**2. Epilepsy**

Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. It is defined as a disease of the brain in which the patient has either (1) two or more unprovoked seizures occurring more than 24 hours apart or (2) one unprovoked seizure and a probability of further seizures to be greater than 60% [1]. The prevalence of epilepsy worldwide is estimated to be between 4 and 10/1000 people with epilepsy accounting for up to 0.5% of the global burden of disease [2, 3]. There is significant geographic variation with prevalence rates of epilepsy prevalence rates being much higher in the developing world [4].

Most children and adults with epilepsy respond well to anticonvulsant therapy with approximately 50% of adults and 70% of children becoming seizure free with their first anticonvulsant medication [5, 6, 7]. Up to 30% of patients with epilepsy can be considered to be drug resistant which is defined by the International League Against Epilepsy as having failed two or more appropriate anticonvulsant treatments at an appropriate dosage [8, 9].

In patients who have failed two appropriate anticonvulsants the likelihood of seizure freedom with the addition of further anticonvulsant therapies is low. Treatment options for patients with drug resistant epilepsy include further trials of anticonvulsants, resective surgery, neural pathway stimulation with receptive or vagal nerve stimulation and dietary therapies [10]. Further trials of anticonvulsants in adults will result in 16% of patients who had failed their first two medications becoming seizure free [11]. In pediatric patients while the likelihood of achieving remission for 1 year or more with further medication trials is higher at 57%, many will continue to have relapses over time [12]. Resective surgery success rates (as defined as obtaining Engel Class 1 seizure freedom) in pediatric and adult patients with surgically amenable epileptogenic lesions range from 34 to 90% depending on the nature and extent of the lesion [10, 13].

A full review of the processes that result in brain abnormalities causing seizures (epileptogenesis) is beyond the scope of this chapter. However, in order to understand how cannabinoids can have potential in treating epilepsy it is worth knowing the basic principles of these processes. One of the major hallmarks of epilepsy is the presence of abnormal oscillatory events within neuronal networks in the form of recurrent interictal spikes and high frequency oscillations within the epileptic zones of the patients' brain [14]. These abnormal oscillations then result in excessive synchronous firing of neurons causing an epileptic seizure with alteration in the patient's behavior, motor activity or sensorium. Epilepsy can result from injury (either ischemic or traumatic) to cortical brain structures or genetic, inflammatory, structural and metabolic disturbances within the brain. The main components of the development of the abnormal oscillations within neuronal networks and epileptogenesis (seizure development) are (a) neuronal hyperexcitability—the ability of neurons to generate abnormal intrinsic burst discharges (b) a loss of GABA mediated interneuron neuronal inhibition that would normally prevent these discharges from spreading to adjacent neurons and (c) neuronal hypersynchrony in which excessive synaptic enhancement of neighboring neurons through the development of excitatory pathways allows these bursts to spread in a synchronous manner within a group of neurons [15]. Neuronal hyperexcitability can arise from abnormalities in excitatory or inhibitory neurotransmitter receptors resulting in a loss of the normal balance between neuronal excitation and inhibition. Of particular interest in epileptogenesis are the excitatory glutamatergic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors [16]. Alterations in ion channel function as is seen in the channelopathy associated epilepsies such as Dravet syndrome also lead to neuronal hyperexcitability [17].
