NE3 Epilepsy

Epilepsy, the [blank_start]4th[blank_end] most common neurological disorder, is a brain disorder leading to recurring seizures. A seizure is a sudden abnormal and excessive [blank_start]firing[blank_end] of neurons. It affects 1-2% of the population. 1/3 of epilepsy is [blank_start]genetic[blank_end]. It can also be caused by: Brain injury, tumour, stroke, infections ([blank_start]meningitis, encephalitis[blank_end]), other brain disorders (Autism spectrum, dementia) Challenges: Depression, [blank_start]mood[blank_end] disorders, ADHD, sleep, falls, [blank_start]reproductive[blank_end] issues, osteoporosis, risk of death. Diagnosis involves [blank_start]EEG and MRI[blank_end].

Types of epilepsy: Note - Site of discharge and extent of spread affects symptoms. [blank_start]Simple[blank_end] (consciousness not affected) or [blank_start]Complex[blank_end] (consciousness affected) [blank_start]Focal[blank_end] (begins and remains local) or [blank_start]Generalised[blank_end] (whole brain inc. reticular system) Generalised can be classesd as: Absence, Myoclonic, Clonic, Tonic-clonic (very bad)

Neural mechanisms are poorly understood. Epileptogenesis: • Facilitation of [blank_start]excitatory[blank_end] neurotransmission • Reduced [blank_start]inhibitory[blank_end] transmission • Abnormal [blank_start]electrical properties[blank_end] of cells Repeated epileptic [blank_start]discharge[blank_end] causes cell death ([blank_start]excitotoxicity[blank_end])... this is brain damage.

Which of these is NOT a drug that lowers seizure threshold?

Antiepileptic drug action is effective in 70-80% of patients. Three main mechanisms: • Inhibition of [blank_start]Na+ channel[blank_end] function • Enhancement of [blank_start]GABA[blank_end] action • Inhibition of [blank_start]Ca2+[blank_end] channel function (T type)

Moa: Inhibition of sodium channels. Affect membrane excitability. Inhibit high [blank_start]frequency[blank_end] neuronal firing through their action on Na+ channels. 1. Phenytoin [blank_start]Tonic-clonic and focal[blank_end] seizures (not absence and myoclonic). [blank_start]Non-linear[blank_end] kinetics – acute toxicity. >[blank_start]90%[blank_end] bound to plasma proteins. Hepatic metabolism CYP1A2 and 3A4. Toxicity signs: [blank_start]Nystagmus[blank_end](uncontrolled eye movements), [blank_start]diplopia[blank_end](double vision), slurred [blank_start]speech[blank_end], ataxia, confusion, hyperglycaemia. Unwanted effects: GI, drowsiness, tremor, dizziness, headache, [blank_start]gingival hypertrophy, hirsuitism, acne.[blank_end] 2. Carbamazepine Widely used: [blank_start]focal and generalised TC[blank_end], only. Substrate and autoinducer of CYP3A4. [blank_start]Variable[blank_end] half-life (3-5 wks, OK). Decreases [blank_start]warfarin[blank_end], increases [blank_start]erythromycin[blank_end]. Adverse effects are [blank_start]dose[blank_end] related and dose limiting: headache, N&V, ataxia, drowsiness, blurred vision, [blank_start]hyponatraemia.[blank_end] 3. Sodium Valproate All forms of epilepsy. Chemically [blank_start]unrelated[blank_end] to other antiepileptics. Increases [blank_start]GABA[blank_end] content, weak [blank_start]Na[blank_end]+ block. Interactions: AEDs([blank_start]defibrillator[blank_end]), antidepressants, antimalarials, antipsychotics, carbapenems. Unwanted Effects: GI irritation, thrombocytopenia, transient [blank_start]hair loss[blank_end], liver toxicity and pancreatitis. 4. Lamotrigine Focal seizures, generalised tonic-clonic, [blank_start]absence, Lennox-Gastaut syndrome[blank_end]. Valproate will [blank_start]increase[blank_end] its concentration. Carbamazepine and phenytoin will [blank_start]decrease[blank_end] its concentration. SEs: Nausea, dizziness, ataxia, (serious) skin reactions

Which two sodium channel inhibitors can never be used in pregnancy?

MoA: Enhancement of GABA. 1. Clobazam, clonazepam - Enhances [blank_start]activation of GABA(A) R[blank_end], facilitates Cl- channel [blank_start]opening[blank_end] ([blank_start]lower[blank_end] threshold for AP) 2. Tiagabin - [blank_start]inhibits GABA uptake[blank_end]. • Confusion, difficulty [blank_start]speaking[blank_end], mild [blank_start]sedation[blank_end], paraesthesia Overdose: lethargy, [blank_start]respiratory depression, tachycardia[blank_end] 3. Vigabatrin - [blank_start]prevents GABA breakdown[blank_end]. (GABA transaminase inhibitor.) • 1/3 experience [blank_start]visual[blank_end] field disturbances • [blank_start]behavioural[blank_end] adverse effects

MoA: Inhibition of calcium channels. 1. Ethosuximide • Specific block of T type Calcium channels (thalamic relay) • [blank_start]Absence[blank_end] seizures • Side Effects: [blank_start]Nausea, anorexia, lethargy,[blank_end] dizziness, hypersensitivity (rarely) 2. Gabapentin (Pregabalin) • T type calcium channels ([blank_start]Low[blank_end] voltage activated) • [blank_start]Adjunct[blank_end] Relatively SE free: [blank_start]sedation, ataxia[blank_end]. Abuse/addiction/safety risks. 3. Levetiracetam [blank_start]Focal[blank_end] w/wo generalisation; prophylaxis post [blank_start]neurosurgery[blank_end] • Binds to a [blank_start]synaptic vesicle glycoprotein[blank_end], SV2A • Inhibits [blank_start]presynaptic[blank_end] calcium channels ([blank_start]N[blank_end] type) • No CYP450 interactions • 100% oral bioavailability Side Effects: ataxia, dizziness, headache, tremor, behavioural disturbances, GI, [blank_start]suicidal ideation[blank_end]

Drag the drug to match the interactions and unwanted side effects. (Assessable Task...) 1. [blank_start]Phenytoin[blank_end] UE: GI, drowsiness, tremor, dizziness, headache, gingival hypertrophy, hirsuitism, acne Interactions: MANY including amiodarone, trimethoprim, SSRIs, TCAs, MAOIs, warfarin 2. [blank_start]Carbamazepine[blank_end] UE: • headache, N&V, ataxia, drowsiness, blurred vision, hyponatraemia. blood, hepatic and skin disorders. Interactions: warfarin, clopidogrel, simvastatin, oestrogens/progesterone, erythromycin 3. [blank_start]Sodium Valproate[blank_end] UE: GI irritation, thrombocytopenia, transient hair loss, liver toxicity and pancreatitis Interactions: [blank_start]Defibrillator[blank_end]/AEDs, antidepressants, antimalarials, antipsychotics, carbapenems 4. [blank_start]Lamotrigine[blank_end] UE: Nausea, dizziness, ataxia, (serious) skin reactions (SJS and TEN). hypersensitivity syndrome) Interactions: valproate, carbamazepine, phenytoin 5. [blank_start]Tiagabine[blank_end] UE: Confusion, difficulty speaking, mild sedation, paraesthesia 6. [blank_start]Ethosuximide[blank_end] UE: Nausea, anorexia, lethargy, dizziness, hypersensitivity (rarely) 7. [blank_start]Gabapentin (Pregabalin)[blank_end] UE: Sedation, ataxia 8. [blank_start]Levetiracetam[blank_end] UE: ataxia, dizziness, headache, tremor, behavioural disturbances, GI, suicidal ideation

Antiepileptic hypersensitivity syndrome: [blank_start]Rare[blank_end], potentially fatal. Between [blank_start]1-8[blank_end] wks exposure. [blank_start]Fever, rash,[blank_end] lymphadenopathy. Danger of multi-organ failure. Risk meds: Carbamazepine, lacosamide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, primidone

Treatment is initiated after the first seizure to decrease risk and time to second seizure.

Common comorbidities: • [blank_start]Psychiatric[blank_end] disorders (depression, anxiety) • Cognitive disorders • Migraine • [blank_start]Sleep[blank_end] disorders More common in people with epilepsy: • Cardiovascular • Respiratory • Inflammatory disorders Other: - SUDEP (Sudden unexpected death in epilepsy) - 2-6 times greater risk of [blank_start]fractures[blank_end], 35% attributed to seizures

Pregnancy: Dose adjustment needed because of [blank_start]increased[blank_end] clearance Increased risk of teratogenicity - esp. [blank_start]first[blank_end] trimester, >[blank_start]2[blank_end] drugs. Valproate = [blank_start]neural tube[blank_end] defects, cognitive outcomes. Breastfeeding: Encouraged with monotherapy Infant [blank_start]monitoring[blank_end] = sedation, feeding [blank_start]difficulties[blank_end], weight [blank_start]gain[blank_end], developmental milestones