Discuss the biology and treatment of epilepsy.

Bio1022 Essay

Discuss the biology and treatment of epilepsy

Epilepsy is a complex disorder of the brain, which affects approximately 1.7% of the general population. (Leppert, M. et al; 1989) Epilepsy is defined as a chronic brain disorder of various etiologies characterized by recurrent seizures due to excessive discharge of cerebral neurons. (Gastaut, H. et al; 1973)

Extensive research has been ongoing to ascertain the precise causes of epilepsy, and therefore to produce treatments which target these key areas.

This paper will explore the causes of these excessive discharges, the roles of glutamate and γ-amino butyric acid in brain function and epileptic disorders, how epilepsy can also be classified as an inheritable disorder, and the treatments that have been developed to help patients with epilepsy manage their condition.

There is no single cause of epilepsy. Epilepsy can be genetically inherited, can result from major head trauma, and has also been linked to alcoholism. (Lehman, L.B., Andres Pilich, M.D. and Nii, A; 1993)

What causes epilepsy?

The brain is comprised of millions of cells called neurons. It is these neurons that regulate the nervous system by a series of electrical impulses that are passed on from one neuron (named the pre-synaptic neuron) to another neuron (named the post-synaptic neuron).

In order for these neurons to transmit these electrical signals, a special group of chemicals, named neurotransmitters, are used. These neurotransmitters can be categorized into two categories, excitory neurotransmitters, and inhibitory neurotransmitters.

By definition, excitory neurotransmitters act to excite the post-synaptic neuron into passing on the electrical impulse, whereas inhibitory neurotransmitters act to inhibit the post-synaptic neuron from passing on the signal. A disruption in this system of excitory and inhibitory neurons can cause abnormalities to occur, and epilepsy may result.

Research has established that a major cause of epilepsy lies with an inhibitory neurotransmitter called γ-amino butyric acid (GABA). GABA is the primary inhibitory neurotransmitter synthesized in the central nervous system (CNS), and is produced from a substance called glutamate. Research conducted found that a mutation in a gene encoding for the specific neuronal receptor for GABA, called GABAAR (Wallace, R.H et al; 2001), which is located on the post-synaptic neuron, is a large contributor to epilepsy. If GABA is unable to inhibit the neurotransmission of electrical impulses due to an abnormal receptor, seizures can occur.

Furthermore, another cause of epilepsy recognized is the alteration or mutation of specific brain cells, called glia. Glia provide the transporter proteins GLAST and GLT-1, which are used to transport glutamate for GABA synthesis. These two proteins carry out more than 60% of glutamate transport. Inhibition of the production of these proteins, or alterations or mutations of the genes encoding these proteins, have a dramatic effect in that the glutamate is not able to be transported efficiently, thus reducing the level of GABA production greatly. It is from this information that the concepts of head trauma, alcoholism and genetic ...

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On top of this, epilepsy also has heritable characteristics, with a lot of epilepsy disorders displaying this. One notable example is the research carried out on Benign Familial Neonatal Convulsions (BNFC). Linkage analysis using DNA markers revealed that BNFC was an autosomal dominant disorder, with a locus on chromosome 20. (Leppert, M. et al; 1989)

Subsequent research has revealed that many epileptic disorders show a heritable trait, for example childhood absence epilepsy (chromosome 8), febrile seizures (chromosomes 2,8 and 19) and juvenile absence epilepsy (chromosome 21). (Willmore, L.J, Ueda, Y; 2002)

Many of the hereditary epileptic conditions appear to be autosomal dominant, however this is not always the case. (Willmore, L.J., and Ueda, Y; 2002)

Contrary to this, epilepsy may also be triggered by other disorders, which affect the function of the brain, for example cerebral palsy (Singhi P, Jagirdar S, Khandelwal N, Malhi P; 2003) or brain tumors (Khan RB, Marshman KC, Mulhern RK; 2003)

It may also be caused by complications in prenatal brain development, when the brain is very susceptible to damage. (Thompson RA, Nelson CA; 2001) This can be caused if the mother uses excessive methods of alcohol and drug use, or is under-nourished. As the brain develops, if complications arise, the neurons of the brain may not form properly, thus producing abnormalities in the neurotransmission of electrical signals in the brain, which can produce seizures.

A number of environmental factors may also attribute to epilepsy, for example carbon monoxide poisoning. Research has positively correlated carbon monoxide poisoning to epileptic seizures. This is due to the fact that carbon monoxide binds to hemoglobin, the molecule that transports oxygen throughout the body, with a great affinity. Due to this binding, oxygen is not transported to the brain, and brain damage may occur, as oxygen is required for these glia to operate effectively. (Mori T. Nagai K; 2000)

Diagnosis of epilepsy

The first step in the treatment of epilepsy is the diagnosis of epilepsy. Early diagnosis of epilepsy is vital, so treatment can start on the patient immediately.

There are a few techniques employed to diagnose epilepsy. The major one being electroencephalography (EEG). This involves electrodes being applied to the patient’s scalp and the electric signals produced by the brain measured. This can provide near-conclusive evidence to back up the diagnosis of epilepsy, as a patient with epilepsy will provide an abnormally patterned EEG. However, an EEG, which appears to be normal, does not exclude the possibility that the patient has epilepsy. This is due to the fact that the neurons that are measured by the EEG are only the surface neurons of the brain. (Berendt, M; 2001)

Other techniques employed are brain imaging techniques, for example Magnetic Resonance Imaging (MRI), Computer Assisted Tomography (CAT) and Positron Emission Tomography (PET). It is via this that lesions on the brain thought to be causing epilepsy can be diagnosed and then treated.

Treatment of epilepsy

Following diagnosis, the best treatment for the patient must be determined. There are a number of different treatments for epilepsy.

One treatment is surgery. There are a number of procedures that can be carried out, but these are only performed for localized forms of epilepsy, where the problematic area is in one specific part of the brain, which does not play an important role in the overall function of the body. Surgery is also an option when anti-epileptic drugs appear not to be very effective in controlling the seizures (Cross, JH; 1999).

However, the most widely used form of epileptic treatment is anti-epileptic drugs. A majority of these drugs work to stimulate GABA production and enhance its activity by binding to specific parts of the GABAAR.

The downside of using these drugs is they carry a risk of side effects developing. Some side effects include nausea and diarrhea, and in the some cases addiction may occur. (Ashton H, Young AH; 2003) The search for better and safer anti-epileptic drugs is an ongoing concern.

Another treatment, which is relatively new, is vagus nerve stimulation, or VNS. This works by stimulating the vagus nerve, which is responsible for muscle co-ordination involving swallowing and speaking, and also sending information about the heart, lungs and stomach to the brain. A small device is implanted into the chest, and this sends electrical signals to the brain, via the vagus nerve, to prevent seizures by stimulating the production of GABA and another inhibitory chemical, glycine.

Research into the effects of VNS by Sirichai et. al revealed that in 15 out of the 24 people VNS was trialled on, there was a greater than 50% decrease in the frequency of seizures experienced. In the future VNS may provide a sound alternative to anti-epileptic drugs. (Sirichai C. et. al; 2001)

Conclusion

Epilepsy takes on many shapes and forms, and the research into what causes it and the best method to treat it is ongoing.

Having identified the GABAAR and GABA production as a primary source of epileptic seizures is a huge step forward however, and a wide range of treatments have been prepared using this information.

It will be many years yet before a 100% safe treatment is found for epilepsy.

References:

Ashton, H.; Young, A.H: GABA-ergic drugs: Exit stage left, enter stage right. Journal of Psychopharmacology. 17(2): pp. 174, 2003.

Berendt, M: The Diagnosis of Epilepsy: Seizure Phenomenology and Classification, 2001.

Chayasirisobhon, S. et. al: Vagus Nerve Stimulation for Refractory Epilepsy. The Permante Journal, Vol. 5 N°4, Fall 2001.

Cross, J.H.: Update on surgery for epilepsy. Archives of Disease in Childhood. 81(4): 356-9, 1999.

Gastaut, Henri et. al: Dictionary of epilepsy. Part 1. Definitions. Geneva: World Health Organization; 1973.

Khan RB. Marshman KC. Mulhern RK. Atonic seizures in survivors of childhood cancer. Journal of Child Neurology. 18(6): 397-400, 2003.

Lehman, L.B.; Pilich, A.; Nii A: Neurological disorders resulting from alcoholism. In Alcohol World; National Institute of alcohol abuse and alcoholism: Vol 17, N°4, pp. 309, 1993.

Leppert, M.; Anderson, V. E.; Quattlebaum, T.; Stauffer, D.; O'Connell, P.; Nakamura, Y.; Lalouel, J.-M.; White, R.: Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 337: 647-648, 1989.

Mori T.; Nagai K.: Carbon monoxide poisoning presenting as an afebrile seizure. Pediatric Neurology. 22(4): 330-1, 2000.

Singhi, P.; Jagirdar, S.; Khandelwal, N.; Malhi P.: Epilepsy in children with cerebral palsy. Journal of Child Neurology. 18(3): 174 - 9, 2003.

Thompson, RA.; Nelson, CA: Developmental Science and the Media: Early Brain Development. American Psychologist. 56(1): 5-15, January 2001.

Wallace, R.H; Marini, C.; Petrou, S.; Harkin, L.A.; Bowser, D.N.; Panchal, R.G.; Williams, D.A.; Sutherland, G.R.; Mulley, J.C.; Scheffer, I.E.; Berkovic, S.F.: Mutant GABAA Receptor γ2-subunit in Childhood Absence Epilepsy and Febrile Seizures. Nat Genet. 28: 49-52, 2001.

Willmore, L.J.; Ueda, Y.: Molecular Biology and Genetics of Epilepsy. Acta Medica Okayama. 56(2): 57-68, 2002.