the keto nutrition at Hopkins complicating her work even more acutely. Later that year when Mrs. Kelly was demoted within the nutrition department, she went to Dr. Freeman to announce her retirement. Freeman, whose rebellious, persistent spirit is loved by all who know him, fully understood Mrs. Kelly’s importance to the very existence of the diet, and would have none of it. He found a way to keep her on board as Pediatric Dietary Consultant to Pediatric Neurology. Mercifully, she stayed.
In 1994 the ketogenic diet dramatically circumvented traditional medical information distribution routes, and awareness of its success went straight to millions of families through mainstream media focus. Public demand fueled an enormous resurgence of interest in the diet within the scientific and medical communities. It began to achieve a new foothold in epilepsy treatment and has begun to restore its rightful focus within the neurology community. Today, with over 200 ketogenic diet centers world wide, it is once again becoming a priority in the treatment of children and adults with difficult to control seizures, other neurological disorders, and certain cancers.
But one has to wonder where this story might have ended were it not for the Livingston/Kelly/ Freeman connection. What might have happened if Mrs. Kelly had simply gone away? So I asked her recently what kept her going through all those years of hard work, little pay, and even less recognition. “I thought it was my job,” she said. “I met some of the nicest people. Some of those mothers and fathers and families--what they had to endure. If I could do something, I had to.”
Jim Abrahams
The Charlie Foundation
The Ketogenic Diet: One Decade Later
*Photo at left is of Charlie Abrahams and Tim Indermittee - 2 seizure free kids, circa 1996.
When Charlie started the Ketogenic Diet and his seizures went away so dramatically at the end of 1993, I asked Dr. Freeman from Johns Hopkins three questions.
1) Why did we have to find the diet on our own?
2) Why didn't any of the pediatric neurologists we saw tell us about the diet?
3) Why, even when we learned of the diet as a treatment option, did they try to talk us out of it?
Although I didn't fully grasp the dark implications of his answer at the time, here's what Dr. Freeman said, "The Ketogenic Diet will never become popular again if you try raise awareness through traditional means of medical communication (meetings, papers, etc.). If you want to help restore the diet's rightful place as an early treatment option for children with seizures you need to circumvent the medical community and go straight to the public with this information."
Dateline NBC found out about Charlie as we were making our introductory video to the ketogenic diet and came to film his story.
In anticipation of what Dr. Freeman called "the deluge" from the huge public demand that would occur when the diet was revealed to the world on a national level, he and the Charlie Foundation held a conference at which directors from seven other epilepsy centers from around the country came to Hopkins with their dietitians to learn about the diet. Nonetheless, the public demand from the broadcast caught the medical community largely flat footed. Dr. Freeman said that his clinic alone got over 5,000 calls during the week following the broadcast.
I also tried to read as many of the thousands of letters and requests for information we received at The Charlie Foundation. They were incredible: grateful for hope, angry about lost years, heartbroken over potential unnecessarily damaged lives.
But one letter stood out as a new direction to reach the public. It was dated 10/27/94 and was kind of a stream of consciousness from Connie Indermittee, a Chicago area mom who had seen Dateline the previous night. The program had triggered memories of her experiences and feelings from the mid 1970's when she found the ketogenic diet for her son, Tim. Though in many details it was uniquely dramatic, in essence it was the story of all the families who have had to battle through epilepsy's costs, stigma, medical resistance, and ineffective and debilitating drug treatments to find diet therapy.
I read her letter and made three phone calls.
The first was to Connie to ask if I could come visit.
The second was to Dr. Freeman to share the story. (Tim had started the diet at Hopkins also).
The third was to Meryl Streep, who had helped us with the introductory video, to ask, "What do you think?
Please take the time to read the letter below from Connie Indermittee which ultimately provided the plot for the movie "First Do No Harm", written and directed by Jim Abrahams. We wanted to share this very special letter beacuse Connie's story represents the story of EVERYONE who at one point, may of felt helpless as a parent to find a treatment that works for their child or loved one. Thank you Connie and the entire Indermittee family for continuing to inspire everyone to never give up.
See transcribed letter below handwritten letter.
"Dear Sir,
In April 1978 my 3 year old son had 1 gran mal seizure. We took him to the hospital and all the tests proved nothing. In the next 7 months, we took him to 6 other hospitals, 21 doctors, and 38 drugs. He had between 150 and 200 seizures a DAY. He spent the last 2 1/2 months at Pres-St. Lukes in Chic (Chicago) in intensive care. He was scheduled for exploratory brain surgery. I was almost praying Tom would die instead of living the rest of his life as a grossly retarded person with this problem.
I must stop for a minute and tell you, as I write this chills run down my spine. This was a nightmare that you relived for me on Dateline. I was going crazy trying to (self) cure my son. I went to the U of I Library and read - for weeks - from the time they opened to closing.
I got a copy of Sam Livingston's book. I read the Ketogenic Diet. I called Baltimore, They told me to come right away -
I tried to take Tim out of the hospital. I realized I'd LOST the custody of him. They would not let me transfer him from Pres-St. Lukes to John Hopkins. I stole him from the hospital. I had the help of 2 others to pull it off. He was on Valium IV 24 hour plus 8 other drugs.
I knew he could die. They knew he could die. He was seizing every 1/2 to 3/4 hour.
We had an ambulance come in the middle of the night. (at shift change) Took him to a commercial flight to Baltimore. Pulled the IV so we could board- wasn’t sure if he'd live to see Baltimore. We arrived - went to Livingston clinic - went to J.H. Hos. - 3 days starvation - went on the Ketogenic diet. A pure miracle -.
Tim is 19. He has not seized since that trip to Baltimore. He is a smart beautiful boy. He attended 1 year of college. He's a lucky kid, like yours.
Since, I tried to tell people about this method of treatment. The doctors here in the Midwest would not even consider its use. They would not admit that this is the cure for children with multi seizure.
If I had to do this all over again - I don’t know if I could. It financially devastated us. My husband lost his job. My other 2 children were virtually abandoned by my husband and I. We begged Fed Land Bank not to take the farm from us. The neighbors helped by taking the other kids, filling the freezer with food and most of all their prayers.
I stayed at Notre Dame Convent in Baltimore, as I had not any money for a motel. I stayed in the cloister as that was the only place there was to stay. All the sisters prayed a miracle would happen. It did. The Ketogenic diet saved my son.
The hospital taught me how to administer the diet. They were great. they wrote all the costs off as they knew we were totally financially broke.
For 2 years I followed the diet with Tim. We found that to be very hard, but we did it.
I have shopping bags full of medical records that would blow your mind showing the various treatments. I had doctors telling me they exhausted every treatment known, so just take him home and live with him seizuring - with no hope for any future for Tim.
As I write this, my heart is skipping. I remember like yesterday the ordeal we went through. I wish that NO ONE, ever. I tried so hard to tell my story to Readers Digest, local and larger news - media, and they weren't interested. Think how many children could have been saved.
Please write me. I may be of help to you and the awareness of this treatment. Keep it in mind that no doctor ever - in Chicago- had ever "tried" this diet. I begged them. They would not. When the tribune writer realized that I was bashing some of the most thought of doctors in the Midwest - they canned the whole story. To this day the pediatrician who first took care of Tim does not believe that is what cured Tim's seizure problem.
I almost hate all doctors now. They almost killed my son.
By the way - how we got to fly to Baltimore - My neighbor was a doctor and a pilot. He arranged the flight - the ambulance - the escape from Pres. St. Luke's. He could have been fired from his airline and lost his license to practice medicine. The risk he took was huge - the results were worth it.
Again please let me know you received this. I now realize someone else went thru the ordeal of this size.
Please excuse this poorly written letter. I shake when I think of those days - I forgot to slow down while writing - but it's readable, so I'm sending it. I kept a daily journal during those days and you relived them last night.
Please send me the video. thxs-"
Connie Indermittee
