Epilepsy

"As a scientist, I am of the opinion that animal experiments bring no progress in the diagnosis and therapy of epilepsies. I have a well-founded suspicion that similar facts apply in other areas of medicine." Dr. Med. Bernhard Rambeck, director of Biochemistry Dept. of the Society for Epilepsy Research, Bielefeld-Bethel, Germany. Speech at International Symposium, 25 April 1987.

“...none of the (animal) models is fully trustworthy as an imitation of clinical epilepsy”. Fisher, R.S. Brain Research Reviews vol. 14 pp.

Seizures can occur naturally in cats or can be induced by different techniques, such as the electrical stimulation of specific regions of the brain or the application of convulsants. It is also possible to use photosensitive species, cortical freezing and intracerebral injections of tetanus toxin. (1-2) Nevertheless, it has been difficult to establish satisfactory animal models of epilepsy because they do not show recurring seizures, one important clinical symptom of the human disease.

In fact, such animal models are considered models for seizures and not epilepsy. In epilepsy research, several strains of genetic mutant rats are available. For instance, WAG/Rij rats and the spontaneous epileptic rats show some electrographic and behavioral patterns observed in humans but seizures do not disappear with age and the rats exhibit ataxia (i.e. lack of co-ordination of movements) in contrast to human patients. (3) Furthermore, electroencephalographic studies (EEG) indicate that the electric discharges are typically faster than 3 Hertz, whereas in the patients, it is rare to see discharges above 4 Hertz.

When young rats are injected with N-methyl D aspartate, which is a neurotransmitter used to induce seizures, two major symptoms such as spontaneous seizures and pathological damage are not observed. Both kainic acid, a glutamate analogue and pilocarpine, a cholinergic agonist, which mimic the effect of acetylcholine, generate lesions in the brain of rodents similar to those seen in patients but have age-dependent effects in rats, which is a major weakness of these models.

Kindling, which is the electric stimulation that results in intense partial and generalized convulsive seizures do not provide a good model for spontaneous seizures because animal subjects require extensive stimulation before the seizures occur. Dissimilarities to human primary generalized epilepsy include a lack of absence seizures in Papio papio, a Senegalese baboon, and abnormal spike-wave bursting during brain electric activity. In mice, attempts have been made to induce seizures by subjecting the mice to an intense auditory stimulus (10-20 Hz- 90-100 dB), which is pretty much the same noise made by a jet taking off. The DBA/2 mice developed seizures that often cause them to die due to respiratory failure. Other models do not survive post-natally.

Despite genetic alterations, occurring naturally or induced by artificial manipulation, it is difficult to determine how mutations lead to alterations in brain excitability. This is a major problem in making animal models valuable and that is the reason why transgenic animals were created to address the relationship between the pathology and its cause. But they fall short of answering this kind of question yet. While a particular animal model of epilepsy can be used to screen anti-epileptic drugs, which have a limited action on symptoms but do not affect the cause of the disease, most epileptic disorders remain without any model at all. As Matthew R. Sarkistan points out in his review of animal models for human seizure and epilepsy: "These examples demonstrate the difficulty in faithfully reproducing a model that perfectly reflects a human condition, these models provide hope that information gained about basic cellular and molecular mechanisms underlying these disorders which may allow for new therapeutic targets." (4)

Scientists continue to use animals searching for cues although cellular and molecular mechanisms can be studied on human tissue. Animal experiments do not provide the information they need; instead they hope to overcome the obstacles inherent to their methodology by more animal tests. Again, Papio papio, which presents with a form of genetic epilepsy, was found to be susceptible to intermittent light. This model is claimed to have served to describe the importance of the involvement of cortical regions and the modulation of excitatory and inhibitory neurotransmitters in the course of the disease; it is also claimed to help in the choice of anti-epileptic drugs. The models have dubious value because some conclusions were drawn from normal animals and not models of seizures. Also, the behavioral manifestations associated with each model differ and look nothing like the human's behavior. This is a major criterion that animal models of epilepsy cannot meet and logically these models fail to reproduce the many forms of epileptic disorders. So far, the data from a large number of different models have been gathered to draw conclusions about the human brain. Nevertheless, scientists argue that more animal models must be found.

The scientists working in the field of epilepsy would like to find a satisfactory animal model and if any, it would be a primate but the use of primates poses financial and ethical problems. It is well known that several species of monkeys including baboons are being "kidnapped" from Africa for experimental procedures in the West. These primates are often held in appalling conditions before shipment and they suffer greatly during long period of transportation. When local trappers catch baboons, they tie them together with rope and leave them there for several days until the dealers come to collect them. Once an order from overseas laboratories has been confirmed, the primates are trucked in crates to about a 10 hour-drive away, with the main buyers coming from the U.S. (5) Other laboratories involved in experimental xenotransplantation also use primates and namely baboons. This procedure consists in transplanting cells or organs of a species into another species.

For instance, experimental baboons are transplanted with genetically modified pig organs containing human genes. Further on, these baboons suffer and die from fatal blood clots, heart attacks, infection or from acute rejection of the transplanted organ. Baboons are hard to breed in captivity and most research baboons are caught in the wild. This information is rarely mentioned in scientific papers. However, there are alternatives to help researchers in the quest for medications and understanding of diseases. They were devised due to the need to find better tools of research; in fact, of all the research carried out on animals today, little, if any, is essential to the development of useful applications. A research project that is directed to understand epilepsy may give insights into a treatment for AIDS or multiple sclerosis instead, some say. Can researchers determine if something valuable will come out of animal research? Should we favor science over animal welfare? Does the quest for knowledge justify the means? To answer those questions comes down to ethical choices. Generally, it is not possible to determine the utility of an animal experiment beforehand. As a consequence, the waste of research resources had been substantial in the past, reported, documented and acknowledged but today we have the opportunity to develop alternatives and take advantage of new technologies in order to promote basic and clinical studies. The pseudo-scientific dogma of animal experimentation relies on random chance and happy luck; it works to obtain a great deal of information from different animal species, selected based mostly on non-scientific criteria among hundreds of other animal species. This is the wasteful and inefficient methodology that has misled and delayed the understanding of human pathologies and the safe and useful application of drugs.

The first drugs used for the treatment of epilepsy date back before the systematic testing of drugs on animals. Bromides and phenobarbital (the latter is still used) were not found through animal-based research and testing but thanks to clinical trials and errors. The other substances and derivatives were also the result of chance rather than useful animal testing. All the animal models produced a mono-causative imitation of seizures irrelevant to the human disease. No matter the amount of neuro-physiological information that was gathered after performing cruel animal tests, side effects and efficacy were assessed in human subjects because the animal data was of no use. After a hundred years of research on animals, the scientists in this field have been able to understand animal seizures although a cure for epilepsy could not be based on their models. Today, increasingly human tissue will have to be obtained to test new drugs and study the molecular basis of the disorder.

Another method to treat epilepsy is surgery and once again, it can be said that research on animals has been a minor, if not, insignificant anecdote in the history of surgical approaches to epilepsy treatment. Hughlings Jackson (1835-1911), a neurologist, experimented on his patients, while combining his judgment and talents to treat focal epilepsy by innovative surgeries. (6) Likewise, Dr. Penfield and his associates operated on their patients suffering from epilepsy because the observations made in animals could not be applied to human medicine.

In fact, researchers derive tangible medical understanding based on the anatomical and neurophysiological structures of speech, vision, memory, reading, calculus, in human primates, as we know, through comparative studies, that the brain topology and neural connections are different between animal species. The possibility to stimulate and identify cortical targets in the human brain contributed to the understanding and treatment of epilepsy until today. This process responsible for the advancement of medicine should be called biomedical research.

• 1. Appleton D. B. and DeVivo D. C. Proceedings of the National Academy of Science 71:21 (1974)
• 2. Hartman E. R. et al. Epilepsia 15:121 (1974)
• 3. Prasad A.N. et al. "Recent advances in the genetics of epilepsy: insights from human and animal studies." Epilepsia 40: 1329-1352 (1999)
• 4. Matthew R. Sarkistan. "Overview of the current animal models for human seizure and epileptic disorders." Epilepsy and behavior 2, 201-216 (2001)
• 5. Gregory Mthembu-Salter. "Tanzania's Grim Baboon Trade" Mail and Guardian November 10, Johannesburg (2000)
• 6. Horsley V. Brain-Surgery. British Medical Journal 2: 670-675; 1886.
• 7. Penfield W, Erickson, TC. Epilepsy and Cerebral Localization; A Study of the Mechanism, Treatment and Prevention of Epileptic Seizures. Springfield, IL: Charles C Thomas, 623; 1941.