The Ketogenic Diet Through the Ages

Saba Ahmad, MDAssistant Professor of Clinical Pediatrics and Neurology

University of Illinois, Chicago

Disclosures

• Nothing to Disclose

What is the Ketogenic Diet?

• Dietary measures to induce a state of ketosis

• Ketosis is the formation of ketone bodies when a body’s metabolism is burning fats as a primary fuel source to generate ATP

Why do we care about ketosis?

The generation of ketosis is the OLDEST KNOWN method for treating epilepsy In the modern day, it is also seen as one of the most effective methods of treating medication resistant epilepsy.

On the Sacred Disease“It is thus with regard to the disease called Sacred: it appears to me to be nowise more divine

nor more sacred than other diseases, but has a natural cause from the originates like other affections. Men regard its nature and cause as divine from ignorance and wonder, because it is

not at all like to other diseases.”

• A medical description of epilepsy from Epidemics, the first monograph on epilepsy from 400 B.C.

• “the brain is the cause of this affection”

• “the patient loses his speech, and chokes, and foam issues by the mouth, the teeth are fixed, the hands are contracted, the eyes distorted, he becomes insensible, and in some cases the bowels are evacuated. And these symptoms occur sometimes on the left side, sometimes on the right, and sometimes in both.“

“Let food be thy medicine and thy medicine, food”-Hippocrates (maybe)

The only therapeutic measure for epilepsy described in the Hippocratic collection refers to a man who had convulsions after anointing himself in a bath before a fire in the winter. He subsequently abstained from food and drink, and he was considered cured from his epileptic convulsions

ErasistratusErasistratus the cause of illness in Antiochus

• Erasistratus, an Alexandrian physician (3rd century BC), is credited to have said:

“One inclining towards epilepsy should be made to fast without mercy and be put on short rations”

Galen of PergamonSupported the use of an “attenuating diet” in the treatment of mild epilepsy as well as more chronic, severe forms

Moribus Divinus

• The terms “Sacred Disease” moribus divinus or “Great Disease” moribus maior are found in the Hippocratic Corpus and ancient texts

• The term moribus maior continued to be used as a term for epilepsy, and made its way into medieval French as “grand mal” which continues to be used today as a term for the “great” epileptic attack

Ancient physicians

• Hippocrates and few of his contemporaries did not seem to give credence to the idea that these illnesses were “Divine” in nature

• However, popular theories at the time did indicate that most people thought that epilepsy was sacred because it was “sent by a deity” or a that demon had entered the patient

A Spiritual Affliction

• The notion that epilepsy was caused by a sort of spiritual affliction or demonic possession was widely accepted until very recently in history

• Fasting, long considered an act of spiritual purification, helped epileptic patients

• This may have caused the notion of epilepsy being a spiritual affliction to persist

New TestamentMark 9:14-29 (circa 30 A.D.)These verses tell the tale of a father who brings his son to Jesus because he was “possessed by an unclean spirit”Verse 18“Master, I have brought unto thee my son, which hath a dumb spirit; And wheresoever he taketh him, he teareth him: and he foameth, and gnasheth with his teeth, and pineth away...”

Biblical Texts• (Jesus picture) Verse 29

“And he (Jesus) said unto them, This kind can come forth by nothing, but by prayer and fasting.”

"The Possessed Boy at the Foot of Mount Tabor” (circa late 1890s) by James Tissot

Modern Day

The first published medical literature regarding dietary manipulation in epilepsy was published in 1911. Two French physicians Guelpa and Marie describe fasting followed by a very restrictive vegetarian diet in the treatment of epilepsy

1921-22• Hugh Conklin, was

treating epilepsy patients with an 18-25 day fast, and claimed a 90% cure rate in children and a 50% cure rate in adults

• H. Rawle Geyelin, an American endocrinologist, noted that fasting suppressed seizures, sometimes for many months after the fast was over

• He was also the first to note the cognitive improvement observed with fasting

Why did fasting work?• In the early 1920’s Dr.

Stanley Cobb and W.G. Lennox observed that seizure improvement was noted at 2-3 days into the fasting period.

• In 1921, Woodyatt observed that acetone and beta-hydroxy butyric acid were produced in normal fasted subjects

• That same year Russell Wilder, from the Mayo Clinic, proposed that ketonemia, produced by other means may be effective at treating seizures

Biochemical Overview of

Ketogenesis and ATP production

ATP production

Beta Oxidation-the process of breaking down fatty acids

Kreb’s Cycle

Electron Transport Chain

Not all Acetyl-CoA goes into the Kreb’s Cycle

What happens during ketosis

• Fatty acids cannot readily cross the blood brain barrier

• When there is no carbohydrate source, ketones readily cross the blood brain barrier and used as fuel

The problem with fasting

• NOT a long term solution• While seizures went away for some months

after a prolonged fast, they often returned• The ketogenic diet, proposed by Wilder,

allowed for sustained nutrition, primarily in the form of dietary fat, and continued to provide the benefits of long term ketonemia to control seizures

The Ketogenic Diet is born

• Wilder’s colleague, Mynie Peterman, a pediatrician formulated the classic ketogenic diet.

• “anti-ketogenic foods” such as carbohydrates and excessive protein were limited: 10-15 grams of carbohydrates daily and 1 gram/kilogram of bodyweight of protein

• “ketogenic foods” (fats) made up the rest of the calories

The Ketogenic Diet• Peterman showed the diet to be very successful

in children with 95% of patients having improved seizure control, with 60% of children becoming seizure free on this regimen

• Peterman was also the first to observe the cognitive improvements in children on the ketogenic diet

• The ketogenic diet was described in almost every textbook on pediatric epilepsy published between 1941 and 1980

The Ketogenic Diet in Adults

• Clifford Barborka, also at the Mayo Clinic, studied the diet in teenagers and adults

• While more than 50% of patients had a reduction in seizures, and 12% of these patients became seizure free-it was concluded that adults were less likely to benefit from this treatment, and this mode of therapy was not studied in adults again until the end of the century

The “classic” ketogenic diet protocol

• Also called the “Hopkins ketogenic diet protocol” was popularized by Livingston and Freeman

• Patients were fasted for a period of 24-72 hours until ketonuria was established and then initiated on the diet over 3 days to a “4:1 ratio” is achieved

• The ratio refers to 4 grams fat per every 1 gram of protein + carbohydrates

• Patients less than 2 years old typically given a 3:1 ratio diet

The problem with palatability

• While incredibly effective, the diet was considered HIGHLY unpalatable and restrictive

• Medium chain triglycerides (MCT’s), were found to produce more ketone bodies per calorie than traditional dietary fats which consist mainly of long chain triglycerides

• Peter Huttenlocher, in 1971, devised a form of the diet which was 60% MCT oil, which allowed patients to consume higher amounts of protein and carbohydrates, with similar effectiveness as the classic ketogenic diet

The early days of the ketogenic diet

• Was the mainstay of epilepsy treatment in children throughout the 1920’s and 1930’s

• In 1972, Livingston from Hopkins, published data on over 1000 children that were followed over the prior decades. His data indicated that 52% of children achieved complete seizure freedom on the diet, and 27% had improved seizure control.

The pharmacological era

• In 1938, Merrit and Putnam developed the medication phenytoin

• In the 70’s and 80’s valproic acid and carbemazepine were developed

• The increased variety of available medications, along with their ease of use compared to the ketogenic diet caused the diet to fall out of favor

• This led to fewer dieticians trained in its administration, and subsequently a change in the perception of it’s effectiveness

Charlie’s story• In 1994, the spotlight was again shown on the

ketogenic diet in a program on NBC’s Dateline

• Charlie Abrahams was a 2 year old who suffered medication resistant generalized epilepsy

• He ultimately went to Hopkins and was started on the ketogenic diet, and became seizure free

• Charlie’s father started the Charlie Foundation, which supplied information for medical providers and families regarding the ketogenic diet

Modern data on effectiveness in children

• A meta-analysis of the more rigorous studies of the ketogenic diet, the overall effectiveness observed• 56% of patients see a 50% or greater reduction in seizures• 32% of children had a greater than 90% reduction in

seizures• and 16% became seizure free

• Most patients in these studies were medication resistant

Zupec-Kania BA, Spellman E. An overview of the ketogenic diet for pediatric epilepsy. Nutr Clin Pract 2008;23:589-96

Modern data on effectiveness in adults

• A meta-analysis of studies of adults on any type of ketogenic diet confirmed that adults have a better seizure response but have lower compliance/long-term adhesion, on the classic ketogenic diet than on the modified Atkins diet

Ye F, Li XJ, Jiang WL, Sun HB, Liu J. Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: a meta-analysis. J Clin Neurol 2015;11(1): 26–31

Problems

• Like any therapy for epilepsy, the ketogenic diet is not side effect free, and many side effects are not trivial• Can cause renal calculi, vitamin and mineral

deficiencies, pancreatitis, hyperlipidemia, growth failure, cardiovascular disease (in adults), bone mineral loss (in children)

Contraindications

• Fatty acid oxidation disorders are an ABSOLUTE contraindication

• Caution should be exercised with disorders of energy metabolism • with the exception of GLUT1 deficiency,

pyruvate dehydrogenase deficiency, phosphofructokinase deficiency-where the ketogenic diet is the therapy of choice

Why does it work to control seizures?

• The short answer is, nobody knows. • There have been many proposed

mechanisms, but few have been supported by basic science research

Some theories on why it might work

• Some proposed mechanism have been disproved by later research

• Lennox and Lennox in 1960 proposed that the the seizure control was due to intracerebral acidosis. However, intracerebral pH does not seem to change in animals (Al-Muldallal 1996) or humans (Novotny 1997)

• Millichap in 1964 proposed that negative sodium and potassium balances were the reason for the anti-convulsant effect. Huttenlocher later showed this did not seem to have significant effect.

More theories-Lipids• There were also theories that hyperlipidemia had a direct

anticonvulsant effect. Huttenlocher in 1976 also showed this have little contribution to the anticonvulsant effect

• More recently, many people have proposed that elevations polyunsaturated fatty acids have a role in seizure control. Cunnane in 2002 showed that arachidonate and docosahexaenoate have some anticonvulsant role. Cullingford in 2004 showed that longer-chain and unsaturated fatty acids are associated with the anticonvulsant activity. • Elevated polyunsaturated fatty acids may work in concert with

ketones• Polyunsaturated fatty acids may decrease cyclooxegenase 2 (COX2)

synthesis of eicosanoids. Eicosanoids are thought to play a role in kainic acid induced hippocampal cell death and seizure potentiation (Cullingford 2004, Kunz and Oliw 2001)

Neuroprotection and anti-epileptogenesis

• The ketogenic diet has been shown to inhibit caspase-3 mediated hippocampal neuronal cell apoptosis in rat models with kainic acid induced seizures. • This might suggest an anti-epileptogenic

effect• May also indicate that early implementation of

the diet may mediate some epilepsy associated learning and memory deficits (Noh 2008)

Neurotransmitter modulation

• Increased GABAergic effects either directly or indirectly• Cheng et al in 2004 suggested demonstrated that

caloric restriction augments brain glutamic acid decarboxylase (thereby increasing glutamate conversion to GABA)

• Yudkoff et al in 2005 demonstrated that in ketosis there is greater production of acetyl-CoA. • This disrupts the equilibrium of the aspartate

aminotransferase reaction • Diminished aspartate production • Potentially enhanced synthesis of glutamine and GABA.

Possible direct anti-convulsant effect of ketone bodies

• Acetone seems to have anticonvulsant effects in animal models (Keith 1933, Likhodii 2003)

• In vitro ketone bodies potentiate GABAA-mediated inhibitory post-synaptic potentials in hippocampal CA1 neurons (Ge and Neisen 1998)

Chronic changes in hippocampal excitability

• In 1999, Stafstrom demonstrated that in rats made chronically epileptic by kainic acid, the ketogenic diet is associated with• Fewer spontaneous seizures• Decreased in vitro excitability of hippocampal

CA1 neurons• Decreased mossy fiber sprouting

• Xu et al in 2006 demonstrated that the ketogenic diet may upregulate young rat GluR(5) in inhibitory interneurons of CA1

The likely story is that ketosis induces

multifactorial metabolic changes that occur on the cellular level to promote

seizure control and possibly epileptogeneis

Uses other than medication resistant epilepsy

• GLUT1 deficiency, phosphofructokinase deficiency, pyruvate dehydrogenase deficiency

• Acute refractory status epilepticus• Possible indications as adjunct treatment in

brain tumors, mood disorders

Its not just for epilepsy anymore

• Strong interest in the ketogenic diet for patients with various cancers/tumors (brain, lung, head and neck)

• As a treatment for metabolic syndrome, obesity, type 2 diabetes

• Effects on autism spectrum disorders• Effects on Tourette's syndrome• Effects in pediatric brain injury• Effects in acute stroke• Effects in multiple sclerosis and other autoimmune diseases• Effects in ALS• Effects in Alzheimer’s disease

Selected referencesTemkin O. The Falling Sickness, 3nd ed. Johns Hopkins University Press, Baltimore, 1994; Hippocrates. Epidemics. VII, 46: vol. 5.Galen, De victu attenuante, c. 1.Galen, De venae sect. adv. Erasistrateos Romae degentes, c. 8; vol. 11.Mark 9:14–29. Bible: New King James Version. Guideposts, Carmel, NY, 1982. Wheless JW. History and origin of the ketogenic diet. In: Epilepsy and the ketogenic diet. Stafstrom CE, Rho JM, editors. Totowa: Humana Press; 2004.Peterman MG. The ketogenic diet in epilepsy. JAMA 1925; 84:1979-8.2Barborka CJ. Epilepsy in adults: results of treatment by ketogenic diet in one hundred cases. Arch Neurol Psychiatry 1930 23:904-14.Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology. 1971 Nov; 21(11):1097–103.Ketogenic diet. “Dateline” NBC television. October 26, 1994.Zupec-Kania BA, Spellman E. An overview of the ketogenic diet for pediatric epilepsy. Nutr Clin Pract 2008;23:589-96.

Thank youQuestions?