The
length of the life-span, and of the period of youth or immaturity, is
closely associated with the size of the brain, and the brain has a very
high rate of metabolism. When something interferes with this very high
metabolic rate, the consequences may be instantanteous,* or developmental,
or chronic and degenerative, or even transgenerational. The issue of
epilepsy centers on questions of brain metabolism, and so it has all
of those dimensions.
As
I discuss the mechanisms known to predispose a person to epilepsy, I
will emphasize the centrality of oxidative energy production, and show
how "stroke," "stress," "hyperactivity,"
"dementia," and other brain syndromes are related to "epilepsy."
(Similar processes are being studied in the heart and other tissues;
eventually, we might have a general language that will make it easier
to understand the parallels in the various kinds of "seizure"
in any organ.)
As
an old term, "epilepsy" has aquired a burden of pseudoscientific
ideas, covering old superstitions with an overlay of new superstitions.
[Hereditary epilepsy has been discussed in countless textbooks and medical
journals, but I think a much better case could be made for the inheritance
of a tendency to offer stupid genetic explanations.] "Hereditary
epilepsy" and "idiopathic epilepsy" are seriously pathogenic
terms; "brain scar" sometimes has a factual basis, but most
often the term is an evasion of understanding.
As
long as we realize that the essential meaning of the word is "something
that grabs you," "epilepsy" is a convenient way to refer
to a cluster of convulsive states, fainting spells, night-terrors and
nightmares, and strange sensations.
Seizures can be caused by lack
of glucose, lack of oxygen, vitamin B6 deficiency, and magnesium deficiency.
They are more likely to occur during the night, during puberty, premenstrually,
during pregnancy, during the first year of life, and can be triggered
by hyperventilation, running, strong emotions, or unusual sensory stimulation.
Water retention and low sodium increase susceptibility to seizures.
When I was in high school, our dog found and ate a pint of bacon grease,
and shortly afterward had a convulsive seizure. I knew of veterinarians
who treated seizures in dogs with a vermifuge, so it seemed obvious
that a metabolic disturbance, especially if combined with intestinal
irritation, could cause fits.
It was undoubtedly such observations
that led some physicians to advocate removal of the colon as treatment
for epilepsy. Pregnancy and the menstrual cycle have been recognized
as having something to do with seizures, but when seizures occurred
only during pregnancy, they were classified as nonepileptic, and when
they had a clear premenstrual occurrence, they were likely to be classified
as "hysterical fits," to be treated with punishment.
It has been observed that all
"recognized" anti-seizure drugs are teratogenic, and women
who are taking such drugs are told that pregnancy might kill them if
they stop the drug, but that their babies will have a greatly increased
risk of birth defects if they take the drugs during pregnancy. This
is why a better understanding of epilepsy is very important. Old therapies
are mainly important for the insight they can give into the nature of
the physiological problem. Some of the well established clinical-laboratory
observations (F. Mora, and C. S. Babel, for example) give strong hints
as to the physiological problem, for example, low albumin, high prealbumin,
low magnesium and high calcium all suggest hypothyroidism. (Problems
with the bowel, liver, and sex hormones are highly associated with hypothyroidism,
both as causes and as effects.) Water retention was so clearly involved
in seizures that increased water intake was used as a diagnostic procedure.
(R. Grinker) Unfortunately, animal experiments showed that water intoxication
increased susceptibility to seizures even in normal individuals. Low
sodium content in the body fluids also predisposed to seizures, so that
someone with hyponatremia (low blood sodium) would be more susceptible
to induction of a seizure by excessive water intake. (Excessive water
uptake is still recognized as a factor in seizures, but now it is seen
as part of a complex process, involving energy, hormones, and transmitter
substances. E.g., Kempski; Chan.)
Hypothyroid
people tend to lose sodium easily, and unopposed estrogen increases
water retention, without an equivalent sodium retention, so low thyroid,
high estrogen people have two of the conditions (edema and hyponatremia)
known to predispose to seizures. Another outstanding feature of seizures
of various sorts is that they are most likely to occur at night, especially
in the early pre-dawn hours. Low blood sugar and high adrenalin predominate
during those hours. Hypoglycemia, in itself, like oxygen deprivation,
is enough to cause convulsions.
Progesterone
and thyroid promote normal energy production, and their deficiency causes
a tendency toward hypoglycemia, edema and instability of nerves.
Twenty years ago, a woman who
was considered demented visited me. From the age of 21, she had been
increasingly disabled by premenstrual migraines. When she was 35 she
was a school teacher, and during the summer a neurologist told her that
dilantin would help her headaches, because "migraine is similar
to epilepsy." Although she told the neurologist that the drug made
her "too stupid to teach school," he offered her no alternatives,
and didn't mention that sudden withdrawal from the drug could trigger
a seizure. When classes started she discontinued the dilantin and had
a seizure. The neurologist said the seizure proved that migraines were
a form of epilepsy. At the age of 52, she spent about 20 hours a day
in bed, and couldn't go outside by herself, because she would get lost.
After using a little progesterone for a few days, she stopped having
seizures, discontinued her drugs, and was able to work. When she returned
to graduate school, she got straight As, and earned her masters' degree
in gerontology. But she had lost 17 years because the drug industry
had covered up the role of the hormones in epilepsy, migraine, and the
perimenstrual syndrome.
The
most popular anticonvulsant drugs are both neurotoxic and teratogenic,
that is, they damage the patient's brain, and greatly increase the incidence
of birth defects. The Nazis justified their horrible medical experiments
as "science," but the effects of epilepsy medicine in the
last half century have been similar in effect, grander in scale, and
without any scientific justification.
Besides the specific promotional efforts of the drug industry and their branch of government, there is a broader situation that makes their work easier. It is a culture of goony ideas, that ultimately emanates from the academic elite, which (since Descartes, and before) places "thought" above evidence. In biology, "genes" and "membranes" are confused ideas that are used to justify actions that aren't based on evidence. For the Nazis, "cultural degeneracy" was a medical-biological-political category based on that style of thinking. In the United States, "genes" for epilepsy, hyperactivity, language development, IQ, eclampsia, etc., are "found" at Harvard/MIT/Stan- ford/Yale/Univ. of California, etc., by an elite whose wits have been dulled by environmental deprivation, that is, by a lack of criticism.
By manipulating the diet and environment,
animals can be made more or less seizure-prone, and it happens that
the changes that affect the brain affect all other organs, in ways that
are now fairly well understood. Examining the cellular events associated
with a seizure is useful for therapy and prevention of seizures, but
the same methods are helpful for many other conditions. It is now clearly
established that stress can cause brain damage, as well as other diseases.
Now that our public health establishment has eliminated smoking from
public places, maybe they can find a way to reduce stress and disease
by removing morons from positions of power.
Excitotoxicity,
in its simplest sense, is the harmful cellular effect (death or injury)
caused by an excitatory transmitter such as glutamate or aspartate acting
on a cell whose energetic reserves aren't adequate to sustain the level
of activity provoked by the transmitter. Once an excitotoxic state exists,
the consequences of cell exhaustion can increase the likelihood that
the condition will spread to other cells, since any excitation can trigger
a complex of other excitatory processes. As calcium enters cells, potassium
leaves, and enzymes are activated, producing free fatty acids (linoleic
and arachidonic, for example) and prostaglandins, which activate other
processes, including lipid peroxidation and free radical production.
Protein kinase C (promoted by unsaturated fats and estrogen) facilitates
the release of excitatory amino acids. (See J. W. Phillis and M. H.
O'Regan, "Mechanisms of glutamate and aspartate release in the
ischemic rat cerebral cortex," Br. Res. 730(1-2), 150-164, 1996.)
Estrogen supports acetylcholine release, which leads to increased extracellular
potassium and excitatory amino acids. (See R. B. Gibbs, et al., "Effects
of estrogen on potassium-stimulated acetylcholine release in the hippocampus
and overlying cortex of adult rats," Br. Res. 749(1), 143-146,
1997.)
Estrogen
also stimulates the production of free radicals. Calcium, free radicals,
and unsaturated free fatty acids impair energy production, decreasing
the ability to regulate potassium and calcium. The increased estrogen
associated with seizures is associated with reduced serum calcium (Jacono
and Robertson, 1987). Feedback self-stimulation of free radicals, free
fatty acids, and prostaglandins create a bias toward increased excitation.
Ammonia
is produced by stimulated nerves, and normally its elimination helps
to eliminate and control the excitotoxic amino acids, glutamate and
aspartate. The production of urea consumes aspartic acid, converting
it to fumaric acid, but this requires carbon dioxide, produced by normal
mitochondrial function. A deficiency of carbon dioxide would reduce
the delivery of oxygen to the brain by constricting blood vessels and
changing hemoglobin's affinity for oxygen (limiting carbon dioxide production),
and the failure to consume aspartate (in urea synthesis) and glutamate
(as alpha-ketoglutarate) and aspartate (as oxaloacetate) in the Krebs
cycle, means that as energy becomes deficient, excitation tends to be
promoted. This helps to explain the fact that seizures can be induced
by hypoxia. (Balloonists and mountain climbers at extremely high elevations
have mentioned suffering from severe insomnia. The mechanisms of excitotoxicity
are probably involved in other forms of insomnia, too.) Antioxidants
help to control seizures, by reducing the excitatory contribution of
free radicals and lipid peroxidation. Since excitation can promote the
toxic forms of oxidation, many surprising substances turn out to have
an "antioxidant" function. Magnesium, sodium (balancing calcium
and potassium), thyroid and progesterone (increasing energy production),
and in some situations, carbon dioxide. Aspirin, by inhibiting prostaglandin
synthesis (and maybe other mechanisms) often lowers free radical production.
Adenosine seems to have a variety of antioxidant functions, and one
mechanism seems to be its function as an antiexcitatory transmitter.
One of estrogen's excitant actions on the brain probably involves its
antagonism to adenosine (Phillis and O'Regan, 1988).
Albumin,
besides maintaining blood volume and preventing edema, serves to protect
respiration, by binding free fatty acids. Estrogen blocks the liver's
ability to produce albumin, and increases the level of circulating free
fatty acids. Free fatty acids cause brain edema. This is probably another
aspect of estrogen's contribution to seizure susceptibility. Magnesium
sulfate has been used for generations in India to treat eclampsia and
"toxemia" of pregnancy, and its effectiveness is gradually
coming to be recognized in the U.S. Increasingly, magnesium deficiency
is recognized as a factor that increases susceptibility to seizures.
(Valenzuela and Benardo, 1995; Slandley, et al., 1995). Hypothyroidism
reduces the ability of cells to retain magnesium. Thyroid does
many things to protect against seizures. It keeps estrogen and adrenal
hormones low, and increases production of progesterone and pregnenolone.
It facilitates retention of magnesium and of sodium, and prevents edema
in a variety of ways.
Progesterone,
because of its normal anesthetic function (which prevents the pain of
childbirth when its level is adequate), directly quiets nerves, and
in this way suppresses many of the excitotoxic processes. It has direct
effects on mitochondria, promoting energy production, and it facilitates
thyroid hormone functions in various ways. It promotes the elimination
of estrogen from tissues, and is a "diuretic" in several benign
ways, that are compatible with maintenance of blood volume. It antagonizes
the mineralocorticoids and the glucocorticoids, both of which promote
seizures. (Roberts and Keith, 1995.) The combination of hypoglycemia
with elevation of cortisone probably accounts for the nocturnal incidence
of seizures.
If
progesterone's antiepileptic effectiveness were not enough (and it is
very effective even in irrational pharmaceutical formulations), the
fact that it reduces birth defects, and promotes brain development and
nerve repair should assure its general use in women with a history of
seizures, until it is established that they are no longer "epileptic."
Although thyroid, progesterone, and a high quality protein diet will
generally correct the epilepsy problem, it is important to mention that
the involvement of unsaturated fats and free radicals in seizure physiology
implies that we should minimize our consumption of the unsaturated fats.
Even years after eliminating them from the diet, their release from
tissue storage can prolong the problem, and during that time the use
of vitamin E is likely to reduce the intensity and frequency of seizures.
Coconut oil lowers the requirement for vitamin E, and reduces the toxicity
of the unsaturated fats (see Cleland, et al.), favoring effective respiration
and improving thyroid and progesterone production. Endotoxin formed
in the bowel can block respiration and cause hormone imbalances contributing
to instability of the nerves, so it is helpful to optimize bowel flora,
for example with a carrot salad; a dressing of vinegar, coconut oil
and olive oil, carried into the intestine by the carrot fiber, suppresses
bacterial growth while stimulating healing of the wall of the intestine.
The carrot salad improves the ratio of progesterone to estrogen and
cortisol, and so is as appropriate for epilepsy as for premenstrual
syndrome, insomnia, or arthritis.
NOTES:
When
the brain loses its oxygen supply, consciousness is lost immediately,
before there is much decrease in the ATP concentration. This has led
to the proposal of interesting "electronic" ideas of consciousness,
but there is another way of viewing this. While ATP constitutes a kind
of reservoir of cellular energy, the flow of carbon dioxide through
the brain cell is almost the mirror image of the flow of oxygen. Oxygen
scarcity leads directly to carbon dioxide scarcity. The "sensitive
state," consciousness, might require the presence of carbon dioxide
as well as ATP, to sustain a cooperative, semi-stable, state of the
cytoplasmic proteins. The ability of ordinary light to trigger a conformation
change in the hemoglobin-carbon monoxide-carbon dioxide system shows
how sensitive a system with only a few elements can be. At the other
extreme from consciousness, there is the evidence that carbon dioxide
is essential for even the growing/living state of protozoa, algae, and
bacteria.(O. Rahn, 1941.)
O. Rahn, "Protozoa need carbon
dioxide for growth," Growth 5, 197-199, 1941. "On page 113
of this volume, the statement of Valley and Rettger that all bacteria
need carbon dioxide for growth had been shown to apply to young as well
as old cells." "...it is possible...to remove it as rapidly
as it is produced, and under these circumstances, bacteria cannot multiply."
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hypothalamic-hypophyseal
C. A. Kristensen, et al., "Effect of estrogen withdrawal on energy-rich phosphates and prediction of estrogen-dependence monitored by in vivo 31P magnetic resonance spectoscopy of four human breast cancer xenografts," Cancer Research 55(8), 1664-1669, 1995. This is a very important confirmation of the idea that estrogen, by blocking energy, constrains cell function.
A. J. Roberts and L. D. Keith, "Corticosteroids enhance convulsion susceptibility via central mineralocorticoid receptors," Psychoneuroendocrinology 20(8), 891-902, 1995. ("...increase corticosterone levels are associated with increased severity of ethanol, pentobarbitol, and diazepam withdrawal. Further work with chemical convulsants suggests that mineralocorticoid receptors mediate excitatory effects of corticosteroids on convulsion susceptibility. The circadian rhythm in convulsion susceptibility varies with the circadian rhythm of plasma corticosterone levels and MR binding." "...MR are substantially bound at rest and maximally occupied during the circadian peak in corticosteroid levels and during stressor exposure, these receptors are implicated in the maintenance of and in changes in the arousal state of animals.") L. Murri, et al., "Neuroendocrine evaluation in catamenial epilepsy," Funct. Neurol. 1(4) 399-403, 1986. "Our data showed a reduction of luteal phase progesterone secretion; an imbalanced secretion of ovarian steroids plays a role in the catamenial exacerbation of epilepsy." S. Bag, et al., "Pregnancy and epilepsy," J. Neurol. 236(5), 311-313, 1989.
"Patients with increased seizure frequency had significantly higher oestrogen levels, lower level of progesterone...." "...abortions and status epilepticus had high serum oestrogen levels." M. I. Balabolkin, et al., "The role of the female sex hormones in the pathogenesis of catamenial epileptic seizures," Ter. Arkh. 66(4), 68-71, 1994. "...a tendency to deficient luteal phase and relative hyperestrogenemia in all the cycle phases." C. A. Guerreiro, "Ovulatory period and epileptic crisis," Arq. Neuropsiquiatr. 49(2), 198-203, 1991. "We think the estrogen peak is probably the main cause of the increased frequency of epileptic seizures during the ovulatory period."
U. Bonuccelli, et al., "Unbalanced progesterone and estradiol secretion in catamenial epilepsy," Epilepsy Res. 3(2), 100-106, 1989. (Luteal secretion ratio, progesterone to estrogen, was significantly reduced in patients versus controls.)
T. Backstrom, "Epilepsy in women," Experientia 32(2), 248-249, 1976. "...a significant positive correlation between estrogen/progesterone ratio and scores of fits."
A. G. Herzog, "Hormonal changes in epilepsy," Epilepsia 36(4), 323-326, 1995. A. G. Herzog, "Progesterone therapy in women with partial and secondary generalized seizures," Neurology 45(9), 1660-1662, 1995. A. G. Herzog, "Reproductive endocrine considerations and hormonal therapy for women with epilepsy," Epilepsia 32(Suppl.6), S27-33, 1991. "Seizure frequency varies with the serum estradiol to progesterone ratio." "... propensity for onset at menarch and exacerbation of seizures during the months or years leading up to menopause..." polycystic ovarian syndrome and hypogonadotropic hypogonadism are significantly overrepresented among women with epilepsy.
R.H. Mattson and J. A. Cramer, "Epilepsy, sex hormones, and antiepileptic drugs," Epilepsia 26(Suppl. 1), S40-51, 1985. There were fewer seizures during the luteal phase but they increased when the progesterone level declined.
J.J. Jacono and J. M. Robertson, "The effects of estrogen, progesterone, and ionized calcium on seizures during the menstrual cycle of epileptic women," Epilepsia 28(5), 571-577, 1987. A positive relation of serum estrogen and seizures, negative relation between serum ionized calcium and seizures, and negative relation between serum estrogen and calcium. F. E. Jensen, et al., "Epileptogenic effect of hypoxia in the immature rodent brain," Ann. Neurol. 29(6),629-836, 1991. E. C. Wirrell, et al., "Will a critical level of hyperventilation-induced hypocapnia always induce an absence seizure?" Epilepsia 37(5), 459-462, 1996. A. Nehlig, et al., "Absence seizures induce a decrease in cerebral blood flow: Human and animal data," J. Cereb. Blood Flow Metab. 16(1), 147-155, 1996.
Some clinical laboratory findings in epilepsy: Folic acid, serum decrease, R. E. Davis, et al., "Serum pyridoxal, folate, and vitamin B12 levels in institutionalized epileptics," Epilepsia 16, 463-8, 1975.
Serum GGT, constantly elevated. Ewen and Griffiths, "Gamma-glutamyl transpeptidase: Elevated activities in certain neurologic diseases," Am. J. Clin. Pathol. 59, 2-9, 1973.
IgA, CSF decreased, F. Mora, et al.
Iron-binding capacity, total, serum decrease. F. Mora, et al. Magnesium, serum, decreased; between seizures. C S Babel, et al Prealbumin, CSF, increased, the only protein to increase in epileptics. F. Mora, et al.
Pyridoxine, serum, sometimes decreased. R. L. Searcy, Diagnostic Biochemistry, McGraw-Hill, 1969.
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