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.
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.)
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.
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.)
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.
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
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.
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,
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.
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).
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.
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
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.
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."
E. Tauboll, et al., "The
progesterone metabolite 5-alpha-pregnan-3-alpha-ol-20
E. Tauboll and S. Lindstrom, similar article in Epilepsy Research 14(1), 17-30, 1993.
G. K. Herkes, et al., "Patterns of seizure occurrence in catamenial epilepsy," Epilepsy Research 15(1), 47-52, 1993. (Seizures are more frequent at ovulation, during the two days before menstruation, and during menstruation.)
M. S. Myslobodsky, "Proconvulsant and anticonvulsant effects of stress--the role of neuroactive steroids," Neuroscience & Biobehavioral Reviews 17(2_, 129-139, 1993. (Discusses steroid-induced sedation, excitatory steroids, stress and epilepsy, GABA and respiratory functions, and asymmetric brain injury.)
P. Berbel, et al., "Organization of auditory callosal connections in hypothyroid adult rats," European J. of Neuroscience 5(11), 1465-1478, 1993.(Changes in cortical connectivity related to epilepsy associated with early hypothyroidism.)
D. A. Marks and B. L. Ehrenberg, "Migraine-related seizures in adults with epilepsy, with EEG correlation," Neurology 43(12), 2475-2483, 1993. ("Patients with catamenial epilepsy and patients with migraine with aura were at an increased risk for an association between..." migraine and epilepsy.)
R. D. Brinton, "The neurosteroid
J. O. McNamara, "Human hypoxia and seizures: Effects and interactions," Advances in Neurology 26, S. Fahn, et al., eds., Raven Press, N.Y., 1979. (Seizures can cause hypoxia, etc.)
M. R. Liebowitz, et al., "Lactate provocation of panic attacks: 2. Biochemical and physiological findings." Arch. Gen. Psychiatry 42(7), 709-719, 1985. "Before receiving lactate, patients showed higher heart rates than controls and also signs of hyperventilation." R. H. Mattson, et al., "Treatment of seizures with medroxyprogesterone acetate: Preliminary report," Neurology 34, 1255-7, 1984. M. W. Newmark, et al, "Catamenial epilepsy: A review," Epilepsia 21, 281-300, 1980.
J. W. Phillis and M. H. O'Regan, "Effects of estradiol on cerebral cortex neurons and their responses to adenosine," Br. Res. Bull. 20(2), 151-155, 1966. (Antagonism to endogenous adenosine may account for the excitant actions of estradiol in the brain.)
J. W. Phillis, et al., "Acetylcholine output from the ischemic rat cerebral cortex: Effects of adenosine agonists," Br. Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxicity, could contribute to ischemic brain injury.)
T. Backstrom, "Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle," Acta Neurol. Scand. 54, 321-347, 1976. (Seizures are more frequent at menstruation and ovulation.) T. Backstrom, et al., "Effects of intravenous progesterone infusion on the epilepsy discharge frequency in women with partial epilepsy," Acta Naurol. Scan. 69(4), 240-248, 1984.
A. W. Zimmerman, "Hormones and epilepsy," Neurol. Clin. 4(4), 853-861, 1985. "Progesterone appears to be especially effective in treating seizures." J. Bauer, et al., "Catamenial seizures--an analysis," Nervenarzt 66(10), 760-769, 1995. "...when anticonvulsants have failed to suppress seizures, progesterone or progesterone-derivates have been administered with success." R. H. Mattson, et al., "Seizure frequency and the menstrual cycle: a clinical study," Epilepsia 22, 242, 1981. J. Logothetis, et al., "The role of estrogens in catamenial exacerbation of epilepsy," Neurology (Minneap) 9, 352-360, 1959. J Laidlaw, "Catamenial epilepsy," Lancet 2, 1235-7, 1956. S. Landgren and O. Selstam, "Interaction between 17-beta-oestradiol and 3alpha-hydroxy-5alpha pregnane- 20-one in the control of neuronal excitability in slices from the hippocampus in vitro of guinea-pigs and rats," Acta Physiologica Scandinavica 154(2), 165-176, 1995. C. A. Frye, "The neurosteroid 3 alpha, 5 alpha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy," Brain Research 696(1-2), 113-120, 1995.
G. K. Herkes, "Drug treatment of catamenial epilepsy," CNS Drugs 3(4), 260-266, 1995. (Mentions use of diuretics, progesterone, and the very high incidence of premenstrucal seizure, and of abnormal menstrual cycles in women with epilepsy.)
E. Spiegel and H. Wycis, "Anticonvulsant effects of steroids," J. Lab. Clin. Med. 33, 945-957, 1947.
G. Holmes, "Anticonvulsant effect of hormones on seizures in animals," 265-268, in: R. Porter, R. H. Mattson, A. Ward, and M. Dam, eds., Advances in Epileptology, 15th Epilepsy International Symposium, New York, Raven Press, 1984.
H. W. Zimmerman, et al., "Medroxyprogesterone acetate in the treatment of seizures associated with menstruation," J. Pediatr. 83, 959-963, 1973. R. H. Mattson, et al., "Medroxy-progesterone treatment of women with uncontrolled seizures," Epilepsia 22, 242, 1981. A. Rosenfield, et al., "The Food and Drug Administration and medroxyprogesterone acetate: What are the issues?" JAMA 249, 2922-2928. 1983. V. Valenzuela and L. S. Benardo, "An in vitro model of persistent epileptiform activity in neocortex," Epilepsy Research 21(3), 195-204, 1995. C. A. Slandley, et al., "Magnesium sulfate reduces seizures induced by central administration of the excitatory amino acid N-methyl-D-aspartate in rats," Hypertension in Pregnancy 14(2), 235-244, 1995. ("Magnesium is a physiological blocker of the NMDA receptor.") M. Simonale, et al., "Adenosine JA(1) receptors in the rat brain in the kindled model of epilepsy," Eur. J. of Pharmac. 265(3), 121-124, 1994. (Adenosine has potent anticonvulsive effects in various seizure models.) P. S. Timiras and H. F. Hill, Chapter 43, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. Glaser, et al, Raven Press, N.Y., 1980. (Estrogens increase cortical excitability, lower convulsive thresholds, and are clearly associated with certain cases of petit mal epilepsy. "The mechanisms of this so-called 'catamenial' epilepsy are unknown. Water retention and electrolyte changes in the brain...have been implicated..." "...acetazolamide (diamox), a carbonic anhydrase inhibitor and diuretic, is successful in the treatment of many cases of these seizures, and in refractory cases progestational agents are effective." "...seizures were more severe and frequent during the estrogen-dominated preovulatory phase of the menstrual cycle than in the progesterone-dominated postovulatory phase." "...ACTH may trigger epileptic convulsions by increasing intracellular sodium concentration throughout the body." "Progesterone can effectively reduce the frequency and severity of intractable seizures associated with menstruation..." "Considering the markedly proconvulsant effects of estrogens, it is surprising that the differential effects of sex hormones on central neurotransmitter mechanisms have been only sparingly investigated." "...estradiol decreases monoamine oxidase activity and increases choline acetyltransferase activity in various brain regions." "...hypothyroidism in perinatal animals has striking suppressant effects on GABA metabolism and also causes a persistent lowering of electroconvulsive threshold.")
P. S. Timiras and H. F. Hill, "Antiepileptic drugs," Chapter 43; E. Roberts, "Epilepsy and antiepileptic drugs: A speculative synthesis," Chapter 44, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. Glaser, et al., Raven Press, New York, 1980. E. V. Nikushkin, et al.,"Relationship between peroxidation and phospholipase hydrolysis of lipids in synaptosomes," B.E.B.M.107(2)183-186, 1989. Free unsaturated fatty acids are liberated in nerve endings and contribute to lipid peroxidation in epileptic seizures. P. A. Long, et al., "Importance of abnormal glucose tolerance (hypoglycemia and hyperglycemia) in the aetiology of pre-eclampsia," Lancet 1, 923-925, 1977.
M. M. Singh, "Carbohydrate metabolism in pre-eclampsia," Br. J. Obstet. Gynaecol. 83, 124-131, 1976.
N. A. Ziboh, et al., Prostaglandins 5, 233, 1974. (Eicosatrienoic (20:3 n-9) acid is a potent inhibitor of prostaglandin synthetase.) C. Galli and C. Spagnuolo, "The release of brain free fatty acids during ischaemia in essential fatty acid-deficient rats," J. of Neurochemistry 26, 401-404, 1976.
B. Meldrum, "Excitatory amino acids and anoxic-ischemic brain damage," Trends Neurosci. 8, 47-48, 1985.
B. Halliwell, "Oxidants and human disease: Some new concepts," FASEB J. 1, 358-364, 1987. "...injury to the brain causes release of metal ions that stimulate lipid peroxidation." "..lipid peroxidation...could be important in spreading injury to adjacent cells...." P.H. Chan, et al., "Effects of excitatory neurotransmitter amino acids on swelling of rat brain cortical slices," J. Neurochem. 33, 1309, 1979. P. H. Chan and R. A. Fishman, "Alterations of membrane integrity and cellular constituents by arachidonic acid in neuroblastoma and glioma cells," Brain Res. 248, 151, 1982.
T. O. Kokate, et al., "Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice," Neuropharmacology 35(8), 1049-1056, 1996. (With a second dose, "complete protection from the...limbic seizures and status epilepticus was obtained.") J. W. Phillis, et al., "Effect of adenosine receptor agonist on spontaneous and K+-evoked acetylcholine release from the in vivo rat cerebral cortex," Brain Res. 605(2), 293-297, 1993.
J. W. Phillis, et al., "Acetylcholine output from the ischemic rat cerebral cortex: Effectss of adenosine agonists," Brain Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxic depolarization, intracellular calcium levels, and neural degeneration, and could contribute to ischemic brain injury.
R. L. Grief, "Thyroid status influences calcium ion accumulation and retention by rat liver mitochondria," Proc. Soc. Exp. Biol. & Med. 189(1), 39-44, 1988.
L. G. Cleland, et al., "Effects of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and tissue plasma lipids," Lipids 31(8), 829-837, 1996. "Dietary enrichment with ETrA warrants further investigation for possible beneficial effects in models of inflammation and autoimmunity, as well as in other conditions in which mediators derived from n-6 fatty acids can affect homeostasis adversely." A. A. Starkov, et al., "Regulation of the energy coupling in mitochondria by some steroid and thyroid hormones," Bioch. Biophys. Acta 1318(1-2), 173-183, 1997. (Thyroid and progesterone improve respiratory efficiency, lowering oxygen consumption which restoring energy production.) R. B. Gibbs, et al., "Effects of estrogen on potassium stimulated acetylcholine release in the hippocampus and overlying cortex of adult rats," Brain Res. 749(1), 143-146, 1997. (Increased response.) I. V. Gusakov, et al., "Investigation of the role of free-radical processes in epilepsy and epileptogenesis," Bull. Exp. Biol. & Medicine 117(2), 206, 1994.
B. K. Shakenova, "A new treatment of epilepsy resistant to traditional antiseizure pharmacotherapy," Bull. Exp. Biol. & Medicine 117(2), 227, 1994. (Antihypoxant with antioxidant activity.) R. N. Rzaev and M. N. Aliev, "The use of antioxidants in the treatment of tic-accompanied hyperkineses in children," Bull. Exp. Biol. & Medicine 117(2), 222, 1994.
D. A. Sutkovoi and N. I. Lisyanyi, "Relationship between the kinetics of lipid peroxidation and autoimmune reactions after craniocerebral injury," Bull. Exp. Biol. & Medicine 117(2), 2, 1994. Winfried G. Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology 30(3/4) 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a pituitary site, have been determined as concomitants of aging in women." "...aging may impair the negative feedback sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of functional aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure facilitates the loss of hypothalamic neurons...."
J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107, 274-279, 1980. J. Herbert and S. Zuckerman, "Ovarian stimulation from cerebral lesion in ferrets," J. Endocrinology 17(4), 433-443, 1958. G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals." "...this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results "in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic effects of estradiol cause a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." Treatment with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian cycles" in estrogen-treated rats. G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women using naloxone," Neuroendocrinology 39, 60-63, 1984.
H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. ...the estradiol phenoxyl radical abstracts hydrogen from...NADH to generate the NAD radical." "...the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence." S. Santagati, et al., "Estrogen receptor is expressed in different types of glial cells in culture," J. Neurochem. 63(6), 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..." D. X. Liu and L. P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo," Free Radical Biol. Med. 18(3), 571-576, 1995. "Free radicals and some free fatty acids, such as arachidonic acid metabolites...may form a feedback loop in which generation of one type leads to formation of the other." "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...." J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2 alpha," Brain Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its metabolites may bias neurons towards excitation." [Estrogen appears to support this excitatory system at every level, while prostaglandin F2 alpha alters steroid balance, by suppressing progesterone synthesis.] J. G. Liehr, et al., "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes: Implications for the mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995. "... elicits biological activities distinct from estradiol, most notably an oxidant stress response induced by free radicals generated by metabolic redox cycling reactions."
J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8, 415-423, 1990. P. Aschheim, "Resultats fournis par la greffe heterochrone des ovaires dan l'etude de la regulation hypothalamo-hypophyso-ovarienne de la ratte senile," Gerontologia 10, 65-75, 1964/65. "Our last experiment, grafting ovaries...into senile rats which had been castrated (ovariectomized) when young, and its result, the appearance of estrous cycles, seems explicable by this hypothesis. Everything happens as if the long absence of ovarian hormones... had kept the cells of the hypothalamus in the state of youth. It's as if the messages of the circulating steroids fatigued the hypothalamic memory." "What are the factors that cause this diminution of the hypothalamic sensitivity...? Kennedy incriminates a decrease in the cellular metabolism in general...."
P. Ascheim, "Aging in the
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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