Travis Christofferson M.S. Dominic D’Agostino Ph.D.
If you haven’t read Part 1, check it out here.
The father of Geyelin’s young cousin, Charles Howland, was a wealthy New York corporate attorney. Shocked that the cure to his son’s epilepsy lie so far outside the medical establishment, Howland became obsessed with a single question: why did fasting cure his son of epilepsy? Conklin already thought he knew the answer. He claimed epilepsy emanated from the intestines. He speculated that toxins were secreted from the lymph nodes surrounding the small intestine then stored in the lymph system, and from time to time, discharged into the bloodstream, causing seizures. Simply not eating allowed the toxins to be cleared. Conklin had no evidence to back his claim; his reasoning was nothing more than a wild guess, probably pushed along by Macfadden. Along with many doctors, Charles Howland wasn’t satisfied with Conklin’s contrived explanation. Instinctually, Howland felt there was more to it. He desperately wanted to know – he wanted an answer backed by actual evidence. In hope of finding an answer, he wrote a check to his brother, a professor of Pediatrics at Johns Hopkins, for five-thousand dollars.
Five thousand dollars went a long way in the early 1900’s and Dr. Howland used the money to set up a state of the art laboratory at Johns Hopkins dedicated to the new mission. As with his brother, the question quickly became a particular obsession. The answer, reasoned Howland, was sure to lie within some shift in the epileptic’s metabolism. To find the answer would be an exercise in comparison. What did the metabolism of the epileptic look like before and after fasting, and could the relevant factor be isolated from the noise? Far too steep a task for any individual, he turned to Dr. James Gamble, an unusually precise and methodical clinical chemist. The canvas for Gamble’s search consisted of four fasting epileptic children. He carefully monitored every known biochemical variable as they transitioned into the fasting state. He collected and exhaustively analyzed their urine and blood with painstaking detail – from water loss, to electrolytes balance, acid/base balance, and the curious mention of the strange occurrence of two ketones, beta hydroxybutyrate and acetoacetate, in the fasting patient’s plasma and urine. To Gamble, the compounds were a mystery. He speculated that they were meaningless; the byproduct of the “incomplete oxidation of fats” – nothing more than a useless exhaust expelled as the patients began to burn fat.
In the end, despite an extensive search, the report held no definitive answer, the biochemical shift that reduced seizures in fasting epileptics, for the time being, remained a mystery. As Howland’s team continued its frenzied search, about a thousand miles west, in Chicago, the seeds were being planted to offer up a different explanation.
Food Becomes Medicine
Rowland Woodyatt and Evarts Graham, both medical doctors in Chicago, were having an argument over lunch. The waiter was already tense. Their voices were elevated and, worse, they had scribbled arcane symbols all over the table cloth, it was most likely ruined. The argument had drifted away from the scribblings into something more personal. “Your perfectionism is holding you back, can’t you see that,” said Graham, clearly frustrated. “Did you know it took Lorenzo Ghiberti twenty years just to sculpt the bronze doors of the baptistery of San Giovanni. Perfection doesn’t care how long something takes,” retorted Woodyatt, in a measured voice. Woodyatt was a perfectionist, in every sense of the word, and Graham was not the first to notice. He could agonize over the wording of a single sentence, sometimes for an entire day. Graham found this absurd, a waste of time and talent. But for the study of human metabolism, Woodyatt’s peculiar personality trait was perhaps his greatest strength. He was intensely passionate about the details. He could zero in, focus with singular purpose, and not allow himself to be railroaded by the incredibly complex maze of metabolic pathways where others quickly became overwhelmed.
In the summer of 1921, Woodyatt’s passion for metabolism culminated in an article titled: Objects and Method of Diet Adjustment in Diabetes. Although insulin had yet to be isolated, researchers knew that the pancreas was the site of pathology – injecting diabetic dogs with pancreatic extract could normalize blood sugar levels. Woodyatt realized that the problem in the diabetic lie solely in pancreatic dysfunction, resulting in an inability to utilize excessive carbohydrate. At the time, physician’s often fasted diabetics until glucose disappeared from the urine, the idea being to “rest” the pancreas. A normal diet was then slowly reintroduced, usually with carbohydrates first. Unfortunately, the diabetics soon found themselves back where they started, with sugar building up to malevolent levels within the blood stream.
That fasting cleared the bloodstream of sugar made Woodyatt curious, inspiring him to ask a simple question: if fasting diabetic patients resort to burning their own fat, why not just provide fat through diet, keep the carbohydrates away, and keep the diabetic in the fasted state indefinitely? It was a simple proposal of exclusion. It was a question that perhaps should have been asked sooner, but at the time it was easy for researchers to get lost in the details. Big questions still lingered, the largest was the fate of dietary fat: it was not clear if fat could be converted directly into sugar. But Woodyatt refused to let the gaps in knowledge lead to a dead end – when a pathway was unknown, he let empirical, macro-evidence guide him. In this case, he knew another group had already experimented with a high fat/low carb diet in diabetics with striking success – even if fat was able to be converted into glucose it really didn’t matter, reasoned Woodyatt, something appeared to be blocking its conversion. He was formulating a hypothesis that had only lingered in and out of researcher’s minds, but had never been concretely suggested. Once he wrote it down, it seemed obvious: why not shift the ratio of the diet in favor of fat, this way the diabetic would be able to rest his pancreas, remove the excess sugar from his bloodstream, and utilize fat instead as an energy source. The smoldering problems of insulin, carbohydrates, and blood sugar were removed from the equation. He couldn’t help chastising the medical community for their inflexible, dogmatic assumptions, isolating the problem as a tendency toward dietary groupthink: “the universal custom of thinking of the food supply simply as so much carbohydrate, so much protein, so much fat and so many calories without further analysis,” wrote Woodyatt. The patient doesn’t even have to be deprived, he reasoned, they could consume the same amount of total calories. In a single sentence Woodyatt toppled the monolithic view of diet. Now, because of him, diet was no longer viewed as a concrete pillar, now it was a column built from subcategories (carbohydrate, protein, and fat) that could be manipulated, shifted, and restacked in different combinations depending on the needs of the patient.
While Woodyatt was exposing fissures in dietary preconceptions, in the summer of 1921, three hundred and fifty miles north east of Chicago at the Mayo clinic in Rochester Minnesota, a doctor named Russell Wilder published three short paragraphs in The Clinical Bulletin. The letter described the same dietary epiphany as Woodyatt — maintaining the fasting state by replacing carbohydrates with fat – but Wilder imagined treating a different disease: epilepsy. “It has occurred to us that the benefit of Dr. Geyelin’s procedure may be dependent on the ketonemia which must result from such fasts, and that possibly equally good results could be obtained if a ketonemia were produced by some other means,” wrote Wilder. But Wilder had made an additional leap of logic. Woodyatt had suggested the dietary protocol simply as a means to sidestep the impaired carbohydrate metabolism of diabetics. How fasting, or the dietary maintenance of fasting, worked to control seizures demanded another explanation. Wilder reasoned perhaps there was more to it – suggesting the ketones generated from the diet might be of unrecognized significance. After all, they were the single metabolic variable shared between the fasting state and a low/carb high/fat diet. Until now, researchers assumed ketones were nothing but unhealthy metabolic debris, but now, because of Wilder, that assumption was questioned. Perhaps it was ketones themselves that were pulling the metabolic levers inside the brain of fasting epileptics. Wilder was anxious to test his theory. “It is proposed, therefore, to try the effect of such ketogenic diets on a series of epileptics.”
It’s hard to quantify the influence that words have. Attaching a name to an idea converts it from an abstraction into something tangible and concrete. Wilder’s naming of the “ketogenic diet” was to thrust it into the clinic, now it was real, now it was something that could be measured, tested, and prescribed.
Under the lamp of Woodyatt and Wilder’s clarifying epiphanies, Dr. Mynie Peterman, a mayo clinic pediatrician, enthusiastically put Wilder’s theoretical diet to a clinical test. First, he strictly defined the ketogenic diet to be tested, parceling it into one gram of protein per kilogram of the child’s body weight, 10-15 grams of carbohydrates per day, and the remainder of the calories in fat. Next, he began recruiting epileptic patients and convincing them to try the strange protocol. The scientific community was watching closely – they eagerly waited for the results. Once released, Peterman’s report revealed the diet’s effect was incredible. Most of the children, once racked with convulsions, experienced an immediate and powerful remission. They began to live normal lives. The price was minimal. Occasional a child became nauseated and vomited, and so Peterman found a little orange juice was an instant fix. But most transitioned to the new diet well and had few complaints.
The ketogenic diet, at first only a fragile theory, was working. While running his clinical trials Peterman noticed something else. Not only were the vast majority of kids either experiencing greatly diminished numbers of seizures, or free of them altogether, but there seemed to be a striking change in their character. Peterman noticed the children were “sleeping better, were less irritable, and displayed an increased interest and alertness.” This was in sharp contrast to the pharmacological treatments that dulled and muted the children, as if a wet blanket was pulled over their brains. The ketogenic diet, Peterman observed, lifted the fog. Peterman followed 37 children on the diet for 4 months up to two and a half years. All tallied, sixty percent of the children became seizure free, 34.5% were improved, and 5.5% were not improved. The ketogenic diet was a resounding success – undeniably better than phenobarbital and bromides.
While the newly débuted “ketogenic diet” was being studied at the Mayo clinic, doctors on the East coast were still deeply immersed in neurochemical transformation induced by fasting. Therapeutically, fasting had obvious limitations. The biggest problem, doctors realized, is that fasting was clearly only a temporary solution. The seizures were greatly diminished, if not stopped altogether while the child was not eating, but of course, it could not be maintained. In some of the more mild cases, after the fast, the seizures never returned. But in many cases, once the child resumed eating, the seizures gradually resumed. Wilder’s ketogenic diet offered an immediate solution to this problem. The therapeutic effect of fasting could now be extended on a patient by patient basis. News from the Mayo clinic trial quickly spread. Massachusetts General Hospital, in 1924, pivoted away from fasting and adopted the ketogenic diet as a treatment for epilepsy. Others were soon to follow. New studies tallied similar results as the original done by Peterman, and others also noticed the positive effects the diet seemed to have on the children, one researcher commented, “the diet is well tolerated without causing any untoward symptoms in the patients. On the contrary, they seem to be more alert and less nervous.” After tinkering with the ratios, clinicians determined that a formula of 4 parts fat to 1 part protein/carbohydrate seemed to work best (a ratio that has stood the test of time and today is known as the classic ketogenic diet.) Instructions for the ketogenic diet, meal plans, and extensive tables listing the nutritional composition of foods were added to textbooks. In response to rising demand, the Mayo Clinic published a pamphlet describing detailed meal plans and recipes for the ketogenic diet. Soon clinicians and dietitians at hospitals across the county were prescribing the new dietary treatment for epilepsy. Untold numbers of families with epileptic children were restocking their pantries and adjusting their family dinners. For doctors, and the families of the afflicted, it was probably an easy choice, the only two drugs on the market were highly sedative, and the diet was the opposite; it required some work, it wasn’t an easy fix, but the benefit was striking, immediate, and enduring for most. Word swiftly spread and the ketogenic diet became the preferred therapy for epilepsy across the country. “The results of fasting and the ketogenic diet are apparently the best that are obtained by any therapeutic procedure that we have to offer the epileptics in childhood today,” Geyelin told the American College of Physicians at a gathering in New Orleans in 1928.
“Like Stones for a Mosaic”
Charles Howland refused to give up. In 1922, undeterred by his brother and Gamble’s failure to find a definitive answer, he set out to expand the list of experts to help answer his question. He singled out Dr. Stanley Cobb, the associate professor of neuropathology at Harvard Medical School. Cobb was a cautious and careful scientist from a prominent Boston family that was speculated to have entered the neurosciences as a result of a childhood stammer. Cobb was already familiar with Howland’s story – he was in the audience a year earlier when Geyelin presented the case of his young cousin’s trek to Battle Creek and the successful treatment by Conklin. To Cobb, the story was not entirely surprising. Rumors of Conklin’s early results had intrigued him, and he had begun to investigate fasting’s effect within his own lab. When Geyelin had finished his presentation, Cobb excitedly shared his own work with the attendees, commenting that he had witnessed the therapeutic effect first-hand – preventing convulsions in animals by fasting them. What did surprise Cobb, however, was that now, one year later, the father of the child Geyelin spoke of was standing in his office, and asking for his help. Cobb had revealed how he felt about Conklin’s work in an earlier conversation with a colleague when he stated that fasting treatment was significant because it “revealed the relationship between epilepsy and metabolism.” In Cobb’s mind, this relationship demanded to be explored. Cobb agreed to help. Howland scribbled out a check for enough to fund Cobb’s efforts for two years.
Cobb knew the difficulty of what he had just signed up for. He would have to tap the same dogged grit that allowed him to overcome his childhood stammer. To get to the bottom of Howland’s question was to step into the unknown – despite Gamble’s intense effort, few solid leads had been found – all that was known for sure was fasting worked. Instinctually, he knew he would need help.
First on Cobb’s list to conscript into the effort was a Harvard educated doctor named William Lennox. Enthusiastic, innovative, and bold, Lennox became interested in epilepsy after witnessing the unrelenting and mysterious convulsions of a friend’s daughter while studying the health of missionary families in China in 1917. The strange nature of the disease stirred something in Lennox. In a stroke of serendipity, Lennox happened to be visiting Boston in the spring of 1921 and attended the AMA meeting where Geyelin presented. Suddenly, Lennox found himself at a turning point. He commented that he was “thrilled by Geyelin’s demonstration and having a compelling interest in epilepsy and its treatment, my missionary zeal was abruptly transferred from Chinese to epilepsy,” The timing was perfect – infused with Howland’s cash, Cobb offered Lennox a position. It didn’t take much convincing from Cobb to recruit Lennox. The intense curiosity simmering inside him made the decision easy.
Together they launched into the problem. Howland’s question was now expanded to include the ketogenic diet that had been defined a year earlier by Wilder. The diet was the preservation of the fasting state, and so by extension, the same rules probably applied. Whatever mechanism fasting worked through to mitigate seizures was most likely the same for the ketogenic diet. Wilder had added another suspect to the lineup: ketone bodies. Like Gamble, Cobb and Lennox dove into the metabolic transformation that occurred within fasting epileptic patients with painstaking detail. And like Gamble, after some time had passed, they realized the answer was not going to present itself easily. Strangely, it seemed every path they followed ended with a contradiction – as if they were purposefully being toyed with.
For example, Geyelin had noticed his fasting patients excreted acid – the more acid excreted, the fewer seizures. Ketones are acidic, so maybe, they reasoned, it was the increase in acidosis within the patient’s blood plasma from ketosis that was somehow acting to slow seizures. Other clues led them in this direction. Acidifying the patient’s plasma by injecting acid directly into their veins seemed to have an anti-seizure effect. But the problem was in the timing. The anti-seizure effect didn’t exactly track the acidification – once the pH level was made acidic, it took a while for the seizures to slow. Similarly, when the blood pH level was returned to normal, it took some time for the seizures to return. This didn’t match with the fact the induction of ketosis, either by fasting or the ketogenic diet, typically resulted in an immediate reduction in seizures – so clearly it wasn’t the acidity alone that mattered. Also, when they acidified the patients’ blood, their seizures eventually slowed, but then after a period of time, even while the blood was kept acidic, the seizures would roar back with vicious ferocity, as if a damn had been burst.
Maybe, as Wilder suggested, it was the ketone bodies themselves? To test this idea Lennox and Cobb put a patient on the ketogenic diet. Once her seizures stopped, she was injected with bi-carbonate (a compound that counteracts acid). When they tested her blood after the injection of bi-carbonate, surprisingly, there was an increase in ketone bodies, but, even with the increased ketones, her seizures returned with a vengeance – so clearly it wasn’t the ketone bodies by themselves. Every time they tried to isolate the relevant variable it would slip just out of reach.
The nature of the problem was not lost on Cobb and Lennox. They recognized what it was: an incredibly complex and interrelated series of neurochemical alterations. The search, they realized, was probably just getting started: “The painstaking accumulation of apparently unrelated facts must go on,” wrote Lennox, “until, like stones for a mosaic, they are sufficient in number to permit their assembly into a complete and intelligible design.” The answer remained a map of the world before Columbus. The yet-to-be-explored forbade a complete image. And the existing technology was too rudimentary for the time being to fill in the gaps. Howland’s question, it appeared, like the mapping of the earth, might be a multigenerational effort.
“Them Thar Hills”
Even if Cobb and Lennox failed to find a clear, succinct answer to Howland’s question, something special was happening in Boston. In 1930, Cobb, now 44 years old, was appointed Director of the newly formed neurological unit at Boston City Hospital. Under his Directorship, a powerhouse team of researchers, all united by an intense interest in epilepsy, fortuitously fell into place. Lennox followed Cobb to Boston City Hospital and they were soon joined by a Harvard trained neurosurgeon named Tracy Putnam and a John’s Hopkins trained neurologist, Houston Merritt. Putnam and Merritt met while in the throes of a neurological internship at the hospital and they experienced a powerful connection, forming a deep and enduring friendship. Both were described as “brilliant” and capable of having “unusual insights.” Putman had more than a professional interest in epilepsy because two of his relatives – one a cousin whom he regarded as a sister – suffered from the affliction. Their talent, passion and intellect did not go unnoticed by Cobb, he actively recruited them into the research effort. Together the group formed a tempest of creativity. What happened at Boston City Hospital was a rare alignment of the stars, a group of personalities that collectively elevated their work far beyond any single individual’s ability. An uninhibited atmosphere of infectious enthusiasm encouraged bold ideas. A writer described the unit: “its roster establishes the unit among the greatest institutions ever of its kind.”
But the timing couldn’t have been worse. The fragile realization of the extraordinary research team was almost shattered in its infancy. When the great depression struck in 1930, it crushed research programs across the country. For Cobb and Lennox, when Howland’s cash ran out, Harvard rushed to form an “Epilepsy Commission” so their work wouldn’t die on the vine. The program was funded by voluntary donations – which shut off like a spigot in the aftermath of Black Tuesday. At the last second, the Rockefeller institute stepped in – if they hadn’t, the history of epilepsy treatment may have had its course altered in incalculable ways.
The group knew the largest obstacle to understanding and improving treatments was a lack of good animal models to study. The current models used chemicals to induce seizures – a clumsy and inconsistent method that gave sometimes wildly different results. The newly developed electroencephalographic (EEG) instrument was able to record electrical discharge from patient’s brains. When strapped to an epileptic patient’s head, through a frantic amplification of squiggles on paper, the machine revealed a tornado of excessive electrical discharge. No one knew why the storm occurred, where it came from, or what caused it to disappear, but the new machine identified what a seizure was: electrical impulses firing without purpose – an overload of signal pulsating through the brain. Putnam reasoned that if a seizure was an electrical discharge then maybe he could trigger a seizure in animals by the same route: by administering an electric shock. The group seized Putnam’s insight. Using parts from an electric motor taken from a salvaged WWI German airplane, they assembled a makeshift machine that would meter out a trigger – a measured electric shock.
After some deliberation, Putman and Merritt decided to test their new machine on cats. The idea was simple: test the cats to see how much of a pulse caused them to have a seizure, then, give the same cats the drug to be tested, wait two hours, and repeat the test. If the cats required more of a shock to trigger a seizure while on the drug, then it was logical to assume the drug was anti-convulsive. Testing known drugs confirmed their logic. When the cats were given bromide it took 50% more current to generate a seizure than before; when given phenobarbital, it took three to four times more current than before. Their model was consistent and reproducible.
The group then made a vital observation. Ever since the discovery of bromides it had always been assumed it was the hypnotic or sedative effect of drugs that muted convulsions – the two properties were inseparable. The new experimental system allowed them to test that assumption. When Putman and Merritt drugged the cats with bromide and phenobarbital to the exact same sedative-state – to the point that prevented the cats from walking – and then used their apparatus to test the seizure threshold – phenobarbital was still much better. This teased out a critical detail. It implied that the sedative property and the anti-convulsive property were not chained together, they could be separated. They now realized it wasn’t necessarily the sedative property of the drugs that made them work. This discovery unshackled the search for new anti-seizure drugs; effectively it removed a massive barrier that had inhibited anti-seizure drug development for about seventy years. The narrow canyon researchers were searching in was suddenly expanded into an open field.
Putnam and Merritt realized the opportunity and began to use their animal model to test new drugs. As modest as it seems on the surface, the experimental system was revolutionary. This was one of the first scaled-up uses of animals to test drugs that might prove useful in humans, a process now called translational medicine. Given that phenobarbital was the best drug available, Putnam made a short leap of logic; he would test derivatives of phenobarbital –compounds that were chemically similar. Their animal model, and method of screening compounds, was Henry Ford’s newly developed assembly-line recapitulated into the industry of drug discovery – a quantum leap in productivity. Before the process of drug discovery was mostly accidental, now it was purposeful. The system vastly streamlined the probability for successfully finding new drugs because it allowed for screening en masse – they would be able to churn through chemicals with untold speed and precision.
Putnam began to search. He combed through the Eastman Chemical company catalog looking for compounds that were structurally just a shade away from phenobarbital. At the same time, he was calling pharmaceutical companies, asking if they had anything that resembled phenobarbital. Specifically, because they had shown the hypnotic quality of anti-seizure drugs was not essential, he requested “compounds that were thought to be hypnotic but had not proven to be.” Only one returned Putnam’s call, Author Dox, a chemist at Parke-Davis.
At the end of April a package arrived at Boston City Hospital from Dox with Putnam’s name on it. Inside, were 7 analogs of phenobarbital and a dozen other compounds that fit Putnam’s description. Dox warned Putnam of the futility of what he was trying to accomplish. He told him his search was “a waste of time, because the compounds had already been thoroughly tested and were inactive.” But Dox had only tested the compounds for the sedative effect, assuming, like everyone, that was enough to rule them out as anticonvulsive drugs. He was unaware that the Boston group had reason to believe otherwise.
One of the phenobarbital derivatives, called phenytoin, had been sitting on the shelf at Parke-Davis for decades. The company had purchased the compound from a German organic chemist in 1908 hoping it had sedative properties. But when the compound was found to be only mildly sedative it was placed on the shelf in a store room and forgotten. The overlooked compound was first on the list for Putnam and Merritt to test. They knew it had failed as a sleeping pill, and so had less of a sedative effect than current drugs. When they gave the drug to the cats it was clear they weren’t overly impaired; Dox was right, it was only mildly sedative. But when they tested the cat’s seizure threshold it left them in astonishment. The drug raised the threshold far beyond the other known drugs, without heavily sedating them. This was exactly what they were looking for, the holy grail of epilepsy treatment, a drug that was less sedative yet powerfully anticonvulsive.
The early 1930’s were a much different time. Regulators didn’t require preclinical safety testing for new drugs (the Food, Drug, and Cosmetic Act was signed in 1938). Nevertheless, just to be sure, Putnam and Merritt handed the drug over to a toxicologist at Harvard, and one at Parke-Davis. Both found phenytoin could be given to cats, dogs, and rats at very high single and repeated doses without immediate toxic effects. This was enough to clear the path and they started treating patients in May. By the summer of 1938 they had treated 200 adult and pediatric patients with phenytoin, now branded Dilantin, and presented their results at an AMA meeting in San Francisco. The results were remarkable. According to Putnam and Merritt, Dilantin was able to eliminate, or greatly reduce the seizures in 85% of the patients tested. Minor toxic symptoms were reported in 15% of the patients and “more serious toxic reactions” were reported in 5%. Six days later, Parke-Davis added Dilantin to its list of marketed products.
The rest is history. The popularity of the drug grew quickly. By 1940 it was hailed as ushering in a new epoch in the treatment of epilepsy. One doctor called it, “the most remarkable and important chemotherapeutic agent in the convulsive disorders since 1912…” Truly a new era had taken hold for epileptic patients. Across the country, doctors began prescribing Dilantin as a first line treatment for their patients.
The discovery of Dilantin did something else: it aroused and unbridled the capitalistic instinct of pharmaceutical companies. They paid close attention to the discovery of Dilantin. Perhaps even more important than the discovery of Dilantin itself, was the permanent enshrinement of the methodology established by Putnam and Merritt. The significance of Putnam and Merritt’s animal model was not lost on big-pharma. The companies quickly established their own in-house large scale drug screening programs. Putnam and Merritt themselves screened over 700 compounds for anti-convulsive activity between 1937 and 1945. The massively scaled-up efforts produced results. Over the next two decades, a dozen new anticonvulsants hit the shelves at the pharmacy.
As quickly as the new era of anticonvulsive drugs was ushered in, the ketogenic diet was ushered out. Dilantin was viewed as modern medicine at its best. It was a symbol of progress, mankind’s continuous vector of medical advancement. With the advent of seizure control for many patients in the form of a pill, the onerous diet was soon regarded as “rigid and expensive”, and began a sharp decent from favor. A pill was so much easier. A pill took a doctor seconds to scribble its prescription. The diet took the time and effort of many individuals; the doctor, a dietitian, nurses, and the families. With a pill, everyone was released. They no longer had to plan every shopping list and meal. The kids and families could live normal lives. They no longer were cast as outsiders. They could enjoy the same food everybody else was having. They could now have birthday cake, pancakes with syrup, and dessert alongside their friends and family – they didn’t have to watch from the sidelines.
History is full of research that drifts off like an unfinished conversation. Alongside the ketogenic diet, Howland’s original question faded from relevance. It was a strange query from a by-gone era. How fasting, or the ketogenic diet worked to stop seizures no longer mattered to the vast majority of researchers. But not everyone felt that way. It faded from view with a smattering of unheard protest. At the Mayo clinic, Peterman, found Dilantin “disappointing” compared to the ketogenic diet. Ironically, years later, speaking to a group of resident physicians at the NIH (National Institute of Health, Washington D.C.), Dr. Merritt was rumored to tell the young doctors that his discovery of phenytoin was a major setback to the understanding of epilepsy. He felt the line of research started by Howland’s original question of why fasting worked, and then morphing to the ketogenic diet, was a thread that could have ultimately led to a deeper understanding into the mechanisms of epilepsy. In 1960, almost 40 years after he was recruited to work on Howland’s question, Lennox looked back nostalgically, “Though interest in fasting (or the ketogenic diet) as a treatment has almost vanished, doubtless much scientific gold remains in them thar hills”.
By 1990, the ketogenic diet was all but completely forgotten. It was a strange, antiquated side-note that most physicians felt belonged in a history book, not a modern textbook. The diet was labeled “rigid, unpalatable, and constraining on daily life.” Johns Hopkins, one of the original hospitals to help develop and utilize the diet in the 20’s and 30’s, barely managed to preserve a single prescribing physician – Dr. John Freeman, and his dietitian, Millicent Kelly, a seventy-two year old that had been administering the diet for forty years. There was vanishingly little demand for their services. Kelly taught the ketogenic diet to the families of less than 10 children a year. To the doctors around the country, Freeman and Kelly might as well have been a museum exhibit. Kelly scribbled in an old notepad, calculating ratios and jotting down recipes for the families. “Together, we were the keepers of the flame,” Freeman later wrote. Besides Kelly, so few dietitians were trained in the nuances of the diet that when it was used, it was administered sloppily, and the children often had bad outcomes. The lessons of the past, that it took precise calculations to achieve the best seizure control, were all but lost. The bad results were folded into the perception that the diet was old, outdated, and not as effective as the current drugs. The widespread opinion was that the diet “did not work and was difficult to tolerate” and its use was “no longer justified.” Across the country, its use became almost nonexistent.
Stay tuned for Part 3…
Links to relevant information:
Ellen Davis maintains a great site that’s been an excellent resource for many people.
This site has many of Dominic D’Agostino’s ketone publications downloadable for free.
A generally good site.
When it comes to understanding exogenous ketones, this post from Peter Attia is helpful to many.