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Epilepsy Name: Rebecca Irvine Email: ri20@ic.ac.ukOBJECTIVES: ‘The7 Step Process’: 1. Identifythepatient’sproblem Epilepsy Identify which type 2. Specifythe therapeuticobjective Eliminate seizures Avoid adverse effects Maintain a normal lifestyle 3. Select a drug on the basisof comparativeefficacy, safety, cost and suitability Lamotrigine Sodium Valproate Diazepam Levetiracetam Also: Carbamazepine, topiramate, ethosuximide, phenytoinPharmacology of EpilepsyEpilepsy • Seizures:suddenbursts of electricalactivity in the brain causingchanges in muscle tone, behavioural awareness • EpilepsySyndromes: characterisedby repeatedseizures • Diagnosedwith EEGs (seizure type)and MRI (organic causes) • Triggers: • Poor sleep • Alcohol and drugs (and their withdrawal) • Stroke • Intracranial haemorrhage • Space-occupying lesions • Metabolic disturbancesSeizure Classification • Classification: • Locationinthe brain:generalised (affects both sidesof the brainfrom the start) or focal (just one side ofthe brain). • Level ofconsciousness • Involvementofmotor symptoms • Two main types: • Focal • GeneralisedFocal Seizures • With impairmentof consciousness('complex’): • Patients lose consciousness either after an aura, or at seizure onset. • Most commonly originate at the temporal lobe. • Post-ictal symptoms are common (eg. confusion). • Withoutimpairmentof consciousness('simple’): • Patients do not lose consciousness, and only experience focal symptoms. • Post-ictal symptoms do not occur. • Evolvingto a bilateral,convulsiveseizure('secondarygeneralised’): • Focal seizure then evolves to a generalised seizure (typically tonic-clonic). • In 2/3 of patients with focal seizures.Focal Seizures • Temporallobe • Automatisms (eg. lip-smacking); déja vu or jamais vu, emotional disturbance (eg. sudden terror); olfactory, gustatory, or auditory hallucinations. • Frontallobe • Motor features such as Jacksonian features, dysphasia, or Todd's palsy. • Parietal lobe • Sensory symptoms such as tingling and numbness; motor symptoms - due to spread of electrical activity to the pre-central gyrus in the frontal lobe. • Occipitallobe • Visual symptoms such as spots and lines in the visual field. • Treatmentof focal seizures • Carbamazepine (SE: SIADH, drowsiness, diplopia, ataxia) or Lamotrigine (SE: rash, tremor, diplopia) is first-lineGeneralised Seizures • Absence seizures • Often children • Pause briefly, for less than 10 seconds, and then carry on where they left off. • Treatment: Sodium Valproate or Ethosuximide is first-line; avoid Carbamazepine. • Tonic-clonicseizures • Patients lose consciousness; their limbs stiffen (tonic) and start jerking (clonic). • Post-ictal confusion is common. • Treatment: Sodium Valproate or Lamotrigine is first-line. • Myoclonicseizures • Sudden jerk of a limb, trunk, or face. • Treatment: Sodium Valproate or Levetiracetam (or Topiramate) is first-line; avoid Carbamazepine. • Atonicseizures • Sudden loss of muscle tone, causing the patient to fall, whilst retaining consciousness. • Treatment: Sodium Valproate or Lamotrigine is first-line.Complications of Epilepsy • Status epilepticus • 30 minutes of continuousseizures • work and call the anaesthetist Midazolam/rectal Diazepam, then Phenytoin if that does not • Depression • Suicide • Suddenunexpecteddeath in epilepsy(SUDEP) • Thought to be dueto excessive electrical activity causing a cardiac arrhythmia and death.Management of Epilepsy • The focus of drug therapy in epilepsyis optimisationof qualityof life with controlof seizure activity,but any treatmentmust be balanced againstpotentialside effects. • General rulesof thumb: • Lamotrigine, levetiracetamand valproate are good for all seizure types. • Carbamazepine, gabapentin and phenytoin are better for focal (including secondary generalised) seizures. • Ethosuximideis the drug of choicefor absence seizures. • Carbamazepine may worsen myoclonicseizures. • Interactionswithother medications,e.g. phenytoinand carbamazepine,to be considered. • Teratogenicity– sodiumvalproatehas a high riskof neuraltube defects. • Lamotrigine is a good choice for womenof childbearing age.Pharmacology of Epilepsy • How to approachthe question: • What is the type of seizure? • What is the first line drug? • Is this drug appropriate for this patient?Lamotrigine • Mechanism ofAction • Blocks Voltage-gated Na+ channel on presynaptic glutamatergic neurons • Prevents Na+ influx Lamotrigine • Prevents depolarization • ↓ glutamateexcitotoxicity VGNa+channel • Drug-druginteractions • COCP induces UDPGA • ↑ lamotrigine metabolism • Less seizure control • Side effects • Maculo-papular rash (10%) • Drowsiness • Steven-Johnson’s syndrome (1 in 1000) • Suicidal thoughts (rare)Sodium V alproate • Mechanismof Action 1.Inhibits GABA transaminase (enzyme) inside presynaptic GABAergic neurons and non-neuronal cells →prevents breakdown of GABA: a)Directly ↑ GABA concentrations in synapse (presynaptically) b)Indirectly prolongs GABA in synapse ∵↓ extraneuronal metabolism of GABA →slower removal of GABA from synapse Valproate (GABAA receptor)ility →inhibitory activity on postsynaptic neurons • Drug-druginteractions • Broad CYP450 enzyme inhibitor ∴ most other co-admin drugs need reduced doses • Avoid before conception, during pregnancy & breastfeeding • Side effects • GI: Nausea, abdominal pain, diarrhoea • Drowsiness, weight gain, hair loss • Hepatotoxicity, teratogenicity, pancreatitisDiazepam • Mechanism ofAction 1. Binds GABAA (receptor) via benzodiazepine site on postsynaptic neurons 2. ↑ Cl-ion influx→ hyperpolarisation of excitatory neurons • Therapeuticuse: • Status epilepticus • Chlordiazepoxide given for alcohol withdrawal • Sedation effects/short term for anxiety • Side effects • Drowsiness • Respiratory depression (IV or ↑ dose) • Haemolytic anaemia, jaundiceLevetriacetam • Mechanism ofAction • Inhibits SV2Aon excitatory presynaptic neuronal vesicles • Prevents vesicle exocytosis • ↓ Glutamatesecretion presynaptically • ↓ Glutamateexcitotoxicity • Drug-druginteractions • None –no CYP450 enzyme interaction • Requires good renal function • Side effects • Dizziness, headache • Somnolence • FatigueOther Points from Insendi • EEG shows interictalepileptiformdischarge(IED) – risk of seizurerecurrenceSBA 1: A 26 year old man suffers a blackout and is broughtto the emergency department by ambulance. He is accompanied by a friend who describes sudden collapsefollowed by 2-3 minutes of violent jerking with his eyes open. He also reports that his friend had described a strange feeling in his stomach and disturbedsense of taste as they sat eating together prior to the onset of the event. On examination, the man is drowsy and confused. There are subtleabrasions on the lateral aspect of his tongue, but no evidence of incontinence or residual neurological deficit. What is the singlemost likely diagnosis? A. Vasovagal syncope B. Stokes-Adams attack (arrhythmogenic syncope) C. Seizure D. Pseudoseizure (psychogenic non-epileptic attack) E. Anxiety attackSBA 1 - ANSWER: A 26 year old man suffers a blackout and is broughtto the emergency department by ambulance. He is accompanied by a friend who describes sudden collapse followed by 2-3 minutes of violent jerking with his eyes open. He also reports that his friend had described a strange feeling in his stomach and disturbedsense of taste as they sat eating together prior to the onset of the event. On examination, the man is drowsy and confused. There are subtle abrasions on the lateral aspect of his tongue, but no evidence of incontinence or residual neurological deficit. What is the singlemost likely diagnosis? A. Vasovagal syncope B. Stokes-Adams attack (arrhythmogenic syncope) C. Seizure D. Pseudoseizure (psychogenic non-epileptic attack) E. Anxiety attackSBA 2: Whilst eating dinner with his family, an 11-year-old boy suddenlydrops his cutlery and begins to stare blanklyinto space. His eyelids begin to flutter,his eyes roll upwards and this continues for 10 seconds. His dad notices the event and asks him about it, but he can’t remember what happened. What type of seizure is this describing? A. Absence B. Simple partial C. Complex partial D. Myoclonic E. AtonicSBA 2 - ANSWER: Whilst eating dinner with his family, an 11-year-old boy suddenly drops his cutlery and begins to stare blankly into space. His eyelids begin to flutter,his eyes roll upwards and this continues for 10 seconds. His dad notices the event and asks him about it, but he can’t remember what happened. What type of seizure is this describing? A. Absence B. Simple partial C. Complex partial D. Myoclonic E. AtonicSBA 3: A 29-year-old man presents to his GP, complainingof "crazy movements". Upon further questioning,he explains that every now and then, his right arm jerks violently. He mentions that at times, he has thrown cups and plates against the wall, unintentionally.He is completely aware of these episodes and otherwise reports no additional symptoms. Neurological examination shows no physical abnormalities. His GP suspects epilepsy. What is the best description for this patient's symptoms? A. Myoclonic seizure B. Cortico-basal degeneration C. Atonic seizure D. Tonic-clonic seizure E. Reflex anoxic seizureSBA 3 - ANSWER: A 29-year-old man presents to his GP, complainingof "crazy movements". Upon further questioning,he explains that every now and then, his right arm jerks violently. He mentions that at times, he has thrown cups and plates against the wall, unintentionally.He is completely aware of these episodes and otherwise reports no additional symptoms. Neurological examination shows no physical abnormalities. His GP suspects epilepsy. What is the best description for this patient's symptoms? A. Myoclonicseizure B. Cortico-basal degeneration C. Atonic seizure D. Tonic-clonic seizure E. Reflex anoxic seizureSBA 4: A 28 year old lady has been newly diagnosed with epilepsy, describing her seizures as muscle stiffeningthen jerking while unconscious, lasting 3m. She is not on the COCP and is currently trying for children. Which anti-epileptic medication is appropriate for her? A. Diazepam B. Sodium Valproate C. Lamotrigine D. Ethosuximide E. LevetiracetamSBA 4: A 28 year old lady has been newly diagnosed with epilepsy, describing her seizures as muscle stiffeningthen jerking while unconscious, lasting 3m. She is not on the COCP and is currently trying for children. Which anti-epileptic medication is appropriate for her? A. Diazepam B. Sodium Valproate C. Lamotrigine D. Ethosuximide E. LevetiracetamSBA 5: A 25-year-old man is seen in clinic with 5 unprovoked episodes of rapid bilateral upper and lower limb musclecontraction and relaxation that last around 10 seconds before stopping.These episodes cause him to fall to the floor; however, he denies any loss of consciousness and is able to continuedoing his activities after.A collateral history is taken, and it is established that no incontinenceor tonguebiting occurs. Given the likely diagnosis, what is this patient most likely to be started on? A. Ethosuxamide B. Lamotrigine C. Levetiracetam D. Sodium Valproate E. TopiramateSBA 5: A 25-year-old man is seen in clinic with 5 unprovoked episodes of rapid bilateral upper and lower limb muscle contraction and relaxation that last around 10 seconds before stopping.These episodes cause him to fall to the floor; however, he denies any loss of consciousness and is able to continuedoing his activities after. A collateral history is taken, and it is established that no incontinenceor tonguebiting occurs. Given the likely diagnosis, what is this patient most likely to be started on? A. Ethosuxamide B. Lamotrigine C. Levetiracetam D. SodiumValproate E. TopiramateSUMMARY: Focal Seizure Absent Seizure • Specific focal symptoms • Child, blank starefor 10s • Carbamazepine • Ethosuxamide Other 3 Generalised Seizures Status Epilepticus • Tonic-clonic, Myoclonic,Atonic • Lasting>30mins without regaining consciousness • Males = sodium valproate • Females = lamotrigine or leveracitam • BenezodiazepamsTHANK YOU! Please fill in the Feedback form! Name: Rebecca Irvine Email: ri20@ic.ac.uk tion=imperial-pharmacology-ning/feedback/anonymous?organisa society&keyword=ecdb6d067f045960da2d5b4b