The
ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in
medicine is used primarily to treat difficult-to-control (refractory) epilepsy
in children. The diet forces the body to burn fats rather than carbohydrates.
Normally, the carbohydrates contained in food are converted into glucose, which
is then transported around the body and is particularly important in fuelling
brain-function. However, if there is very little carbohydrate in the diet, the
liver converts fat into fatty acids and ketone bodies. The ketone bodies pass
into the brain and replace glucose as an energy source. An elevated level of
ketone bodies in the blood, a state known as ketosis, leads to a reduction in
the frequency of epileptic seizures.
The original therapeutic diet for paediatric epilepsy provides just enough
protein for body growth and repair, and sufficient calories to maintain the
correct weight for age and height. This classic ketogenic diet contains a 4:1
ratio by weight of fat to combined protein and carbohydrate. This is achieved by
excluding high-carbohydrate foods such as starchy fruits and vegetables, bread,
pasta, grains and sugar, while increasing the consumption of foods high in fat
such as nuts, cream and butter.
Most dietary fat is made of molecules called long-chain triglycerides (LCTs).
However, medium-chain triglycerides (MCTs)�made from fatty acids with shorter
carbon chains than LCTs�are more ketogenic. A variant of the classic diet known
as the MCT ketogenic diet uses a form of coconut oil, which is rich in MCTs, to
provide around half the calories.
As less overall fat is needed in this variant of the diet, a greater proportion
of carbohydrate and protein can be consumed, allowing a greater variety of food
choices. The classic therapeutic ketogenic diet was developed for treatment of
paediatric epilepsy in the 1920s and was widely used into the next decade, but
its popularity waned with the introduction of effective anticonvulsant drugs. In
the mid-1990s, Hollywood producer Jim Abrahams, whose son's severe epilepsy was
effectively controlled by the diet, created the Charlie Foundation to promote
it. Publicity included an appearance on NBC's Dateline programme and ...First Do
No Harm (1997), a made-for-television film starring Meryl Streep. The foundation
sponsored a multicentre research study, the results of which�announced in
1996�marked the beginning of renewed scientific interest in the diet.
Almost half of children and young people with epilepsy who have tried some form
of this diet saw the number of seizures drop by at least half, and the effect
persists even after discontinuing the diet. The most common adverse effect is
constipation, affecting about 30% of patients�this was due to fluid restriction,
which was once a feature of the diet, but this led to increased risk of kidney
stones, and is no longer considered beneficial. There is some evidence that
adults with epilepsy may benefit from the diet, and that a less strict regimen,
such as a modified Atkins diet, is similarly effective. Clinical trials and
studies in animal models suggest that ketogenic diets provide neuroprotective
and disease-modifying benefits for a number of adult neurodegenerative
disorders. As of 2012, there is limited clinical trial data in these areas, and,
outside of paediatric epilepsy, use of the ketogenic diet remains at the
research stage.
Epilepsy is one of the most common neurological disorders after stroke, and
affects at least 50 million people worldwide. It is diagnosed in a person having
recurrent unprovoked seizures. These occur when cortical neurons fire
excessively, hypersynchronously, or both, leading to temporary disruption of
normal brain function. This might affect, for example, the muscles, the senses,
consciousness, or a combination. A seizure can be focal (confined to one part of
the brain) or generalised (spread widely throughout the brain and leading to a
loss of consciousness). Epilepsy may occur for a variety of reasons; some forms
have been classified into epileptic syndromes, most of which begin in childhood.
Epilepsy is considered refractory (not yielding to treatment) when two or three
anticonvulsant drugs have failed to control it. About 60% of patients will
achieve control of their epilepsy with the first drug they use, whereas about
30% do not achieve control with drugs. When drugs fail, other options include
epilepsy surgery, vagus nerve stimulation and the ketogenic diet.
The ketogenic diet is a mainstream therapy that does not use pharmaceutical
drugs, which was developed to reproduce the success and remove the limitations
of the non-mainstream use of fasting to treat epilepsy. Although popular in the
1920s and 30s, it was largely abandoned in favour of new anticonvulsant drugs.
Most individuals with epilepsy can successfully control their seizures with
medication. However, 20�30% fail to achieve such control despite trying a number
of different drugs. For this group, and for children in particular, the diet has
once again found a role in epilepsy management.
Physicians of ancient Greece treated diseases, including epilepsy, by altering
their patients' diet. An early treatise in the Hippocratic Corpus, On the Sacred
Disease, covers the disease; it dates from c. 400 BC. Its author argued against
the prevailing view that epilepsy was supernatural in origin and cure, and
proposed that dietary therapy had a rational and physical basis. In the same
collection, the author of Epidemics describes the case of a man whose epilepsy
is cured as quickly as it had appeared, through complete abstinence of food and
drink. The royal physician Erasistratus declared, "One inclining to epilepsy
should be made to fast without mercy and be put on short rations." Galen
believed an "attenuating diet" might afford a cure in mild cases and be helpful
in others.
The first modern study of fasting as a treatment for epilepsy was in France in
1911. Twenty epilepsy patients of all ages were "detoxified" by consuming a
low-calorie vegetarian diet, combined with periods of fasting and purging. Two
benefited enormously, but most failed to maintain compliance with the imposed
restrictions. The diet improved the patients' mental capabilities, in contrast
to their medication, potassium bromide, which dulled the mind.
Around this time, Bernarr Macfadden, an American exponent of physical culture,
popularised the use of fasting to restore health. His disciple, the osteopathic
physician Hugh Conklin, of Battle Creek, Michigan, began to treat his epilepsy
patients by recommending fasting. Conklin conjectured that epileptic seizures
were caused when a toxin, secreted from the Peyer's patches in the intestines,
was discharged into the bloodstream. He recommended a fast lasting 18 to 25 days
to allow this toxin to dissipate. Conklin probably treated hundreds of epilepsy
patients with his "water diet" and boasted of a 90% cure rate in children,
falling to 50% in adults. Later analysis of Conklin's case records showed 20% of
his patients achieved freedom from seizures and 50% had some improvement.
Conklin's fasting therapy was adopted by neurologists in mainstream practice. In
1916, a Dr McMurray wrote to the New York Medical Journal claiming to have
successfully treated epilepsy patients with a fast, followed by a starch- and
sugar-free diet, since 1912. In 1921, prominent endocrinologist H. Rawle Geyelin
reported his experiences to the American Medical Association convention. He had
seen Conklin's success first-hand and had attempted to reproduce the results in
36 of his own patients. He achieved similar results despite only having studied
the patients for a short time. Further studies in the 1920s indicated that
seizures generally returned after the fast. Charles Howland, the parent of one
of Conklin's successful patients and a wealthy New York corporate lawyer, gave
his brother John a gift of $5,000 to study "the ketosis of starvation". As
professor of paediatrics at Johns Hopkins Hospital, John Howland used the money
to fund research undertaken by neurologist Stanley Cobb and his assistant
William G. Lennox.
Diet
In 1921, Rollin Woodyatt reviewed the research on diet and diabetes. He reported
that three water-soluble compounds, β-hydroxybutyrate, acetoacetate and acetone
(known collectively as ketone bodies), were produced by the liver in otherwise
healthy people when they were starved or if they consumed a very
low-carbohydrate, high-fat diet. Russel Wilder, at the Mayo Clinic, built on
this research and coined the term ketogenic diet to describe a diet that
produced a high level of ketone bodies in the blood (ketonemia) through an
excess of fat and lack of carbohydrate. Wilder hoped to obtain the benefits of
fasting in a dietary therapy that could be maintained indefinitely. His trial on
a few epilepsy patients in 1921 was the first use of the ketogenic diet as a
treatment for epilepsy.
Wilder's colleague, paediatrician Mynie Peterman, later formulated the classic
diet, with a ratio of one gram of protein per kilogram of body weight in
children, 10�15 g of carbohydrate per day, and the remainder of calories from
fat. Peterman's work in the 1920s established the techniques for induction and
maintenance of the diet. Peterman documented positive effects (improved
alertness, behaviour and sleep) and adverse effects (nausea and vomiting due to
excess ketosis). The diet proved to be very successful in children: Peterman
reported in 1925 that 95% of 37 young patients had improved seizure control on
the diet and 60% became seizure-free. By 1930, the diet had also been studied in
100 teenagers and adults. Clifford Barborka, also from the Mayo Clinic, reported
that 56% of those older patients improved on the diet and 12% became
seizure-free. Although the adult results are similar to modern studies of
children, they did not compare as well to contemporary studies. Barborka
concluded that adults were least likely to benefit from the diet, and the use of
the ketogenic diet in adults was not studied again until 1999.
Anticonvulsants and decline
During the 1920s and 1930s, when the only anticonvulsant drugs were the sedative
bromides (discovered 1857) and phenobarbital (1912), the ketogenic diet was
widely used and studied. This changed in 1938 when H. Houston Merritt and Tracy
Putnam discovered phenytoin (Dilantin), and the focus of research shifted to
discovering new drugs. With the introduction of sodium valproate in the 1970s,
drugs were available to neurologists that were effective across a broad range of
epileptic syndromes and seizure types. The use of the ketogenic diet, by this
time restricted to difficult cases such as Lennox�Gastaut syndrome, declined
further
The brain is composed of a network of neurons that transmit signals by
propagating nerve impulses. The propagation of this impulse from one neuron's
synapse to another is typically controlled by neurotransmitters, though there
are also electrical pathways between some neurons. Neurotransmitters can inhibit
impulse firing (primarily done by γ-aminobutyric acid, or GABA) or they can
excite the neuron into firing (primarily done by glutamate). A neuron that
releases inhibitory neurotransmitters from its terminals is called an inhibitory
neuron, while one that releases excitatory neurotransmitters is an excitatory
neuron. When the normal balance between inhibition and excitation is
significantly disrupted in all or part of the brain, a seizure can occur. The
GABA system is an important target for anticonvulsant drugs, since seizures may
be discouraged by increasing GABA synthesis, decreasing its breakdown, or
enhancing its effect on neurons.
The nerve impulse is characterised by a great influx of sodium ions through
channels in the neuron's cell membrane followed by an efflux of potassium ions
through other channels. The neuron is unable to fire again for a short time
(known as the refractory period), which is mediated by another potassium
channel. The flow through these ion channels is governed by a "gate" which is
opened by either a voltage change or a chemical messenger known as a ligand
(such as a neurotransmitter). These channels are another target for
anticonvulsant drugs.
There are many ways in which epilepsy occurs. Examples of pathological
physiology include: unusual excitatory connections within the neuronal network
of the brain; abnormal neuron structure leading to altered current flow;
decreased inhibitory neurotransmitter synthesis; ineffective receptors for
inhibitory neurotransmitters; insufficient breakdown of excitatory
neurotransmitters leading to excess; immature synapse development; and impaired
function of ionic channels.
Seizure control
Although many hypotheses have been put forward to explain how the ketogenic diet
works, it remains a mystery. Disproven hypotheses include systemic acidosis
(high levels of acid in the blood), electrolyte changes and hypoglycaemia (low
blood glucose). Although many biochemical changes are known to occur in the
brain of a patient on the ketogenic diet, it is not known which of these has an
anticonvulsant effect. The lack of understanding in this area is similar to the
situation with many anticonvulsant drugs.
On the ketogenic diet, carbohydrates are restricted and so cannot provide for
all the metabolic needs of the body. Instead, fatty acids are used as the major
source of fuel. These are used through fatty-acid oxidation in the cell's
mitochondria (the energy-producing parts of the cell). Humans can convert some
amino acids into glucose by a process called gluconeogenesis, but cannot do this
for fatty acids. Since amino acids are needed to make proteins, which are
essential for growth and repair of body tissues, these cannot be used only to
produce glucose. This could pose a problem for the brain, since it is normally
fuelled solely by glucose, and most fatty acids do not cross the blood�brain
barrier. Fortunately, the liver can use long-chain fatty acids to synthesise the
three ketone bodies β-hydroxybutyrate, acetoacetate and acetone. These ketone
bodies enter the brain and substitute for glucose.[56]Medium-chain fatty acids
octonoic and heptanoic acids can cross the barrier and be used by the brain.
The ketone bodies are possibly anticonvulsant in themselves; in animal models,
acetoacetate and acetone protect against seizures. The ketogenic diet results in
adaptive changes to brain energy metabolism that increase the energy reserves;
ketone bodies are a more efficient fuel than glucose, and the number of
mitochondria is increased. This may help the neurons to remain stable in the
face of increased energy demand during a seizure, and may confer a
neuroprotective effect.
The ketogenic diet has been studied in at least 14 rodent animal models of
seizures. It is protective in many of these models and has a different
protection profile than any known anticonvulsant. Conversely, fenofibrate, not
used clinically as an antiepileptic, exhibits experimental anticonvulsant
properties in adult rats comparable to the ketogenic diet. This, together with
studies showing its efficacy in patients who have failed to achieve seizure
control on half a dozen drugs, suggests a unique mechanism of action.
Anticonvulsants suppress epileptic seizures, but they neither cure nor prevent
the development of seizure susceptibility. The development of epilepsy
(epileptogenesis) is a process that is poorly understood. A few anticonvulsants
(valproate, levetiracetam and benzodiazepines) have shown antiepileptogenic
properties in animal models of epileptogenesis. However, no anticonvulsant has
ever achieved this in a clinical trial in humans. The ketogenic diet has been
found to have antiepileptogenic properties in rats.
Recently, a saturated medium-chain fatty acid called decanoic acid (C10) has
shown promise in both the control of seizures and of neurodegeneration. Decanoic
acid is a major constituent of the MCT ketogenic diet, and the authors suggest
its action may be through inducing mitochondrial biogenesis and helping provide
more ATP to maintain the resting membrane potential of the neuron.
The ketogenic diet may be a successful treatment for several rare metabolic
diseases. Case reports of two children indicate that it may be a possible
treatment for astrocytomas, a type of brain tumour. Autism, depression, migraine
headaches, polycystic ovary syndrome and diabetes mellitus type 2 have also been
shown to improve in small case studies. There is evidence from uncontrolled
clinical trials and studies in animal models that the ketogenic diet can provide
symptomatic and disease-modifying activity in a broad range of neurodegenerative
disorders including amyotrophic lateral sclerosis, Alzheimer's disease and
Parkinson's disease, and may be protective in traumatic brain injury and stroke.
Because tumour cells are inefficient in processing ketone bodies for energy, the
ketogenic diet has also been suggested as a treatment for cancer, including
glioma.
A 2013 review said that there is enough suggestion of potential benefit from
ketogenic diets in cancer therapy that establishing clinical trials is probably
warranted. At present the only evidence of benefit is anecdotal, but designing
effective trials to measure the effect of adopting a ketogenic diet could prove
challenging.
In March 2009, Axona was approved as a medical food by the US Food and Drug
Administration for the "dietary management of the metabolic processes and
nutritional requirements associated with mild to moderate Alzheimer's disease".
Glucose metabolism by the brain is impaired in Alzheimer's disease, and it is
proposed that ketone bodies may provide an alternative energy source.
Caprylidene is a powdered form of a medium-chain triglyceride, specifically
caprylic triglyceride.
The
ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in
medicine is used primarily to treat difficult-to-control (refractory) epilepsy
in children. The diet forces the body to burn fats rather than carbohydrates.
Normally, the carbohydrates contained in food are converted into glucose, which
is then transported around the body and is particularly important in fuelling
brain-function. However, if there is very little carbohydrate in the diet, the
liver converts fat into fatty acids and ketone bodies. The ketone bodies pass
into the brain and replace glucose as an energy source. An elevated level of
ketone bodies in the blood, a state known as ketosis, leads to a reduction in
the frequency of epileptic seizures.
The first modern study of fasting as a treatment for epilepsy was in France in
1911. Twenty epilepsy patients of all ages were "detoxified" by consuming a
low-calorie vegetarian diet, combined with periods of fasting and purging. Two
benefited enormously, but most failed to maintain compliance with the imposed
restrictions. The diet improved the patients' mental capabilities, in contrast
to their medication, potassium bromide, which dulled the mind.
Although many hypotheses have been put forward to explain how the ketogenic diet
works, it remains a mystery. Disproven hypotheses include systemic acidosis
(high levels of acid in the blood), electrolyte changes and hypoglycaemia (low
blood glucose). Although many biochemical changes are known to occur in the
brain of a patient on the ketogenic diet, it is not known which of these has an
anticonvulsant effect. The lack of understanding in this area is similar to the
situation with many anticonvulsant drugs.