1. Epilepsy Lecture Neuro Course 4th year

2. Objectives – To Review: What the term epilepsy means Basic mechanisms of epilepsy How seizures and epilepsies are classified How epilepsy is represented in the EEG What are the neuronal substrates of primary and secondary epileptogenesis as represented in animal models and from recordings in humans Molecular genetics offers insight into the basic mechanism underlying some epilepsies By what mechanisms may anticonvulsants be expected to alter the pathophysiology of epilepsy

3. A BRIEF HISTORY OF EPILEPSY Greek verb επιλαμβανειη ("to be seized," "to be taken hold of," or "to be attacked "the sacred disease" Hippocrates

4. DEFINITIONS OF EPILEPSY Epilepsy is not a specific disease, or even a single syndrome, but rather a broad category of symptom complexes arising from any number of disordered brain functions that themselves may be secondary to a variety of pathologic processes. The terms convulsive disorder, seizure disorder, and cerebral seizures are synonymous with epilepsy; Modern concepts of epilepsy originate in the work of mid-l9th century physicians and scientists

5. CAUSES OF EPILEPSY Of seizures –Metabolic upset (e.g. low Na+; Low Ca2+) –Traumatic brain injury –Stroke/haemorrhage –Alcohol & recreational drugs –Infection (encephalitis) Of Epilepsy –Post traumatic –Post stroke –Post encephalitic –Tumours– – Vascular malformations –Developmental abnormalities– – Hippocampal sclerosis –Genetic abnormalities –Unknown (30-40%)–(status epilepticus)

6. Glutamate Receptors At least 3 primary classes with multiple subtypes NMDA AMPA Kainate Activation of NMDA receptors plays an important role in the spread of epileptic activity

7. Synaptic Inhibition: GABA GABA A receptors: mediate brief opening of Cl - channels GABA B receptors: prolong activation of K + channels Repetitive firing depresses inhibitory synaptic activity

8. Cellular Mechanisms of Epilepsy Burst firing Recurrent excitatory connections Synaptic enhancement and potentiation produced by rapid firing Depression of inhibitory synapses by high frequency firing Nonsynaptic spread of electrical activity

9. Experimental seizure models

10. Clasification of seizures Partial Seizures (local or focal) Simple- AWARENESS PRESERVED Complex- AWARENESS LOST Generalized Seizures - AWARENESS LOST Absence (typical) Absence (atypical) Myoclonic short single or multiple jerks Tonic included in most "convulsions" Clonic Tonic-clonic (grand mal) Atonic

11. PRIMARY EPILEPTOGENESIS Expression of epileptiform activity Epileptogenesis Hyperexcitability Hypersynchrony

12. CELLULAR MECHANISMS OF FOCAL EPILEPTOGENESIS (1)intrinsic membrane properties (2)degree of excitatory coupling among the neurons; (3) loss of inhibitory control mechanisms. Paroxysmal depolarization shift (DS, PDS)

13. SYNCHRONOUS POPULATION ACTIVITY SPIKES AND SEIZURES MECHANISMS OF SYNCHRONIZATION (1) recurrent excitatory synapses; (2) electrotonic coupling by way of gap junctions; (3) electrical field and ephaptic effects; (4) changes in extracellular ion concentrations.

14. Outstanding issues Which animal models are most relevant to human epilepsy? What turns a spike into a seizure? Why do most seizures self-terminate What determines individual susceptibility? Why don’t drugs work in some patients? Role of seizure induced brain damage –What are the key pathogenetic mechanisms? –What is the role in epileptogenesis? –What factors determine susceptibility? Will we ever have an antiepileptogenic treatment?