This article on seizures is from the following author. For more information go to www.vrp.com.
By Ward Dean, MD of Vitamin Research Products

Seizures can be attributed to a number of causes including metabolic abnormalities, infections, nutritional deficiencies, or trauma. Emotional stress also increases the frequency of seizures. But most seizures occur due to unknown reasons.

In the 1920s, before anticonvulsant medications were available, high-fat diets were used to control seizures in epileptics. Clinical trials are now confirming that high-fat diets work & better than any other regimen & according to Dr. John M. Freeman, director of the Pediatric Epilepsy Clinic at Children"s Center in Baltimore, Maryland. He recommends a stringent diet consisting of high fat, low protein, low carbohydrate foods. Some experts estimate that this diet can lead to a 50 to 70 percentage reduction of seizures, a record which few drugs can claim. Dr. Freeman has written a book titled, The Epilepsy Diet Treatment: An Introduction to the Ketogenic Diet, Demos Publications, 1994, New York (Maltz, 1994).

Gamma-aminobutyric acid (GABA), the brain"s major inhibitory neurotransmitter, tends to be in lower than normal levels in seizure-prone rats (1) and humans with epilepsy. (2) Seizure-prone preeclamptic patients (hypertensive condition during late pregnancy) also have decreased brain GABA concentrations. (3) Brain GABA levels depend on both zinc and vitamin B6. Zinc is involved in the maintenance of pyridoxal phosphate concentrations by the activation of pyridoxal kinase. Pyridoxal kinase is important in decarboxylation, and lack of this enzyme results in lowered brain levels of GABA. Consequently, zinc deficiency may increase the risk of preeclamptic seizures by reducing brain GABA concentrations and lowering the seizure threshold. Unfortunately, plasma pyridoxal phosphate measurements alone do not appear to accurately reflect vitamin B6 status or true tissue pyridoxal phosphate levels. (3)

Glutamate concentrations in the brain are higher in some seizure patients, and these concentrations can increase to potentially neurotoxic concentrations during seizures. Thus, it appears that a rise in brain glutamate may precipitate seizures. These concentrations may reach levels capable of causing cell death. (2) The importance of relative concentrations of glutamate, gamma-aminobutyric acid, and pyridoxal-5-phosphate with respect to seizures is illustrated by a 33-month-old male seizure patient whose cerebro-spinal fluid glutamate levels were 200 times normal! When he was given vitamin B6 at a dose of 5 mg/kg body weight per day (350 mg), his EEG normalized and his seizures stopped, but the CSF glutamate concentration was still 10 times normal. With a higher dose of B6 (10 mg/kg bw/d-700 mg), the CSF glutamic acid normalized. These results indicate that the optimal dose of B6 for epileptics should be the dose that normalizes CSF glutamate levels, not just the control of seizures. (4)

Dr. Stephen Lasley (1) found that brains of rats that are genetically prone to seizures also have reduced levels of taurine as well as increased levels of aspartate. Therefore, I believe that avoidance of aspartame should be a key element in an anti-seizure diet. Also, taurine, in doses of 1-3 grams per day may be helpful.

In addition to vitamin B6, magnesium and dimethylglycine have also frequently resulted in a rapid, sometimes overnight, appearance of speech in formerly non-speaking autistic children. Magnesium, vitamin B6 and dimethylglycine all have strong anti-seizure properties and can be effective even when other anti-seizure medications fail. (5) The deficiency of another member of the B-complex, B1, has also been reported as a cause of epileptic seizures. (6)

Vitamin E has been helpful in patients with complex partial seizures, which are often resistant to drug therapy, and may compensate for vitamin E deficiencies induced by anticonvulsant medications. Dr. Sheldon Levy (7,8) believes that vitamin E, although not an anticonvulsant or an antiepileptogenic agent, plays a useful role in anticonvulsant therapy as an adjunctive therapy which compensates for anticonvulsant-induced vitamin deficiencies.

Carnitine is an amino acid that is excreted in large amounts when anti-seizure medications like valproic acid (Depakote) or Tegretol are taken. Depakote is a very effective antiepileptic drug but has limited use due to risk of fatal hepatotoxicity. The hepatotoxicity is probably due to valproate-induced carnitine deficiency. Carnitine transports long chain fatty acids into the mitochondria. Valproic acid treatment results in a reduction of free carnitine levels. Carnitine is supplied both by the diet and by endogenous biosynthesis from lysine. Carnitine's primary metabolic role is to transport 12-20 carbon long-chain fatty acids into the mitochondria where they are catabolized to acetyl-CoA for synthesis of mainly citrate and acetoacetate. Carnitine also is involved in a variety of fatty acid and organic acid transacylation reactions, where the acyl moieties of acetyl-CoA esters are transformed to or from carnitine.

There are four metabolic actions of carnitine that have been utilized as therapeutic rationales: to correct an absolute relative carnitine deficiency, to enhance fatty acid oxidation, to accept and shuttle unmetabolized acyl groups from the mitochondria and to increase levels of free unesterified coenzyme A and thereby increase the intracellular free-CoA/acyl-CoA ratio, an important regulator of enzyme activation/deactivation. (9) Carnitine supplementation is effective in reducing valproic acid-associated hyperammonemia. (10) Recommended dosages for carnitine replacement are 50-100 mg/kg/day in children, and 1 to 3 gm per day for adults in 2 or 3 divided doses. (11)

In many cases of epilepsy, there is an association with celiac disease and cerebral calcifications. Gluten-free diets, a mainstay in the treatment of celiac disease, often reduce the incidence of seizures, especially if the diet is started soon after the onset of seizures. The efficacy of the gluten-free diet in epilepsy appears to be inversely related to the duration of epilepsy before the diet, and to the age at the beginning of the diet. (12) The possibility of celiac disease should be investigated in all cases of epilepsy, especially if cerebral calcifications are identified.

In this regard, Dr. A. Ventura reported on two females, 5 and 23 years old, who had focal occipital epilepsy with cerebral calcifications and who were not responding well to anti-epileptic therapy. (13) Both females also had celiac disease as well as documented folic acid deficiency. It is well-known that antiepileptic drugs may induce a folate deficiency. The patients were placed on gluten-free diets with supplementary folic acid (dosage unknown). This led to complete normalization of the EEG in the five year-old and a cessation of seizures. The 23-year-old's EEG improved significantly and seizure frequency was reduced. Folic acid levels returned to the normal range within several months. This report suggests that there is an association between folic acid deficiency and neurologic diseases such as epilepsy. Dr. Ventura believes that the mucosal abnormalities of celiac disease may have caused the folate deficiency, which precipitated the seizures. (13) The causative relationship of cerebral calcifications to seizures is unknown, but this may be a condition that may be helped by EDTA chelation therapy. EDTA chelation is probably the treatment of choice for metastatic calcification in any tissue. Whether resolution of cerebral calcification would help in reducing seizures is unknown, but it certainly wouldn't hurt.

Magnesium sulfate is standard therapy for pregnancy-induced hypertension (eclampsia and pre-eclampsia) to prevent seizures. 10 gm of magnesium are administered intramuscularly initially, followed by 5 gm intramuscularly every 4 hours. If administered intravenously, a 6 gm bolus over 15 minutes is given, followed by 1 to 3 gm per hour. In a comparative study, Dilantin was compared to magnesium in preventing seizures and reducing blood pressure. The investigators found no differences in the patients tolerance, adverse reactions or outcomes between the two groups. The authors then made the amazing conclusion that Dilantin is a well tolerated alternative to magnesium sulfate for seizure prophylaxis in patients with mild pregnancy-induced hypertension(14) My question is, what about magnesium as a well-tolerated alternative to Dilantin?

Seizures may also result from glutathione peroxidase deficiency, which could be from lack of bioavailable selenium. (15) Selenium supplementation in children resulted in a reduction in seizures and improvement in EEG recordings after 2 weeks. Selenium is important in the formation of glutathione peroxidase which may play a role in protecting neuronal cells against oxygen radicals and peroxidative damage. Selenium deficiency in the brain of patients with epilepsy may be an important triggering factor for the origin of intractable seizures and subsequent neuronal damage. (16)

Recently, a colleague related a story of a patient with a history of multiple, intractable, daily grand mal seizures for over 50 years. Because of the frequency of her daily seizures, the patient has been unable to attend school, and is illiterate. She was treated with pregnenolone, with immediate and near-total resolution of her seizures, being reduced in frequency from several each day to less than one per month. She repeats over and over that pregnenolone has finally given her a life. Although this anecdotal report is without precedent or confirmation, pregnenolone certainly seems to be worth trying. I recommend starting with 10 mg each morning for one month, increasing the dose to 30 mg, then to 100 mg, at monthly intervals.

Kava Kava, which I believe to be a nutritional precursor to the now-outlawed GHB, has been used traditionally for its anti-convulsant properties. Consequently, Kava Kava might also be considered for its sedative, muscle relaxant and anti-convulsant effects. (20, 21, 22)

In summary, for seizure disorders I recommend using a nutritional shotgun therapy, which includes:

- Magnesium: 500-1,000 mg/day
- Selenium: 100-200 mcg/day
- Taurine: 1-3 gm/day
- L-carnitine: 1-3 gm/day
- GABA (gamma amino butyric acid): 500-1,000 mg/day
- Vitamin B complex, w/special emphasis on;
- Vitamin B1: 50-100 mg/day
- Vitamin B6: 200-500 mg/day
- Folic Acid: 400-1,000 mcg/day
- Vitamin E: 400-800 IU/day
- DMG (dimethylglycine): 50-200 mg/day
- Pregnenolone: 100-500 mg/day
- Kava Kava: 200-800 mg/day

References:
1. Lasley, S. M. Role of Neurotransmitter Amino Acids in Seizure Severity and Experience in the Genetically Epilepsy-Prone Rat. Brain Res, 1991; 560:63-70

2. During, M.J. and Spencer, D. D. Extracellular Hippocampal Glutamate and Spontaneous Seizure in the Conscious Human Brain. The Lancet, June 26, 1993; 341 (8861): 1607-1610

3. Anonymous. Zinc, Preeclampsia, and Gamma-Aminobutyric Acid. Am Jnl of Obst & Gyn, July 1990, 163, 1, (Part I): 242-243

4. Baumeister, F. Glutamate in Pyridoxine-Dependent Epilepsy: Neurotoxic Glutamate Concentration in the Cerebrospinal Fluid and Its Normalization by Pyridoxine. Ped, September 1994, 94 (3): 318-321

5. Seizures, Vitamin B6, DMG, and Sudden Speech Autism, Res Rev Intl, 1996, 10 (2): 1

6. Keyser, A. Epileptic Manifestations and Vitamin B1 Deficiency. Eur Neuro, 1991, 31: 121-125

7. Levy, S. L. An Evaluation of the Anticonvulsant Effects of Vitamin E. Epilepsy Res, 1990, 6: 12-17

8. Levy, S. L. The Anticonvulsant Effects of Vitamin E: A Further Evaluation. Can Jrnl Neurosci, 1992, 19: 201-203

9. Kelley, R. I. The Role of Carnitine Supplementation in Valproic Acid Therapy. Ped, June 1994, 93 (6): 891-892

10. Sakemi, K., Tohoku, J. The Effect of Carnitine on the Metabolism of Valproic Acid. Exp Med, 1992, 167: 89-92

11. Coulter, Da. L., M.D. Carnitine, Valproate, and Toxicity. Jrnl Child Neuro, January 1991, 6 (1): 7-14

12. Gobbi, G. Celiac Disease, Epilepsy and Cerebral Calcifications. The Lancet, August 22, 1992, 340: 439-442

13. Ventura, A. Celiac Disease, Folic Acid Deficiency and Epilepsy With Cerebral Calcifications. ACTA Pediatrica Scandinavica, 1991, 80: 559-562

14. Appleton, M. P. Magnesium Sulfate Versus Phenytoin for Seizure Prophylaxis of Pregnancy-Induced Hypertension. Am Jnl of Obst & Gyn, October 1991, 907-913

15. Weber, G. Glutathione Peroxidase Deficiency and Childhood Seizures. The Lancet, June 15, 1991, 337: 1443-1444

16. Ramaekers, V., Th. Selenium Deficiency Triggering Intractable Seizures. Neuro Ped, 1994, 25: 216-223

17. Dean, W. Stop criminalization of GHB, VRP Nutrition News, Vol 11, Number 4, April 1997

18. Klunk, W.E., Covey, D.F., and Ferendelli, J.A. Anticonvulsant properties of alpha, gamma, and alpha, gamma-substituted gamma butyrolactones. Molecular Pharmacology, 1982, 22: 438-443.

19. Ikeda, M., Dohi, T., and Tsujimoto, A. Protection from local anesthetic-induced convulsions by gamma amino butyric acid. Anesthesiology, 1982, 56: 365-368.

20. Klohs, M.W., and Keller, F. A review of the chemistry and pharmacology of the constituents of Piper methysticum Forst. J Med, Pharm, Chem 1963, 1(1): 95-103.

21. Klohs, M.W.F., Keller, F., Williams, R.E., Toekes, M.I., and Cronheim, G.E. A chemical and pharmacological investigation of Piper methysticum Forst. J Med, Pharm, Chem, 1959, 1: 95-103.

22. Nickl, J. and Keck, J. Medicines containing lactones from Piper methysticum, Brit Patent 943,121, Nov 27, 1963.

Vinpocetine: Cognitive Enhancer's Role Expands to Incontinence and Epilepsy

Vinpocetine: Cognitive Enhancer's Role Expands to Incontinence and Epilepsy

Kimberly Pryor

The periwinkle has long been an established part of summer gardens. But research has revealed that this flower is more than just a pretty addition to landscaping. Studies have indicated that vinpocetine, a natural substance derived from vincamine, an extract of the periwinkle, may support cognitive health, alleviate some of the symptoms of urinary incontinence, and, when administered intravenously in animals, alleviate some of the negative effects that occur in epilepsy.

Early experiments with vinpocetine indicated it has five main mechanisms of action. It can selectively enhance brain circulation and the brain's use of oxygen without significantly altering circulation throughout the body. Vinpocetine also increases the brain's tolerance toward hypoxia (oxygen deficiency) and ischemia (obstructed blood flow) and acts as an anticonvulsant. In addition, it inhibits the enzyme phosphodiesterase (PDE)-1, which breaks down adenosine monophosphate, an important nucleotide that the body makes from the cellular energy molecule known as adenosine triphosphate (ATP). Finally, vinpocetine stops blood cells from sticking together. Later studies confirmed the above effects and pinpointed other mechanism of actions of vinpocetine (including its ability to act as a sodium channel blocker).[1]

Cognitive Support
Many vinpocetine studies have focused on its potential ability to enhance brain function. Vinpocetine increases blood circulation and metabolism in the brain, which may be why vinpocetine reduced the loss of neurons due to decreased blood flow in animal studies.[2]

In three studies of older adults with memory problems associated with poor brain circulation or dementia-related disease, vinpocetine-treated subjects experienced significantly more improvement than placebo-treated subjects on global cognitive tests reflecting attention, concentration, and memory.[2]

In one study, the efficacy and tolerance of orally administered vinpocetine was investigated in patients suffering from mild to moderate organic psychological syndromes, including primary dementia. In the placebo-controlled, randomized, double-blind trial, 203 patients received daily for 16 weeks either 10 mgs of vinpocetine three times per day, 20 mgs of vinpocetine three times per day, or a placebo three times per day. On both the lower and higher doses, the patients treated with vinpocetine experienced statistically significant improvements in cognitive performance compared to the placebo groups. Vinpocetine was also superior to placebo in improving ratings of the severity of illness. There were no clinically relevant side-effects reported and the frequencies of adverse events between patients treated with vinpocetine and placebo were comparable.[3]

Urinary Incontinence
Although vinpocetine is best known for the part it plays in cognitive support, researchers also have unearthed another potential role for this substance urinary incontinence. The standard drugs available for incontinence and low compliance bladder are limited by a low clinical efficacy and significant side effects. Previous in vitro studies indicated that the enzyme known as phosphodiesterase (PDE)-1 (which breaks down adenosine monophosphate) may be involved in the regulation of contractility in the bladder's layer of muscle. Due to this connection, researchers decided to investigate the effect of vinpocetine, a PDE-1 inhibitor, in people who did not respond to standard drug therapy and who had been told that surgery is needed to correct the problem.

The 19 subjects (10 women and nine men, average age 56) were given 5 mg per day of vinpocetine for two weeks, then 10 mg per day for another two weeks. In 11 subjects (57.9 percent) clinical symptoms and/or the holding and storage of urine were improved. In eight subjects, there was a marked improvement after vinpocetine treatment. In three of the subjects, there was a slight improvement after treatment. The other eight subjects did not respond to vinpocetine.[4] Although the researchers called the initial data preliminary, they pointed out that this study represents the first evidence that a phosphodiesterase (PDE)-1 enzyme inhibitor such as vinpocetine may be a novel approach to the treatment of lower urinary tract disorders.

Vinpocetine appears to be more effective in what's known as urge incontinence because it relaxes or desensitizes the bladder, whereas other agents that stimulate and strengthen the pelvic floor are more effective for stress incontinence. Urge incontinence is when an individual experiences involuntary passage of urine occurring soon after a strong sense of urgency to void. Stress incontinence is the inability to prevent escape of small amounts of urine during laughing, coughing, sneezing or lifting.[5]

Epilepsy
Vinpocetine also has been investigated for its potential role in epilepsy. One group of researchers induced convulsions in guinea pigs by using an agent called 4-aminopyridine (4-AP). The researchers injected the animals with vinpocetine and then observed its effects. Vinpocetine inhibited the undesirable electroencephalogram (EEG) changes induced by 4-AP. In addition, it prevented the hearing loss that usually accompanies 4-AP administration.[6] The researchers concluded, Vinpocetine could be a promising alternative for the treatment of epilepsy.

References
1. Kiss B, Karpati E. [Mechanism of action of vinpocetine] [Article in Hungarian] Acta Pharm Hung 1996, Sep;66(5):213-24.
2. McDaniel MA, Maier SF, Einstein GO. Brain-specific nutrients: a memory cure? Nutrition 2003, Nov-Dec;19(11-12):957-75.
3. Hindmarch I, Fuchs HH, Erzigkeit H. Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes. Int Clin Psychopharmacol 1991, Spring;6(1):31-43.
4. Truss MC, Stief CG, Uckert S, Becker AJ, Schultheiss D, Machtens S, Jonas U. Initial clinical experience with the selective phosphodiesterase-I isoenzyme inhibitor vinpocetine in the treatment of urge incontinence and low compliance bladder. World J Urol 2000, Dec;18(6):439-43.
5. Hampel C, Gillitzer R, Pahernik S, Melchior SW, Thuroff JW. [Drug therapy of female urinary incontinence] [Article in German] Urologe A 2005, Mar;44(3):244-55.
6. Sitges M, Nekrassov V. Vinpocetine prevents 4-aminopyridine-induced changes in the EEG, the auditory brainstem responses and hearing. Clin Neurophysiol 2004, Dec;115(12):2711-7.

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