Epilepsy: Definition and Epidemiology

• Seizure is an abnormal, disorderly discharge of brain nerve cells, characterized by excessive neuronal spiking and temporary disturbances in motor, sensory, or mental function.
• A singular seizure event occurs in 10% of people.
• Epilepsy is a chronic neurological syndrome with a heightened risk of recurrent seizures.
• Epilepsy can be caused by unknown factors, genetics, brain trauma, stroke, brain cancer, or drugs; seizures must be recurrent for diagnosis.

Epidemiology of Epilepsy

• Approximately 3% lifetime risk exists, with a prevalence of 0.5-1%.
• About 180,000 Canadians use anticonvulsant drugs or have experienced a seizure in the past 5 years.
• Prevalence is underestimated due to stigma and symptom heterogeneity.
• On average, 15,500 people are diagnosed with epilepsy yearly.
• 44% of cases are diagnosed before age 5 and 55% before age 10.
• 75-85% of cases are diagnosed before age 18.
• 1% of children will have recurrent seizures before age 14.
• Seizures disappear in 50% of childhood epilepsy cases.
• 1.3% of cases are in people over 60, likely due to the accumulation of injuries over time.
• The economic burden of epilepsy care exceeds $10 billion per year in the USA.

Causes of Epilepsy

• The cause of epilepsy is unknown in 50-60% of cases, labeled as either idiopathic or cryptogenic.
• Symptomatic epilepsy has a known cause and originates from scarred regions in the brain.
• Common causes involve genetic abnormalities, brain tumours, stroke, head trauma, and infections like meningitis or viral encephalitis.
• The likelihood of developing epilepsy increases with the severity of the injury.
• Additional causes include poisoning, substance abuse such as lead or carbon monoxide, and alcohol.
• Causes of epilepsy in children are usually genetic, or result from injury, infection, or systemic illness in the mother during pregnancy, or brain injury to the infant during delivery.

Mortality and Epilepsy

• Seizures are not typically fatal, but they reduce both life expectancy and quality of life.
• Epileptics face a threefold higher mortality rate.
• Mortality is unaffected by controlled seizures, but is shortened with uncontrolled ones.
• Risk factors leading to death involve status epilepticus, suicide related to depression, trauma from seizures and sudden unexpected death in epilepsy (SUDEP), with 1/1000 adults or 1/4500 children affected
• The highest risk occurs with underlying neurological impairment or poorly controlled seizures.

Types of Epilepsy

• Epilepsy syndromes are defined by seizure types (semiology), etiology, EEG findings, brain structure, age of seizure onset, family history of epilepsy or genetic disorders, and prognosis.

Types of Seizures

• Major seizure categories include seizures of general onset, focal/partial onset, and continuous seizures.
• Seizures of general onset feature grand mal (generalized motor) and petit mal (absence) seizures.
• Seizures of focal/partial onset with/without secondary generalization to major motor manifestations are defined as either simple partial seizures (elementary cortex involvement), or motor, sensory, somatosensory, auditory-vestibular, visual, olfactory-gustatory, or complex partial (limbic) seizures
• Continuous seizures require immediate medical attention and is called either generalized (status epilepticus) or focal (epilepsia partialis continua).

Major Seizure Classifications

• "Grand Mal" or generalized tonic-clonic seizures involve unconsciousness, convulsions, and muscle rigidity.
• Absence seizures, also called "petit mal", feature a brief loss of consciousness.
• Myoclonic Sporadic seizures involve isolated, jerking movements.
• Clonic seizures manifest as repetitive jerking movements.
• Tonic seizures are characterized by muscle stiffness and rigidity.
• Atonic seizures involve loss of muscle tone.

Types of Epilepsy

Generalised Seizures are:

• Characterized by bilateral epileptiform activity with bilateral motor manifestations and impaired consciousness
• This activity can result in a Myoclonic (isolated muscle jerking) seizure
• This activity can result in a Tonic (stiffening of body but no jerking) seizure
• This activity can result in a Tonic-Clonic (grand mal) seizure, where tonic (body becomes rigid and the patient often falls) is followed by Clonic (generalised convulsing with bilateral jerking of muscles)
• This activity can result in Absence (Activity ceases; patient stares and pales for a few seconds) seizure
• This activity can result in Akinetic/Atonic (Falls, but no movement) seizure
• These seizures can by Typical (petit mal) with EEG showing 3Hz Spike and wave
• These seizures can by Atypical with Other EEG Changes

Epilepsy Syndromes

• Temporal Lobe Epilepsy can cause odd feelings, affect memory, and alter sensation.
• Frontal Lobe Epilepsy manifests with varied seizure symptoms depending the location of frontal lobes vary widely.
• Parietal Lobe Epilepsy often involves somatosensory, somatic, visual, and language disruptions.
• Occipital Lobe Epilepsy commonly presents as visual hallucinations.
• Primary Generalized Epilepsy, can be idiopathic and manifest as myoclonic, grand-mal, or absence seizures.

Epilepsy Syndromes in Children

• Benign Rolandic Epilepsy causes seizure activity around the central sulcus, affecting facial muscles.
• Juvenile Myoclonic Epilepsy induces seizures associated with sleep status.
• Childhood Absence Epilepsy affects 5-9-year-olds and remits in 80% of cases
• Landau-Kleffner Syndrome results in language loss between ages 3 and 7, with seizures being rare or nocturnal.

mTOR

• mTOR is a protein kinase regulating cell growth, proliferation, motility, survival, protein synthesis, and transcription, and works downstream of NMDA.
• mTOR plays a crucial role in excitatory synaptic neurotransmission.
• Aberrant activation of the mTOR pathway may disrupt excitation/inhibition balance in the brain, increasing vulnerability to seizures.
• Rapamycin can mitigate seizure activity by targeting aberrant mTOR activation, potentially restoring normal brain function.

Etiology of Epilepsy Varies With Age

• For age 0-4 the main cause is development and then infection
• For age 5-14 the main cause is genetic or infectious
• For age 15-24 the main cause is usually Brain Trauma
• For age 25-44 the main cause is unknown
• For age 45-64 the main cause is Brain Tumour or cerebrovascular
• For age 65+ the main cause is degenerative conditions

Genetic Causes of Epilepsy

• One percent of epilepsy cases are attributed to known genetic diseases, but familial factors play a substantial role in 40% of idiopathic cases.
• Children with an epileptic parent faces less than 10% risk of developing epilepsy.

Genetic Causes of Epilepsy-Channelopathies

• SCN1A mutations exhibit defects in fast inactivation gating, leading to persistent, non-inactivating currents during membrane depolarization, thereby causing neuronal hyperexcitability
• KCNQ2/3 mutations disrupt M currents that modulate neuronal excitability by dampening repetitive firing

GABA And Epilepsy

• GABA receptors trigger an influx of chloride ions in the postnatal brain, which hyperpolarizes the neurons
• Mutant GABA receptor subunits in epilepsies may reduce GABA-mediated synaptic inhibition
• CLCN2 is a gene encoding a voltage-gated chloride channel
• CLCN2 mutations completely abolish chloride channel function
• Associated with inherited epilepsy

Pharmacotherapy of Epilepsy

• The pathophysiology of epilepsy is poorly understood, leading to imprecise therapies.
• Current approaches aim to reduce hyper-excitability.
• Side effects are common, and treatment is more effective than curative.
• Major targets are voltage-gated sodium channels and GABA signalling.

Sodium Valproate

• Used as an anticonvulsant and mood stabilizer, also treating anxiety and bipolar disorder, efficient in all seizures especially generalized.
• Mechanism of action blocks voltage-gated sodium channels relatively weakly.
• The medication inhibits GABA transaminase weakly as well.
• The side effects include liver damage, tiredness, sedation, and gastrointestinal issues; also causes a high risk of birth defects but seizures also can be harmful to baby.

Carbamezepine

• Anticonvulsant and mood stabilizer often used for Epilepsy and bipolar disorder
• Stabilizes the inactivated state of voltage-gated sodium channels and potentiates GABA receptors
• Side effects include sedation, headache, motor impairment, gastrointestinal disturbance, liver damage, and birth defects,
• Oxcarbazepine derivative with same mechanisms but has reduced side-effects like liver damage.

Lamotrigine

• Has the function of Anticonvulsant and mood stabilizer often used for Epilepsy and bipolar but has off label use in depression.
• Mechanisms are not defined precisely, but are presumed to act on sodium channels (confirmed in vitro).
• It has unique side effects, such as potentially life-threatening skin reactions; common side effects can be rash, fever, fatigue, incoordination, blurred vision.

Benzodiazepines

• Frequently used are Clonazepam, a sedative useful as a hypnotic, anxiolytic, anticonvulsant and muscle relaxant.
• Mechanism involves BZDs binding to GABA-A receptors, increasing the affinity for GABA, and the frequency of channel opening.
• They aren't major teratogens, but some association can occur with cleft palate, and well tolerated but sedation, dizziness, decreased alertness is common.

Ethosuximide

• It is Antiepileptic
• And used in Absence and is safer because of a lack of hepatotoxicity with the valproic acid that it replicates
• The mechanism involves T-type calcium channel blocker
• Causes T-type calcium channels to contribute to tonic bursting activity and
• Causes Low-threshold spikes (LTS) to occur at negative, membrane depolarizations
• Side effects include Drowsiness and gastrointestinal side effects plus a risk of psychoses in some individuals

Leviteracetam

• Has the function of Anticonvulsant plus efficacy when alone or in conjunction when treat multiple syndromes
• Mechanism is somewhat unknown, theorized to be a GABA agonism as it is theorized as a vesicle glycoprotein, SV2A with action as a presynaptic inhibition of neurotransmission.
• Generally well tolerated causing some drowsiness, coordination change, depression and or suicidal behaviour.

Topiramate

• Topiramate is an anticonvulsant with a multitude of putative mechanisms of action
• These mechanisms include: blockage of voltage-dependent sodium channels, augmentation of GABA-A receptors, AMPA/kainate antagonism and the inhibition of carbonic anhydrase
• Side effects can include some cognitive decline, numbness, and or tingling

Experimental therapies - Tau

• Recurrent seizures can develop after brain injuries leading to neurodegeneration in patients
• Hyperphosphorylated tau tends to be found in patients also associated with neurodegenerative pathology in multiple disorders
• Recent work Hyperphosphorylated tau may also contribute to seizure pathology
• PP2A accounts for over 70% of tau phosphatase activity in the human brain
• Activating PP2A with Sodium Selenate may significantly reduce seizure

Experimental therapies - Chemogenetics

• Inflammation can contribute to the development of epilepsy
• Many known anti-inflammatories
• Cox-2 inhibitors largely ineffective thus far
• A number of markers like IL-1beta, IL-6, TNF-alpha all upregulated by epilepsy should be targeted

Experimental therapies - Neurosteroids

• Neurosteroids are positive modulators of GABA-A activity
• Allopregnanalone is an example of those
• They come from Progesterone metabolites
• Very potent positive modulators of GABA-A
• Affect the inverse and seizure frequency
• Effective treatment for refractory status
• Difficult to make because Endogenous production is not reliable, because of this
• Synthetic Neurosteroids have shown good results

DREADDS

• Used to manipulate the chemogenetics of Epilepsy