Why is epilepsy called the sacred disease

In contrast, the GE mutation appears to act through a different mechanism. It alters ClC-2 gating, resulting in an outward reverse chloride current expected to severely affect membrane potential stability and responses to polarity changes The phenotypic outcomes of the aforementioned mutations were remarkably varied.

These three epilepsies have primarily generalized seizures in common, but each has long been categorized as a separate clinical syndrome 65 , Therefore, the CLCN2 mutations in this study raise the possibility that variations in the same ion channel can underlie major syndrome-defining differences. Alternatively, CLCN2 mutations merely predispose to generalized seizures, and modifier genes, different in each family, account for the phenotypic differences.

It is abundantly evident that epilepsy due to ion channel mutations is characterized by wide clinical and genetic heterogeneity. All the mutations reviewed earlier account for a mere fraction of the genetic contribution to epilepsy, and it is likely that many more ion channel mutations, singly or in groups, or mutations in proteins affecting ion channel functions will be found, tweaking the brain towards synchronized firings and seizures.

However, epilepsy is also expected to result from miswirings in sections of the neural network, and perhaps some of the mutations discussed in the next section act in this fashion. Originally identified in glioma studies 69 , the leucine-rich glioma-inactivated LGI1 gene is currently considered not to play any important role in brain tumors Instead, its mutations result in a focal-onset epilepsy with onset in or near the auditory center in the temporal lobe of the brain, resulting in auditory seizures with or without generalization to convulsion and unconsciousness 71 — It consists of an N-terminal leucine-rich repeat region and a C-terminal EAR epilepsy-associated repeat region 77 , and it is a secreted protein 78 , The EAR region is a common feature with the Mass1 gene product mutated in the Frings mouse model of audiogenic epilepsy Introduction of epilepsy-associated mutations results in unstable protein, suggesting that the mutations act through a loss of function mechanism How LGI1 mutations result in seizure generation remains completely unknown, and why the temporal cortex is affected is equally mysterious.

It is possible that LGI1 affects ion channels with particular relevance to auditory cortex or that it influences proper auditory cortex neuronal network establishment. Its protein product, EFHC1 or myoclonin 1, localizes in the soma and dendrites of neurons in multiple brain regions.

However, further studies raise an alternate or additional possibility. EFHC1-induced apoptosis is also specifically suppressed by a Ca v 2. During normal brain development, neuronal numbers and processes overshoot and are then trimmed as the final structure is established 81 , The few JME brains that have been studied pathologically 83 , or with detailed magnetic resonance imaging 84 , reveal mildly thickened cerebral cortex and dystopic neurons.

It is therefore possible that EFHC1 mutations result in insufficient apoptotic shedding of unnecessary neurons during development and produce an imperfect, overpopulated and epileptogenic, cerebral network BRD2 is a putative developmental transcription regulator expressed in brain and may be involved in the JME cortical microdysgenesis as mentioned earlier ME2 encodes malic enzyme 2, a mitochondrial enzyme involved in the synthesis of GABA, the ubiquitous inhibitory neuromediator The difficulty with the intriguing BRD2 and ME2 observations is in finding ways of establishing animal models to confirm the roles of these genes and as models for pathogenetic studies.

This difficulty is shared with the increasing number of other common genetic diseases found segregating with SNPs. In most such instances, it is problematical to identify the effect of the SNP on its associated gene and find ways to replicate that effect in a mouse. Furthermore, most of these diseases are complex in inheritance, and one would need to identify and recreate several if not many participating polymorphisms. Perhaps, the solution will come not so much from engineered mice, but through detailed clinical and genetic studies in domesticated animals.

A first canine epilepsy gene has already been discovered, albeit in the monogenic Lafora progressive myoclonus epilepsy Epilepsy in dogs is five to 10 times more common than that in man If, for example, naturally occurring JME could be characterized in dog, then one could attempt to replicate the genetic associations with BRD2, ME2 and other JME genes in dog families, confirming the associations in a different organism and, at the same time, establishing an animal model.

Many more epilepsy genes than the ones reviewed in this article remain to be discovered. Epilepsy mutations affect proteins that regulate action potentials and synaptic function, both of which underlie neuronal communication. They also appear to affect proteins involved in proper cortical network establishment. Identifying epilepsy proteins and understanding their functions are clearly critical to better care for the tens of millions of patients afflicted with seizures and with the devastating unpredictability of seizures.

They are also of great value to the understanding of neuronal network formation and communication, i. Figure 1. Electron micrograph of mouse neuropil. Several synapses are shown: black arrows point to the postsynaptic density, which is comprised of the neurotransmitter receptors; white arrows point to presynaptic vesicles, which contain the neurotransmitters. There are at least quadrillion synapses in the human brain.

Image courtesy of Dr Cameron Ackerley. Figure 2. Thalamocortical fibers connect the thalamus to the entire cerebral cortex and allow it to synchronize cortical neuronal firing, in sleep and during generalized seizures. Figure 3. Epilepsy mutations in voltage-gated sodium and potassium channel genes. Figure 4. A At GABAergic synapses inhibitory , Ca can no longer contribute to the activation of the acetylcholine receptor cation channel, because of mutation of its allosteric binding site on the channel red dot.

Decreased conduction through this cation channel results in decreased presynaptic amplification of the sleep-related trains of thalamocortical action potentials, and therefore, decreased synaptic transmission. B At glutamate synapses excitatory , because synaptic Ca is quickly depleted into postsynaptic dendrites through glutamate receptors during repeated thalamocortical firing, it does not normally contribute to acetylcholine receptor activation.

In sum, GABAergic synapses, but not glutamate synapses, are affected by the mutation during sleep, resulting in decreased inhibitory neurotransmission and seizure. Figure 5. Membrane specific labeling was performed by adding FM to the medium used for live confocal imaging. The overlay shows a clear localization in the surface membrane for wild-type, but not for mutant GABA A receptors EGFP, enhanced green fluorescent protein.

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Neuroscientist , 7 , 42 — Wallace, R. Audenaert, D. Neurology , 61 , — Chen, Y. Vitko, I. Suzuki, S. USA , 86 , — Coulter, D. Khosravani, H. Barrett, C. Jodice, C. Jouvenceau, A. Holtmann, M. Chioza, B. Equipped with advanced imaging technologies, Robarts researchers are developing techniques to improve the accuracy and precision of these surgeries.

Using imaging technology, we can identify abnormalities in the region that we suspect the epileptic seizures are coming from and look at the networks surrounding that region. Access to ultra high-field magnetic resonance imaging MRI technology at Robarts enables researchers to see the structure and function of the brain that cannot be visualized using standard imaging modalities.

Khan is working with diffusion MRI, a technique that measures how water molecules move around in the brain. During the course of several milliseconds, researchers can detect the motion of water molecules at microscopic scales. With this microscopic information, he is examining how pathways in the brain are connected, and how they may be disconnected in patients with epilepsy.

Jonathan Lau, a neurosurgery resident who is completing a PhD in biomedical engineering with the VASST and Khan Labs, is exploring ways to apply these sophisticated tools in the clinical environment and provide more personalized therapies for epilepsy patients.

He is using ultra high-field MRI to more precisely implant depth electrodes in the brains of epilepsy patients electrodes are used as diagnostic tools to pinpoint the origin of seizure activity in the brain. Lau says collaboration is essential to shedding light on the disorder. We need to bring together a lot of people to achieve our goal of more focused and personalized therapy for our patients. Robarts scientist Michael Poulter, PhD, has been investigating the neurochemical mechanisms underlying epilepsy for more than 25 years, trying to better understand how the epileptic brain is wired.

Van Lente F. Hercules Myths and Legends. Oxford: Osprey Publishing; Amphitryon: All of this… by one hand. Figure 2. Hercules firing arrows at his children by Antonio Canova De Agostini 9 9. Seneca, Fitch J. Ithaca: Cornell University Press; Depending on the symptoms of the epileptic seizure, it was attributed to several deities, including Hera, Cybele, Poseidon, Mars, Hekate, Hermes, and Apollo 11 Karakis I.

Neuroscience and Greek mythology. J Hist Neurosci. Epilepsy: a disruptive force in history. World Neurosurg. Paris: J. Postictal psychosis. Rev Neurol Paris. Devinsky O. Postictal psychosis: common, dangerous, and treatable. Epilepsy Curr. These are characterized by having a lucid interval between the end of the seizure and the onset of psychotic symptoms , religious delusions, violent behavior, aggression, and visual hallucinations, following a complex partial seizure usually located in the temporal lobe 15 Both verbal and physical violence can occur, and suicide has been associated with PP 15 Aggression is a complex behavior governed by neuroanatomic structures such as the temporal lobe and the amygdala 16 Epilepsy, antiepileptic drugs, and aggression: an evidence-based review.

Pharmacol Rev. Violent acts in epileptic patients have been described in the literature for over a century 17 Epilepsy and homicide.