Epilepsy is characterized by sudden, recurrent and transient disturbances of mental function or movements of the body that result from excessive neuronal activity. Epilepsy refers to a group of symptom complexes that have many causes: some forms are static and some are progressive; some are acquired and some are due to an inherited predisposition.
Epilepsy is common and affects up to ~1% of the population with new diagnoses appearing with an annual incidence rate of 40/100,000, and slightly higher in males than females. About 10,000 Canadians are diagnosed each year. The rate is highest in children under 5 years of age, and drops to a lower level in persons between 20-50 years of age, and rises again in older people. About half of all seizures reported are partial, beginning on one side. The remainder of the reported seizures are generalized, bilateral and symmetric in presentation. The relative importance of perinatal factors, trauma, nutrition, environmental factors or genetics is largely unknown.
Pathogenesis & Clinical Features
Anatomically, the brain’s cortex largely consists of columns of vertically organized pyramidal neurons, with their apical dendrites closer to the surface and cell bodies in deeper layers. The dendrites receive mostly excitatory neurotransmission and integrate those signals through the cell body which receives mostly inhibitory contacts, to subsequently activate its own axon potentials. Normally, a balance of excitatory and inhibitory synaptic influences on neurons is maintained. However, in seizures abnormal excitability of the cerebral cortex may occur localized to groups of neurons (partial or focal seizures) or affecting the entire mantle (generalized seizures).
Biochemically, seizures are accompanied by profound changes in brain metabolism with increased blood flow, oxygenation and glucose utilization. Nevertheless, between partial seizures there may be hypometabolism and, if prolonged or repetitive, the alterations in metabolism may cause irreversible damage. This damage may lead to further neurological impairment and an increased tendency to seizures. At a neuronal level, there are two major mechanisms: 1) impaired ion flux, and ; 2) abnormal synaptic transmission. The former may include genetic anomalies in a number of channels, such as SCN1A mutations in Dravet syndrome whereas the latter may include convulsant agents that block the synthesis or actions of the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA).
The clinical classification of epilepsies is internationally recognized (International League Against Epilepsy), and largely depends on whether the seizure originates unilaterally (partial) or in bilateral brain structures, and whether consciousness is retained. Partial seizures are divided into three types: 1) simple, arise from one area and do not impair consciousness; 2) complex partial, that begins locally but spreads bilaterally and therefore impairs consciousness, and; 3) simple or complex partial attacks that spread widely and secondarily evolve into generalized major motor seizures. Generalized seizures are associated with either bilateral body movements or changes in consciousness or both; absence seizures, myoclonic, clonic, tonic, tonic-clonic and atonic types are the six major types.
Current Therapies/Future Aims
The basic approach to anticonvulsant therapy is to select an appropriate drug for the specific type of seizure disorder and to progressively increase the dose until seizures are controlled or there are toxic side effects. Monotherapy, or use of single drug, is preferable to multidrug therapy as all drugs in the treatment of seizures have significant side effects. Treatment-resistant epilepsy in children is a major problem. Recurrent seizures in this age group are associated with an increased risk of developmental delay/intellectual disability, autism and psychiatric disorders. Mortality risk is high and treatment is ineffective in 30-40% of patients. In >50% of patients, the diagnosis is unknown, but a genetic etiology is suspected. Identifying a specific genetic cause may benefit patient/family in multiple ways including providing an answer to the family for their child’s problem, more accurate counseling regarding prognosis and recurrence risk and, most importantly, implementing appropriate therapy for that specific gene abnormality.
Currently, we are applying whole exome sequencing technology to consenting families of young children with intractable seizure disorders, to help predict and prevent their disease, and to gather the evidence needed to change the current standards of clinical care in British Columbia and Canada.