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EPILEPSY AND SEIZURE DISORDERS PYSC 4080 By: Misha Nili Contents Definitions History Seizure Stages Classification Mechanisms of Action Neurotransmission Genetics Neuroanatomy Neurodevelopment Treatments Cuttlefish https://www.youtube.com/watch?v=l1T4ZgkCuiM Action Potentials & Epilepsy https://www.youtube.com/watch?v=MtJyHp_AZL8 Definitions Seizure: A sudden episode of abnormal electrical activity in the brain characterized by excessive excitation and synchronization of neurons. In other words... Definitions Epilepsy: A chronic neurological syndrome characterized by at least two recurrent seizures that occur without evident cause. Important to note: Seizures that occur with apparent cause are not labelled as epilepsy Seizures are the manifestations/symptoms of epilepsy Historical Overview Described in historical texts as a spiritual condition In Babylonian texts – described as possession by evil or angered spirits, treated with an exorcism Greek mythology – the Sacred Disease Associated with moon spirits Important figures like Hercules and Julius Caesar described to be afflicted Historical Overview Hippocrates first to associate it as a treatable problem with the brain Termed the word ‘grand mal’ or the Great Disease Epidemiology Prevalence: Affects 0.6% of Canadians About 15,500 new cases every year 1% of people worldwide =60 000 000! Age of onset: Often occurs in childhood, but can develop at any point in life 30% of new cases begin in early childhood and adolescence High prevalence in those aged 65+ Epidemiology –Age of Onset Causes – A mystery to neuropsychology! Causes Head trauma Brain malformations Lack of oxygen during birth Maternal drug use Brain tumors Congenital conditions (Down's syndrome, Autism spectrum) Genetic factors Drug use/substance abuse Kidney and liver defects Stroke Alzheimer's disease Stages of a seizure Typically, there are 3 stages: Preictal/prodromal Ictal postictal Preictal/prodromal stage Auras Perceived smells, sights, tastes Forced thinking Physical sensations – nausea, headaches, dizziness Unusual feelings Can happen minutes, hours, or even days before a seizure Can serve as warning sign EEG readings show general decreased brain activity Ictal Stage The seizure itself – what others observe Can be convulsive or non-convulsive May include a temporary loss of consciousness Post-ictal stage Body relaxes, after-effects Loss of consciousness may persist May also include: Numbness Headaches Fatigue Confusion Partial paralysis Biting of the tongue Loss of bladder and bowel control EEG Common way to study and diagnose epilepsy Records electrical activity of cortical neurons by measuring voltage fluctuations caused by ionic currents EEG – Non-epileptic patient EEG – Patient undergoing a seizure Classification by seizure type Focal vs. Generalised – Stadium Analogy Chattering Chanting Cheering Sweeping Lady example Clonic Seizures Repetitive and rhythmic jerking of muscle groups No loss of consciousness Can go straight back to activities after seizure Classification by syndromes Classified based on common features, onset time, and EEG findings Less severe: Benign rolandic epilepsy Childhood absence epilepsy Juvenile myoclonic epilepsy More severe, episodes may cause diffuse brain dysfunction and are resistant to treatment: Lennox-Gastaut syndrome West Syndrome Impact of Epilepsy Effects different for partial and generalised seizures Generalised – affect various functions simultaneously Partial seizures – vary with which part of the brain the are initiated in Hippocampus – memory Broca’s area, Wernicke’s area - language Outgoing Frontal and incoming words lobe – executive functions, planning Mechanisms of Action Causes are more often unknown! Something that triggers: Increased capacity for excitation Decreased capacity for inhibition Mechanisms of Action Initiation of a seizure: 1) high-frequency bursts of action potentials 2) hypersynchronization of a neuronal population At the single neuron level - Action Potentials Mechanisms of Action Bursts of action potentials become a paroxymal depolarizing shift Has a plateau-like depolarization Rapid repolarization, hyperpolarization follows Initiated by a Ca2+ depolarization, which leads to the opening of Na+ channels Hyperpolarization modulated by K+ channels and Cl- influx (mediated by GABA) Mechanisms of Action Kindling hypothesis of epileptogenesis “Seizures beget seizures” Study with animal models – evoked repeated seizures with low-intensity stimuli in the hippocampus Symptoms intensified – freezing to convulsions Mechanisms of Action Seizure propagates, recruits surrounding neurons via local connections Partial seizures spread into the other hemisphere via the corpus callosum Increase in extracellular K+ and accumulation of Ca2+ in presynaptic terminals also causes recruitment of more neurons Type, number and distribution of voltage- and ligand-gated channels Channels determine the direction, degree, and rate of changes that allow for the generation of APs Mechanisms of Action Not understood how seizures end, typically under 2 minutes Neurotransmission -Glutamate Major excitatory amino acid neurotransmitter Receptors found on both principal and inhibitory interneurons Ionotropic Metabotropic Neurotransmission - Glutamate Ionotropic receptors Three subtypes – AMPA, kainate, NMDA All allow for fast transmission by allowing ion influx upon activation by glutamate Specifically inflow of Na+, outflow of K+ NMDA becomes permeable to Ca2+ during depolarization Neurotransmission - Glutamate Interesting study involving rats: Agonists Induce of ionotropic receptors seizure activity Antagonists Suppresses of ionotropic receptors seizure activity Neurotransmission - Glutamate Metabotropic receptors Slow transmission - G-protein coupled signalling pathways Neurotransmission - GABA Major inhibitory neurotransmitter Two receptor types: GABA A Post-synaptic Permeable to Cl- ions, which induces hyperpolarization, thus inhibiting APs Study found that agonists, like barbiturates and benzodiazepines, can suppress seizure activity Neurotransmission - GABA Second receptor type: GABA B Pre-synaptic, therefore, modulate synaptic release Associated K+ channels K+ currents lead to hyperpolarization and the inhibition of APs Agonists like baclofen suppress seizures Factors Affect Excitability Biochemical modification Phosphorylation of glutamate receptors like NMDA may lead to increased permeability to Ca2+, thus greater excitability Modulating gene expression, as by RNA editing Change the ion specificity of glutamate receptors General Factors Affect Excitability Changes in circuitry Sprouting of excitatory neurons Loss of inhibitory neurons Loss of excitatory neurons that “activate” inhibitory neurons Shortening of axons leads to more effective coupling of synaptic contacts Changes in gap junction synaptic function Genetics Mutations in expression of voltage-gated and ion channels Na+ channels: Cl- channels: SCN1A, SCN1B , SCN2A1 CLCN2A GABA receptors: GABRG2 (GABA-receptor gamma-2 subunit) GABRA1 (GABA-receptor alpha-1 subunit) Genetics Twin studies Study with 199 twins Concordance rates were 4 times higher in MZ twins than DZ twins 20% of affected twin pairs had an epileptic firstdegree relative Concordance high for generalized epilepsies compared to partial/focal epilepsies Neuroanatomy-Hippocampus Focus of epileptic seizures Hippocampal sclerosis – seen with temporal lobe epilepsy Not known whether epilepsy is caused by hippocampal abnormalities or whether the hippocampus is damaged by the effects of repetitive seizures Neuroanatomy-Hippocampus Why the hippocampus? Considered one of the most excitable parts of the brain Limbic system One of the very few brain regions that is capable of constant generation of new neurons Neuroanatomy-Thalamus Childhood absence epilepsy GABAergic neurons of the thalamic reticular nucleus in the thalamocortical loop involved in producing bilateral spike and wave discharge loop, characteristic of this form of epilepsy Neuroanatomy - Thalamus Increased activity of GABA A receptor – therefore excessively pruned Decreased inhibition Increased expression of Ca2+ channels in the region Neurodevelopment Defects in cell proliferation in the germinal zone Impaired neuronal migration and differentiation can lead to malformation of important cortical areas Some conditions include focal cortical dysplasia, lissencephaly, heterotopia, and polymicrogyria Neurodevelopment Delayed or inadequate integration of inhibitory neurons in neuronal circuits GABAergic neurons do not migrate sufficiently to cortical centres, leading to imbalance of excitatory/inhibitory conditions Defects in pruning and remodeling during early critical periods can trigger hyperexcitability Pilocarpine Model of Temporal Lobe Epilepsy Pilocarpine – muscarinic agonist Rats repeated injected with this Represents human epileptic condition for complex partial seizures Induces 3 states: Acute period that builds up to limbic status epilepticus Latent period – normalization of behaviour Chronic period with spontaneous recurrent seizures Treatment - Surgical Temporal lobe resection or lesionectomy Remove seizure focus area Multiple Subpial Transection Concerns only gray matter Hemispherectomy Corpus Callosotomy Treatment - Medications Anti-epileptic and anti-convulsant drugs Vary according to age and syndrome type 70% of patients are able to control seizures with medications Phenytoin, carbamazepine and valproate Treatment - Neuropsychological Mind-over-body Medical and surgical treatments can only treat epilepsies with known causes Treatment - Neuropsychological Aura treatments Certain behaviours to offset aura Ex. olfactory auras and jasmine oil Eventually Ex. could use imagination of smell to halt seizures! Visualization of fishing Treatment - Neuropsychological Biofeedback Countermeasures treatment Fights the onset of seizures Ex. Relaxation of muscles and de-stressing exercises Ex. Heightening of arousal levels Treatment - Neuropsychological EEG Biofeedback Seizures must be evoked! “Feed back” EEG information in an easily understandable form Ex. musical tones, spaceship racing games for children Train patients to recognize and control mind states Basically operant conditioning for the brain Rewarded direction for altering the brain states towards the desired References Baars, B.J. and Nicole M. Gage. (2012). Fundamentals of cognitive neuroscience: A beginner's guide. Academic Press. Breitenfeld, T., Jurasic, M.J., Breitenfeld, D. (2014). Hippocrates: the forefather of neurology. Neurol Sci. 35:1349–1352 Cavalheiro, E. A. (1995). The pilocarpine model of epilepsy. The Italian Journal of Neurological Sciences. 16(1): 33-37. Berkovic, S.F. Howell, R.A., Hay, D.A., Hopper J.L. (1998). Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol. 43(2) 435-445. Engel Jr, J. (2006). ILAE classification of epilepsy syndromes. Epilepsy research. 70: 5-10. Gaitatzis, A., Carroll, K., Majeed A., Sander J.W. (2004). The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia. 45(12): 1613-1622. Goldstein, L.H. (1997). Effectiveness of psychological interventions for people with poorly controlled epilepsy.J Neurol Neurosurg Psychiatry. 63:137-142. Johnston, D. and Brown, T. H. (1984), The synaptic nature of the paroxysmal depolarizing shift in hippocampal neurons. Ann Neurol., 16: S65–S71. Li, Y., Li, Q., Gong, H., Liang, P., Zhang P. (2014). Involvement of thalamus in initiation of epileptic seizures induced by pilocarpine in mice. Neural Plasticity. 2014(1-15). Meldrum, B.S. (1994). The role of glutamate in epilepsy and other CNS disorders. Neurology. 44(11 Suppl 8): S14-23. McNamara, J.O. (1986). Kindling model of epilepsy. Adv Neurol. 44:303-18. Slaght, S.J., Leresche N, Deniau J.M., Crunelli, V., Charpier, S. (2002). Activity of thalamic reticular neurons during spontaneous genetically determined spike and wave discharges. J Neurosci. 22(6):2323–2334. Treiman, D.M. (2001). GABAergic mechanisms in epilepsy. Epilepsia. 3:8-12. Vezzani, A. (2009). Pilocarpine-induced seizures revisited: what does the model mimic? Epilepsy Curr. 9(5): 146–148. Zillmer, E., Spiers, M., Culbertson, W. (2007). Principles of neuropsychology. Nelson Education.