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  1. 1. Epilepsy
  2. 2. ‘Sacred illness’ • ‘Sacred illness’: 600 BC • Hippocrates 400 BC: It is thus with regard to the disease called sacred: it appears to me to be in no way more divine nor more sacred than other diseases [...]. The brain is the cause of this affliction [...]. Alexander the Great Julius Caesar Napoleon F. Dostoyevsky
  3. 3. Epileptic seizure  Abnormal synchronous discharge of the cortex leading to transient dysfunction of the brain  A seizure can be evoked by any pathology affecting the brain, transient or permanent  Epileptic seizure = symptom
  4. 4. Acute symptomatic seizure versus epilepsy disease  Acute symptomatic seizure: symptom of a transient pathological state of the brain  Withdrawal of alcohol, drugs  Hypoglycemia  Fever etc.  Epilepsy disease: lasting epileptic dysfunction of the brain → spontaneous seizures
  5. 5. Types of seizures Generalised seizures  Tonic - clonic  Tonic  Clonic  Atonic  Absence  Myoclonus Focal (partial) seizures  Simplex partial  Complex partial  Partial onset with secondary generalisation Seizures of undetermined type
  6. 6. Generalised tonic-clonic seizure (grand mal)  The most common seizure  Acute symptomatic seizures are generalised tonic-clonic seizures  Course:  Cry, loss of consciousness, fall  Tonic phase- generalised muscle contraction, apnoea  Clonic phase- rhythmic contraction of muscles, tongue bite, foaming, enuresis  Terminal sleep and gradual regaining of consciousness (transient confusion)
  7. 7. Absence  Cognitive dysfunction with a sudden onset and end, lasting 5-10 seconds  Stare, expressionless face; arrest of ongoing activity; generally no motor phenomena  EEG: generalised 3 Hz spike and wave activity  Occurs in genetic (idiopathic) epilepsies, mostly in children
  8. 8. Myoclonic seizure  Sudden, quick, arrhythmic muscle contraction, twitch of a limb; no loss of consciousness  EEG: generalised polyspike and wave activity  Occurs in genetic (idiopathic) epilepsies  Not only an epileptic phenomenon- it can be the sign of diffuse encephalopathies
  9. 9. Simplex partial seizures  No loss of consciousness  Symptoms depend on area of brain involved:  Motor  Sensory  Autonomic  Psychosensory  It can be the introductory phase of a complex partial or generalised tonic-clonic seizure (‘aura’)
  10. 10. Complex partial seizures  Origin is most often in the temporal lobe  A common seizure type in adulthood  Can be introduced by a simplex partial psychosensory seizure:  olfactory hallucination  déjà vu, jamais vu  feeling of alienation  Loss of consciousness: stare, ‘going blank’  Automatisms:  oral automatisms  fiddling with the hands
  11. 11. Causes of epilepsy / epileptic syndromes Idiopathic / genetic epilepsies  Localisation related:  Benign centrotemporal epilepsy  Benign occipital epilepsy  Autosom dominant nocturnal frontal lobe epilepsy  Idiopathic generalised epilepsy:  Childhood and juvenile absence  Juvenile myoclonic epilepsy  Grand mal seizures on awakening Symptomatic epilepsies  Localisation related :  Temporal lobe epilepsy  Frontal lobe epilepsies  Parietal, occipital lobe epilepsies  Symptomatic generalised epilepsies:  West- syndrome  Lennox-Gastaut syndrome  Cryptogenic epilepsies
  12. 12. Genetics  Risk of a non-provoked seizure in offsprings of a parent with epilepsy: 6%  Idiopathic generalised epilepsies: 9-12%  Over 140 single gene diseases are accompanied by epilepsy  Inborn metabolic, storage diseases  Mitochondrial diseases  Neurocutaneous diseases  Chromosomal diseases Tuberous sclerosis
  13. 13. Benign centrotemporal epilepsy  Age of onset: 3-15 years  Seizure types: facial, oro-bucco- pharyngeal motor and sensory simplex partial seizures; speech arrest  Nocturnal seizures  Mild disease, therapy not always needed  No neurological or mental alterations  EEG: centrotemporal spike waves  Spontaneous remission by puberty
  14. 14. Childhood absence epilepsy  Age of onset: 3-10 years  Seizure types: absence; often in clusters; hyperventillation and fotostimulation are provoking  No neurological or mental alterations  EEG: generalised 3 Hz spike and wave activity  Good response to treatment  Spontaneous remission by puberty
  15. 15. Juvenile myoclonic epilepsy  Most common form of idiopathic generalised epilepsy  Family history positive in 40%  Age of onset: 15-18 years  Seizure types:  myoclonic  generalised tonic-clonic  absence  EEG: generalised 3-4 Hz spike and wave, polyspike and wave, hyperventillation and fotostimulation are provoking  Good response to treatment, but needs life-long treatment
  16. 16. Common causes of symptomatic epilepsies  Head injury  Tumors  Infarcts, hemorrhages  Blood vessel malformations  Infections  Cortical dysgenesis Cause of newly diagnosed epilepsies is unknown in 60- 65% (cryptogenic).
  17. 17. Temporal lobe epilepsy  Most common epilepsy in adulthood; can be heralded by a few seizures in childhood, but typical age of onset is 20-22 years  Seizure types:  olfactory hallucination (simplex partial)  psychosensory seizures (simplex partial)  complex partial  generalised tonic-clonic  Febrile convulsions in childhood  Hippocampal sclerosis  Often refractory to therapy  Characteropathy, memory dysfunction
  18. 18. West syndrome  Age of onset: 3-5 months  Seizure types: infantile spasms  Causes: inborn metabolic, storage diseases, perinatal hipoxic brain damage  Cryptogenic in 40-50%  Neurological symptoms, mental retardation; bad prognosis; can transform into Lennox-Gastaut syndrome  EEG: hypsarrhythmia
  19. 19. Lennox-Gastaut syndrome  Age of onset: 1-8 years  Seizure types: atonic, axial tonic, myoclonic, atypical absence, tonic-clonic  Injuries are common  Causes: same as in West syndrome; can develop from West syndrome  Neurological symptoms, mental retardation  Unfavourable prognosis, refractory to treatment
  20. 20. Diagnosis / differential diagnosis Is it an epileptic seizure? ? Yes No 1. Seizure type? 2. Acute symptomatic seizure or epilepsy? Epilepsy Idiopathic or symptomatic? Acute symptomatic seizure Cause? Symptomatic epilepsy Cause? Syncope? TIA? Psychogenic?
  21. 21. Epileptic seizure versus syncope Syncope Tonic-clonic seizure Position Upright Any Facial colour Paleness Cyanosis Onset Gradual; introduced by dizziness, blurring of vision Sudden; can start by ‘aura’ (simplex partial seizure) Twitchings Rarely (‘convulsive syncope’) Always Enuresis Rarely Often Tongue bite No Often Duration 10-20 seconds Few minutes Postictal confusion No Yes Perspiration Pronounced Not typical
  22. 22. Diagnostic steps  History  EEG  Negative EEG does not exclude epilepsy  Pozitive EEG without clinical signs does not prove epilepsy  EEG after sleep withdrawal or during sleep  Long-term EEG / video monitoring  CT, MRI Epilepsy is a clinical diagnosis.
  23. 23. Medical treatment of epilepsy  When do we start antiepileptic medication (AED)?  Which AED to choose?  When and how do we switch AEDs?  When is polytherapy needed?  When can AEDs be discontinued?  Pregnancy  Driver’s licence
  24. 24. When do we start treatment?  More than one non-provoked, well-documented seizure  AEDs are usually not started after the first seizure (needs individual assessment)  Preventive treatment is not justified
  25. 25. AEDs Old  Primidon  Phenobarbital  Phenytoin  Clobazam  Clonazepam  Ethosuximid  Valproate  Carbamazepine New  Lamotrigine  Oxcarbazepine  Topiramate  Gabapentin  Felbamate  Vigabatrin  Levatiracetam  Zonisamide  Tiagabin
  26. 26. Mechanism of action of AEDs Inhibition of voltage gated Na, Ca channels Na: phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate, felbamate, zonisamide Ca: ethosuximid, valproate? lamotrigine, topiramate, zonisamide Potentiaton of GABA mediated inhibition phenobarbital, benzodiazepins, vigabatrin, tiagabine, topiramate, valproate, gabapentin, felbamate Decrease of glutamate mediated excitation felbamate, topiramate
  27. 27. Efficacy of AEDs All seizure types: absence, myoclonic, generalised tonic- clonic seizures, partial seizures valproate, lamotrigine, topiramate clobazam, clonazepam phenobarbital, primidon felbamate levatiracetam, zonisamide Partial seizures, generalised tonic-clonic seizures carbamazepine, oxcarbazepine gabapentin, vigabatrin, tiagabine phenytoin Absence ethosuximid
  28. 28. Pharmacology of AEDs I. Hepatic metabolism valproate, carbamazepine, oxcarbazepine, lamotrigine, topiramate, clobazam, clonazepam, phenobarbital, primidon, phenytoin, ethosuximid, felbamate, tiagabin No metabolism gabapentin, vigabatrin (topiramate, levatiracetam) Hepatic enzyme induction carbamazepine, phenytoin, phenobarbital, primidon (oxcarbazepine) Hepatic enzyme inhibition valproate, felbamate
  29. 29. Pharmacology of AEDs II. Phenytoin 7-20 days Phenobarbital 10-30 Primidon 2-5 Valproate 2-5 Carbamazepine 3-5 Ethosuximid 7-12 Clobazam 4-5 Lamotrigine 3-10 Topiramate 3-6 Gabapentin 2-5 Vigabatrin 2-5 Steady state Binding to plasma proteins Pronounced (>90%) binding phenytoin valproate Moderate (30-80%) binding carbamazepine clobazam lamotrigine No or minimal (<20%) binding gabapentin vigabatrin topiramate ethosuximid
  30. 30. Side effects of AEDs  Allergy  Central nervous system side effects (dose dependent)  drowsiness, headache  dizziness, dysequilibrium  cognitive dysfunction (memory)  Idiosynchratic reactions / chronic side effects  bone marrow suppression  hepatic failure  rash  weight gain, weight loss  tremor  polycystic ovary syndrome  visual field defect
  31. 31. Selection of AEDs  Selection of AED is based on:  Seizure type / epilepsy syndrome  Other: side effects, pharmacology, drug interactions, comorbidities  As there are no major differences among first-line AEDs, safety and tolerability must be of paramount consideration in choosing AED.  Matching drugs to patients (holistic approach):  Side effects  Work  Sleep  Mood  Well being
  32. 32. Selection of AEDs Idiopathic generalised epilepsies valproate, topiramate, lamotrigine, levatiracetam Localisation related epilepsies (eg. temporale lobe epilepsy) carbamazepine, oxcarbazepine, valproate, lamotrigine, topiramate, gabapentin, levatiracetam Symptomatic generalised epilepsies West-syndrome Lennox-Gastaut syndrome vigabatrin felbamate, lamotrigine, valproate
  33. 33. Therapeutic principles  Aim: maximal seizure control, minimal side effects  Monotherapy  Usually gradual introduction of AED  Assessment of AED effect (seizure frequency)  After AED has reached steady state  Depends on the average time interval of seizures before treatment
  34. 34. Possible causes of AED inefficacy  Inadequate dose → dose escalation  Lack of compliance → measure blood AED levels  False diagnosis: the patient doesn’t have epilepsy  ‘Pseudoseizures’ → precise description of seizure, EEG / video monitoring  Inadequate selection of AED  True inefficacy of AED → AED switch  Other AED on monotherapy  AED combination
  35. 35. AED combinations  Rules of AED combination:  Establish optimal dose of baseline AED  Avoid combining similar modes of action  Add drug with multiple mechanisms  Titrate new drug slowly  Be prepared to reduce dose of original drug  Replace either drug if response is poor  Some effective combinations:  valproate-lamotrigine  valproate-carbamazepine/oxcarbazepine  valproate-topiramate  etc.
  36. 36. Drug interactions Enzyme inductors carbamazepine, phenytoin phenobarbital, primidon Increase of metabolism / decrease of efficacy valproate, lamotrigine, topiramate, carbamazepine oral contraception oral anticoagulation Enzyme inhibitors valproate Decrease of metabolism / increase in efficacy - toxicity lamotrigine, carbamazepine, phenytoin Does not cause interaction lamotrigine, gabapentin, topiramate, vigabatrin, tiagabin  
  37. 37. Therapeutic success- remission rates Partial epilepsies First AED in monotherapy: 43% Second AED in monotherapy: 7% Other monotherapies: 2% AED combination: 5% Total in remission: 57% Juvenile myoclonic epilepsy First AED (valproate) in monotherapy: 85% Altogether 65-70% of patients with epilepsy respond well to AED treatment.
  38. 38. Discontinuation of AED  After 3-5 seizure free years  A decision of both the doctor and patient  AED should be very slowly tapered, lasting weeks- months.  Discontinuation of AED is not recommended:  Earlier unsuccessful AED withdrawal  Earlier refractoriness to treatment  Known brain lesion  Juvenile myoclonic epilepsy
  39. 39. Epilepsy and pregnancy  Teratogenic risk  In normal population: 2-3%  In women on AEDs: 4-9%  Teratogenic risk is increased  High AED dose  Fluctuating plasma levels  Polytherapy  Occurrence of spina bifida in the family  Folic acid deficiency
  40. 40. Epilepsy and pregnancy: what to do?  Before conception:  Attain the best possible seizure control with the lowest possible AED dose, preferably in monotherapy  Folic acid profilaction 4 mg/day  During pregnancy:  During first trimester supplement folic acid 4 mg/nap  Change medication only if seizure control worsens  Screening of fetal malformations (ultrasound on week 16 and 20, AFP)  In case of enzyme inductor AEDs, give vitamin K in the third trimester
  41. 41. Epilepsy and breast feeding  Breast feeding is not contraindicated with women on AEDs.  Sleep deprivation can provoke seizures.
  42. 42. Epilepsy and driving  Driving is prohibited for one year after a seizure with loss of consciousness  Driving is permitted:  2-3 years of seizure free interval with patients on AEDs  2-3 years of seizure free interval after withdrawal of AEDs