What Causes Epilepsy? From GABA to Zinc
Carly CenedellaEpilepsy is "a diverse collection of disorders" (1) . In the United States, there are close to one million people with epilepsy-- about 1 in 200 people around the world have epilepsy(3) . This is a review of the emerging insights into the mechanisms underlying the most common form of epilepsy, complex partial epilepsy(1) .
Terminology and Classification of Epileptic Seizures
The term seizure refers to a transient alteration of behavior due to abnormal synchronized and repetitive bursts of firing of neurons in the central nervous system. Epilepsy is syndrome of episodic brain dysfunction characterized by recurrent unpredictable spontaneous seizures. Partial seizures begin in a localized brain region, whereas generalized seizures show widespread involvement of both hemispheres. Examples of generalized seizures are absences (petit mal), myoclonic, or tonic-clonic (grand mal) seizures. A complex partial seizure is associated with impairment of consciousness while a simple partial seizure is not. Most complex partial seizures originate from the temporal lobe and are also called temporal lobe seizures. Epileptics frequently have more than one type of seizure. When simple partial seizure precedes a complex partial seizure, it is referred to as an aura. More recent classifications of epileptic syndromes incorporate such features as etiology, age of onset, and the different combinations of seizures that an epileptic has. Other commonly used terms include ictal (of seizure itself) and interictal (between seizures). Convulsion implies ictal behavior with vigorous motor activities. Status epilepticus denotes a very prolonged seizure or series of seizures occurring so frequently that full recovery of brain function does not occur interictally (1) .
Complex partial seizures constitute a major percentage of epilepsies and as a result of impaired consciousness are rather disabling. They are often medically intractable in that the administration of medication will not control the seizures. Most cases of complex partial epilepsy appear to stem from an abnormality in the temporal lobe, since partial resection of the temporal lobe, including the mesial structures, hippocampus, and amygdala, virtually eliminates seizures in more than 80% of selected patients. Examination of tissues of the surgical specimens and autopsy studies of patients with chronic temporal lobe epilepsy most often reveal sclerosis of the hippocampus, termed Ammons horn sclerosis, which is characterized by a marked loss of the principal neurons of hippocampus (1) .
Jackson and his Early Theory on Epilepsy and Brain Organization
In the 1800s, it was noted by Jackson that epileptic seizures begin in isolated parts of the body such as the thumb and from there spread to neighboring regions perhaps the arm and then to the rest of the body. He hypothesized that there were areas in cerebral cortex that controlled isolated movements and that the areas that were adjacent in the brain were anatomically adjacent as well. Therefore, a seizure began in one area and spread to the rest of the cortex. His hypothesis was later substantiated by Fritsch and Hittig's excitation experiments on motor cortex or area 4. It is a band of neural tissue on the cerebral cortex lying on precentral fissure. The body's movements are mapped out on this band giving rise to the spreading fashion that Jackson described during seizures (4) .
Loss of GABA inhibition and hyperexcitability of the hippocampus
Experimental work has demonstrated that repeated or prolonged seizures (status epilepticus) cause hippocampal sclerosis, presumably through excessive activation of excitatory glutamate receptors, which results in excitotoxicity. Removal of sclerotic hippocampus leads to dramatic improvement or even a cure of the epileptic condition in humans, which suggests that the sclerotic hippocampus somehow causes the epilepsy. One could argue, however, that it is the other way around that these individuals have had hypoxic injury that may have caused the hippocampal sclerosis, which then caused the onset of seizures. In the absence of hypoxia though, it seems equally plausible that intense seizures can cause hippocampal sclerosis, which then can cause epilepsy (1) .
Repeated and intense seizures cause a loss g-amino butyric acid (GABA)- mediated inhibition of dentate granule cells in vitro. Thus until recently the leading hypothesis was that death of GABAergic inhibitory internuerons resulted in attenuation of inhibition, which in turn lead to hyperexcitability of the remaining neurons of the hippocampus. However, detailed immunohistcohemical studies of sclerotic hippocampus isolated from experimental models and from humans have provided new potential mechanisms of hyperexcitability. In work that contradicted the prevailing idea at the time, Sloviter demonstrated in an experimental model that GABA neurons were actually more resistant to seizure induced neuronal death than were other hippocampal neurons. Further, the study of tissue from human epileptic surgical specimens confirmed the relative preservation of presumed GABAergic interneurons. In fact, another type of cells was readily destroyed in these specimens-- mossy cells. Mossy cell are located in the dentate hilus (a part of the hippocampus) and were found to be extremely sensitive to seizure induced neuronal death(1) .
Mossy cells are the most common type of neuron in the hilus of dentate gyrus of hippocampus. They receive synaptic inputs both from dentate granule cells and from the entorhinal cortex. Mossy cells project both ipsilaterally (the same side) and contralaterally (to the opposite side) to the molecular layer of the dentate gyrus where they synapse on the granule cells. Functionally, mossy cells are more activating by perforant path stimulation at a low threshold than the dentate granule cells and are thought to be excitatory on the granule cells. Mossy cells are damaged following intense synaptic activation, probably through excitotoxic mechanisms of activation of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors which results in excessive intracellular calcium (1) .
These series of findings lead to the dormant basket cell hypothesis which suggests that the seizure induced death of excitatory neurons in the hilus (probably mossy cells) removes an excitatory projection to GABAergic basket cell, the inhibitory neurons in the dentate gyrus, resulting in disinhibition because basket cells lie dormant when they are not activated by mossy cells. Once initiated, one can imagine a vicious cycle in which a partial loss of this inhibition, combined with excitatory synaptic input, could lead to excessive firing of granule cells, more mossy cell death, further loss of GABAergic inhibition and so on, resulting in an epileptic condition long after the initial injury. In an experimental model of unilateral hippocampal sclerosis from focal electrical status epilepticus, the resulting hyperexcitability of hippocampal neurons was stopped by stimulating the unaffected contralateral hippocampus. One explanation is that dormant basket cells were awakened by preserved contralateral mossy cells projections crossing through the hippocampal commisure (1) .
The relationship between GABA inhibition and seizure is further supported by the fact that many of the antiepileptic medications act on GABA receptors. For example, the new antiepileptic drug, tiagabine, inhibits GABA uptake (7) . This sort of clinic observation suggests that GABA does play a role in epilepsy.
Shoffner et. al. were the first to identify the genetic defect in a human epileptic syndrome. Consistent with maternal inheritance, a mutation of a mitochondrial gene encoding a mitochondrial tRNA coding for lysine was found to be responsible for a condition characterized by myoclonic epilepsy and by a myopathy with a distinctive histochemical abnormality referred to as ragged-red fibers. This disease is known as the myoclonic epilepsy and ragged-red fibers (MERRF) syndrome. It is associated with defects in mitochondrial oxidative phosphorylation. The mitochondrial abnormality in the neurons will have negative effects on aerobic respiration and will lead to neuronal dysfunction underlying the myoclonic seizures (1) .
Linkage analyses have successfully identified the chromosomal localization of the mutant genes underlying three different genetic epilepsies: benign neonatal convulsions, progressive myoclonic epilepsy, and tuberous sclerosis. The success of positional clinging in detecting the responsible gene in diseases such as cystic fibrosis and Huntington's disease offers hope for similar success with these three types of epilepsy. Two classes of genes that may be candidates are glutamate receptor and potassium channel genes, both of which are involved in the regulation of neuronal excitability (1) . Further inquiry on the genetics of epilepsy has suggested that partial and generalized epilepsies are genetically indistinct. Some genotypes raise the risk for both generalized and partial epilepsies (2) .
Zinc and Epilepsy: A Puzzling Relationship
Ever since the discovery that zinc induces seizures in rats, it has resulted in the suggestion that the release of cellular zinc plays a major role in the generation and propagation of epileptic activity. However, as the evidence was gathered, many contradictions accumulated. It has been proposed that zinc may act to attenuate the GABA response and thereby elicit hyperexcitability of the neurons and thereby incur a seizure. Conversely, it has also been found that zinc may act as an inhibitory neurotransmitter decreasing the likelihood of a seizure. Some researchers have noted a post-seizure increase in the level of zinc in the brains of rats and mice while others research do not show an increase. These variations could be due to differing lag times between the seizure and the sacrifice. Zinc has also been implicated in the pathology of cell death in response to activation of glutamate receptors. All in all, there seems to be a connection between zinc and seizures, but there are too many contradictions to clarify the nature of the relationship (5) .
At the beginning of this essay, epilepsy was described as is "a diverse collection of disorders" (1) . After reviewing the many different models on the cause and/or mechanism of epilepsy, one fact becomes abundantly clear that what we call "epilepsy" is a collection of disorders that bringing about similar behaviors but that may be caused by totally different factors-zinc or genes or GABA.
It may also come to mind what is the importance of studying epilepsy. It came to my mind often in moments of frustration during this project too. To me, there are two main contributions to be made by the study of the pathogenesis of epilepsy. First, there are major therapeutic and diagnostic contributions. While there are antiepileptic drugs available that control most epileptic symptoms, understanding the underlying mechanism of epilepsy could revolutionize treatment and perhaps improve current drug therapies. Additionally, proper understanding of the mechanism could perfect a diagnosis down to the specific brain dysfunction. Second, there is a great deal to be learned about the mind itself by studying epilepsy. Temporal lobe epilepsy is focused in the hippocampus and amygdala. The function of these structures could be illuminated by the study of epilepsy. In fact, in an editorial for Brian and Cognition, it was said that epilepsy has "provided the greatest opportunity for the study of higher cortical functions" (6) .
The last comment that I have on epilepsy is in regard to my trigger dispersion theory of epilepsy. I found through my research that my theory seems to fit best with the Jacksonian model. This make sense at some level since he and I both were making models based on observation alone-no immunohistochemical or genetic studies. My model could not describe the action of a generalized seizures; rather it describes the mechanism of partial seizures. The fact that partial seizure begin in the temporal lobe and spread from there is very similar to my theory as well. In sum, making my own anecdotal model made studying epilepsy more challenging. My own critical thinking on the subject helped me tremendously when it came time to sift through the current theories presented in this paper.
WWW Sources1) Database for medical journals , Search for "epilepsy" in the "words in title or abstract" field. This article (Mechanisms of Epilepsy by Shin and McNamara) will be the first hit.
2) AMA Homepage: Archives of Neurology , by Ruth Ottman, PhD et. al.
5) The Ideal library , Search for Zinc Metabolism in the Brain by Cuajungco and Lees.
6) The Ideal library , Search for Guest Editorial in Brain and Cognition by Peter J. Snyder.
7) AMA Homepage: Archives of Neurology , by Basim M. Uthman et. al.
11/02/2005, from a Reader on the Web
Was recently diagnosed with Jacksonian Epilepsy. After research on the Web, I came to the conclusion that this malfunction of the brain can indeed be precipitated by Zinc, something my hospital doctors never considered. Conclusion, avoid ingestion of zinc. Take no more than the 15mgs that most good vitamin/mineral supplements contain. I am 62 years of age. My first episode two years ago was the result of untreated high blood pressure. After possible damage to the hippocampus from prolonged High BP, the recent episode was caused by zinc. Art Haberstich
I have written to you before concerning my work in dogs (and now more and more people) with epilepsy and the use of the glutamate-aspartate restricted diet (The GARD). The results have been ASTOUNDING, with every case that has been placed on this diet showing significant response and most having dramatic improvements. The basis for the diet is the elimination of all gluten, casein, soy, and corn...the four foods that induce villous atrophy of the duodenum. These foods are also HUGE sources of the non-essential, neurostimulating amino acids glutamate and aspartate (the parent amino acids in MSG and aspartamerespectively.
The reason for my contacting you again is my attempt to locate Carly Cenedella. I have enjoyed her articles and contributions to your site and really want to run the diet and phenomenal results I have seen over the past 6 years past her and get her response. Again, more and more people are writing to me and sharing their amazing testimonials on the diet. I do believe that it is THE epilepsy diet, showing MUCH better results than the ketogenic and modified Atkins diets. NONE of my now countless patients have had to undergo any ketosis.
Is it possible for you to contact her and ask her to contact me? I am in the process of writing journal articles and speaking to annual conferences of both veterinarians and MDs. In fact, I just spoke on this topic at the annual conference of the A4M (www.worldhealth.net)in Chicago this past weekend, an international meeting of over 4,000 MDs and PhDs.
My email is email@example.com. My Website is www.dogtorj.net.
Thanks for your help. Great site, BTW.:):):) ... John Symes 18 July 2006
The Perils of Vaccines: Epileptic Seizures and Schizophrenia
The following case study was submitted by a physician as a wake up call to young parents and enlightened doctors.
The perils of vaccines goes beyond just the cheap mercury preservative, Thimerosal, a known neurotoxin capable of destroying nerves and damaging brain tissue. The so called "gold" standard of testing, the "double blind" study is not even being used to validate vaccine "benefits". According to Dr. Sherri Tenpenny's research, the Center For Disease Control's (CDC) vaccine testing program provides multiple vaccines to one group of healthy children and only one vaccine to a second group of healthy children. And when adverse side effects are reported they are quickly dismissed as not having any relationship to the vaccine. The vaccine "researchers" do not even use a "placebo" in their "gold standard" testing. Most physicians are not even aware of this distorted testing technique and faulty reporting being used to snow the scientific community.
As if the unscientific testing and faulty reporting techniques are not bad enough, most physicians are not aware of the latent adverse residual effects of vaccines. Once injected into the body, the components of the vaccine travel through the blood stream and become trapped in organs and tissues of the body. Years later symptoms may surface. Very few healthcare practitioners will ever recognize the link. That was the case with J.B. an 8 year-old who was diagnosed by Children's Hospital, several top neurologists and psychiatrists as suffering from Epileptic Seizures and Schizophrenia. This child would go into altered states, not recognizing his parents and then calling them by different names. These altered states as well as the seizures would occur randomly and without obvious initiating events. Traditional medicine's solution was to prescribe anti-seizure and anti-hallucinogenic medications.
Using diagnostic testing based on quantum physics, J.B. was diagnosed as having Thimerosal in the right side of his brain and the residue of six vaccines in his liver. It is a well recognized fact among researchers that mercury in the brain is capable of causing epileptic seizures. Vaccine residues provide antigens or foreign substances, which can stimulate an allergic type reaction. The toxins released circulate throughout the blood stream eventually passing through the brain. The toxicity of these reactive substances, like taking multiple medications, will cause brain dysfunction similar to the elderly who experience hallucinations when taking too many drugs. Treatment involved natural chelating substances to pull the mercury out of the brain and homeopathic nosodes to neutralize the vaccine residues in the liver. In one month J.B. was back to normal and has not had a single episode of either a seizure or altered state since September 2006. The key to any successful medical treatment is to define the underlying cause and neutralize it with natural remedies. This concept has eluded allopathic or traditional medicine and is the primary reason why the "sick" care system is failing miserably ... Gerald H. Smith, 1 January 2007