Neuroscientific Context

It is made quite clear that Mr Klaerner suffers from epilepsy, and experiences generalised tonic-clonic seizures and bouts of unconsciousness. Epilepsy is a neurological disorder characterised by the brain’s increased susceptibility to seizure. The origin of seizures, behavioural manifestations, and contributing genetic mutations involved widely differ depending upon the type of epilepsy, the two most significant types being partial and generalised. Partial epilepsy is when there is a specific area of seizure onset that can be causally identified, whereas generalised epilepsy is when such a direct link to a particular system or region is not yet able to occur. Thankfully, various functional methods, such as fMRI (functional magnetic imaging), EEG (electroencephalogram) and SPECT (single positron emission topography), are becoming more available, and slowly researchers are unravelling the mystery of these seizures.

Within the article it was not mentioned what exact type of epilepsy Mr Klaerner suffered from, as a result of this the seizure type (generalised tonic clonic seizures) shall be focused upon instead of the type of epilepsy. The reason for this is that such a seizure can cause a patient to lose consciousness, and it was not stated whether or not such incidences occurred in Mr Klearner after a seizure or regardless of them. In doing so it is most likely that he suffered from a form of idiopathic generalise epilepsy (IGE), as he may or may not have also suffered from absence seizures as well as generalised tonic-clonic ones as well. IGE is one of the epilepsies that appears to have no structural cause, the the name of 'idiopathic'. It's onset varies with the various subdivisions, and can start as young as the second day of life (in the case of benign familial neonatal convulsions) or as 35 years old (evident in epilepsy with grand mal (another name for GTCS) on awakening). GTCS is known to occur in most of IGEs, and can be accompanied by other forms of seizure, like absence seizures (a seizure in which the patient appears to lose contact with reality for a period of time, do not remember having 'tuned out' and are unresponsive throughout, they often appear to be awake), with a genetic predisposition commonly thought to be one of the underlying reasons (Nair & O'dwyer, 2010).

Generalised tonic-clonic seizures (GTCS) are the most dramatic and stigmatised seizures, causing a patient to go contract and flex all muscles, fall over, convulse and sometimes howl (Blumfeid et al., 2009). Seizures occur without warning and appear to have no trigger contributing to their onset (Sommerville, 2012). Despite the name, GTCS is seen in both generalised, like in juvenile myoclonic epilepsy, and partial, as seen in temporal lobe epilepsy, subtypes. The only difference is that partial GTCS starts in one area and spreads, thus it is called secondarily GTCS while the other is known as primary GTCS. People who suffer such seizures are often unconscious throughout, and usually remain that way for a few minutes afterwards as well. But just because the patient suffering the seizure is usually unaware of it, does not mean that it goes unnoticed by anyone else nearby. The patient will be seen to go rigid, and sit up if they are slouching, this is the tonic phase. After a few seconds they will collapse and begin to convulse for a few minutes. They shall then appear to be asleep, and many people are disorientated upon awaking. Due to the jerking movements during ictal state (during the seizure) many imaging techniques are useless as too much noise is present to produce reliable results, EEG is thankfully not affected by this and can be used for both research and diagnostic purposes within epilepsy.

Figure 1: Normal Brain EEG compared with Generalised Epilepsy EEG - showing the completeness of the seizure and disruption of regular function

Hrachovy & Frost (2006), outline stereotypical EEG results for during a GTCS. the findings of numerous EEG studies of patients undergoing various seizures, their explanation remaining one of the most comprehensive one of EEG activity during GTCS seizures. Seizure onset is easily seen through generalised polyspike-wave closely followed by a generalised attenuation in voltage lasting a few seconds. Rhythmic activity at ~20-40Hz marks the beginning of the tonic phase, however this frequency is reduced to ~ 10-12Hz, and the amplitude is increased, as the phase progresses. On average, the tonic phases only lasts 8 to 10 seconds. The turn over to the clonic phase is marked by slower generalised activity with progressively increased amplitude and slow frequency, which becomes mixed with the polyspikes of the tonic phase. These are known as polyspike-wave discharges are thought to be indicative of rhythmic firing throughout the brain, as they are accompanied by uncontrollable muscular contractions and relaxations. As the seizure comes to an end, these cycles become increasingly intermittent. The way you know a seizure has is when the last cycle displays normal EEG activity sustained over a few seconds. EEG activity at this point shows irregular delta waves at low voltage, which gradually increase in amplitude and frequency as the patient returns to baseline and recovers consciousness (Hrachovy & Frost, 2006; Seneviratne, Cook, & D’Souza, 2012).

There has been much debate as to the underlying mechanisms of GTCS. Much of the literature diverges on the involvement of thalamocortical (TC) involvement inthese seizures. One currently well supported hypothesis poses alterations of rhythmic firing in TC and reticular-thalamic neurons (RT), thus implicating an alteration in the rhythmic cycles of sleep (Beenhakker & Huguenard, 2009). During sleep, rhythmic firing of cortical neurons causes RT excitation and γ-aminobutyric acid (GABA). This restults in GABA-A and GABA-B receptors in TC neurons to activate and hyperpolarise both themselves and other RTs. TC hyperpolarisation creates regenerative calcium spikes and, despite Ca2+ channel deactivation, produces delayed burst rebound action potentials, resulting in RT and TC neuron activation. This completes the overall alternating synchronised cycle seen in the slow (<1 Hz) cortical oscillations of sleep.

According to the theory of hypersynchrony, RT neurons lack a particular subunit in their GABA-A receptors, causing them to fire at the same time as the TC neurons do. (Beenhakker & Huguenard, 2009). This is further supported by the hypothesis of cortical hyperexcitibility, which poses the idea that increased excitation of specific regions of the cortex causes spike-wave discharges that are stereotypic of epilepsy. Supporting evidence is provided by the fact that Blumfeld & McCormick (2000) found that fast sparse corticothalamically delivered shocks resulted in spike wave discharges, but were restored by a GABA antagonist
Normal Brain Compared with Epileptic Brain PET

The majority of important treatment targets are still a mystery when it comes to epilepsy. It is unknown how or why certain people develop it and others don't. Genetic susceptability and environmental interactions, along with increased potential to seizure due to an inflammatory response or brain insult, are still clamouring for causation to be proved. However it is obvious from research that the mechanisms underlying it are becoming clearer, and better treatments shall be able to developed from these findings. Regardless of treatment or epilepsy type, it is still a debilitating disorder which affects sufferers in all aspects of their lives.

Beenhakker, M.P., & Huguenard, J.R., (2009). Neurons that fire together also conspire together: Is normal sleep circuitry hijacked to generate epilepsy? Neuron 62(5), 612-632. Doi: 10.1016/j.neuron.2009.05.015
Blumfeld, H., & McCormick, D.A., (2000). Corticothalamic inputs control the pattern of activity generated in thalamocortical networks. Journal of Neuroscience 20, 5153-5162
Blumfeld, H., Westerveld, M., Ostroff, R.B., Vanderhill, S.D., Freeman, J., Necochea, A., Uranga, P., Tanehco, T., Smith, A., Seibyl, J.P., Stokking, R., Studholme, C., Spencer, S., & Zebal, I.G. (2003). Selective frontal, parital, and temporal networks in generalized seizures. NeuroImage, 19(4), 1556-1566. doi: 10.1016/S1053-8119(03)00204-0
Blumfeld, H., Varghese, G.I., Purcaro, M.J., Motellow, J.E., Enev, M., McKnally, K.A., Levin, A.R., Hirsch, L.J., Tikofsky, R., Zubal, I.G., Paige, A.L., & Spencer, S.S., (2009). Cortical and subcortical networks in human secondarily generalised tonic-clonic seizures. Brain; A Journal of Neurology, 132, 999-1012. Doi: 10.1093/brain/awp028
DeSalvo, M.N., Schridde, U., Mishra, A.M., Motelow, J.E., Purcaro, J., Danielson, N., Bai, X., Hyder, F., & Blumfeld, H., (2010). Focal BOLD fMRI changes in bicuculine-induced tonic-clonic seizures in the rat. NeuroImage, 50(3), 902-909
Hrachovy, R.A., & Frost, J.D. (2006) The EEG of selected generalized seizures. Journal of Clinical Neuroscience, 23(4), 312-324.
Gotman, J., Grova, C., Bagshaw, A., Kobayashi, E., Aghakhani, Y., & Dubeau, F., (2005). Generalized epileptic discharges show thalamocortical activation and suspecnsion of then default state of the brain. Proceedings of the National Academy of Sciences of the United States of America, 102(42), 15236-15240. Doi: 10.1073/pnas.0504935102
Nair, D.R., & O'Dywer, R., (2010). Epilepsy: Atlas of investigation and management. Oxford: Clinical Publishing E-ISBN:
Seneviratne, U., Cook, M., & D’Souza, W., (2012). The electroencephalogram of idiopathic generalized epilepsy. Epilepsia, 53(2), 234-248. Doi: 10.1111/j.1528.1167.2011.03344.x.
Sommerville, E., (2012, August, 17). Clinical aspects of Epilepsy [Lecture notes from Neuroscience Fundamentals (Neuro2201) Semester 2, 2012]. Unpublished raw data.
Wang, Z., Zhang, Z., Jiao, Q., Liao, Q., Chen, G., Sun, K., Shen, L., Wang, M., Li, K., Liu, Y., & Lu, G., (2012). Impairments of thalamic nuclei in idiopathic generalized epilepsy revealed by a study combining morphological and functional connectivity MRI. PLoS, 7(7), e39701. Doi:10.1371/journal.pone.0039701
Zhong, Y., Lu, G., Zhang, Z., Jiao, Q., Li, K., & Liu, Y., (2011) Altered regional synchronisation in epileptic patients with generalized tonic-clonic seizures. Epilepsy Research, 97(1-2), 83-81. doi:10.1016/j.epilepsyres.2011.07.007

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