1. Epilepsy Prof Akram M Al-Mahdawi CABM,MRCP,FRCP,FACP,FAAN

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. Definition  Epilepsy: Chronic brain disorder of various etiologies characterized by recurrent unprovoked seizures.  Epileptic Sz: Discrete epileptic event due to transient, hyper-synchronous, abnormal neuronal behavior.  Epileptic Syndromes: Grouping of similar epileptic patterns according to sz type, EEG, age of onset, familial episodes, prognosis, other clinical signs.

4. Event that may mimic seizures Physiological event  Syncope  TIA  TGA  Sleep disorder  Dizziness/vertigo Psychiatric-based events  Panic/anxiety  Conversion  Dissociative  Hyperventilation  Acute psychosis  malingering

5. Events features favoring epileptic seizures  Aura  Brief duration(1-2 min)  Postical confusion  Amnesia for the event  Events arising from sleep  Self injury  Eye open at the onset of the event

6. Epileptic seizure versus syncope SyncopeTonic-clonic seizure PositionUprightAny Facial colourPalenessCyanosis OnsetGradual; introduced by dizziness, blurring of vision Sudden; can start by ‘aura’ (simplex partial seizure) TwitchingsRarely (‘convulsive syncope’)Always EnuresisRarelyOften Tongue biteNoOften Duration10-20 secondsFew minutes Postictal confusionNoYes PerspirationPronouncedNot typical

7. Epilepsy: Etiology Vs. Age of Onset

10. Trigger factors for seizures Sleep deprivation Alcohol (particularly withdrawal) Recreational drug misuse Physical and mental exhaustion Flickering lights, including TV and computer screens infections and metabolic disturbances Uncommonly: loud noises, music, reading, hot baths

11. Localization of Partial Seizure Focus 70% 10% 20%

12. Clinical features associated with localization  Temporal lobe-Déjà vu,epigastic aura,fear/fright,formed visual images.  Frontal lobe-muscle/motor activity,forced eye deviation,speech arrest.  Parietal lobe-parasthesias,sensory phenomenon  Occipital-flashes,colors

14. Simple 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’)

15. 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

16. 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

17. 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.  Normal neurological and mental  EEG- centrotemporal spike waves  Spontaneous remission by puberty

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  R:corticotropin,steroid,vigabatrin  Prognosis: often poor but depend on etiology

19. Lennox-Gastaut syndrome  Age of onset:2-8 years  3-10 of childhood epilepsy  Seizure types: atonic, axial tonic, myoclonic, atypical absence, tonic- clonic  30%of WS syndrome will have LGS  Causes: same as in West syndrome; can develop from West syndrome  Neurological symptoms, mental retardation  Unfavourable prognosis (refractory seizure,mental handicap{80%}.  Ketogenic diet,1 st line AEDs {valproate,lamotrigine,topiramate

20. Generalised tonic-clonic seizure (grand mal)  The most common seizure  Course: Cry, loss of consciousness, fall Tonic phase- generalised muscle contraction, apnoe Clonic phase- rhythmic contraction of muscles, tongue bite, foaming, enuresis Terminal sleep and gradual regaining of consciousness (transient confusion) 10-25 yrs,65 controlled with AEDs but relapse

21. Juvenile 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  90% remit with AEDs but relapse if AEDs withdrawn  R-Na valproate.Levetiracetam

22. Absence  Cognitive dysfunction with a sudden onset and end, lasting 5-10 seconds  Stare, expressionless face; arrest of ongoing activity; generally no motor phenomena  Occurs in genetic (idiopathic) epilepsies, mostly in children

23.  CAE-4-8 yrs,frequent brief absence,3/sec spike and wave,R- ethosuximide,Na valproate.levetiracetam.40% develop GTCS,80 remit in adulthood  JAE.10-15 yrs, less frequent abcence,polyspike and wwave.R Na valproate,levetiracet am.80% develop GTCs,80% seizyre free in adulthood

25. Diagnostic steps  History  EEG Negative EEG does not exclude epilepsy Positive 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.

26. EEG Abnormalities Background abnormalities -Significant asymmetries and/or degree of slowing inappropriate for clinical state Transient abnormalities associated with seizures -Spikes (< 70 m sec) -Sharp waves (~70 – 200 msec) -Spike-wave complexes May be focal, lateralized or generalized

27. Indications for brain imaging in epilepsy Epilepsy starting after the age of 20 years Seizures having focal features clinically EEG showing a focal seizure source Control of seizures difficult or deteriorating

28. How to administer first aid for seizures Move person away from danger (fire, water, machinery, furniture) After convulsions cease, turn into 'recovery' position (semi-prone) Ensure airway is clear, but do NOT insert anything in mouth (tongue-biting occurs at seizure onset and cannot be prevented by observers) If convulsions continue for more than 5 minutes or recur without person regaining consciousness, summon urgent medical attention Do not leave person alone until fully recovered (drowsiness and confusion can persist for up to 1 hour

29. First Seizure Whether to treat first seizure is controversial Increased risk of relapse 1-Abnormal imaging 2-Abnormal EEG 3-Family history of epilepsy Currently, most patients are not treated for the first seizure unless there is an increased risk for relapse

30. 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

31. 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

32. AEDs Old  Primidon  Phenobarbital  Phenytoin  Clobazam  Clonazepam  Ethosuximid  Valproate  Carbamazepine New  Lamotrigine  Oxcarbazepine  Topiramate  Gabapentin  Vigabatrin  Levatiracetam  Zonisamide  Tiagabin

33. 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

34. Pharmacology of AEDs I. Hepatic metabolismvalproate, carbamazepine, oxcarbazepine, lamotrigine, topiramate, clobazam, clonazepam, phenobarbital, primidon, phenytoin, ethosuximid, felbamate, tiagabin No metabolismgabapentin, vigabatrin topiramate, levatiracetam Hepatic enzyme inductioncarbamazepine, phenytoin, phenobarbital, primidon (oxcarbazepine) Hepatic enzyme inhibitionvalproate

35. 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  

38. Guidelines for anticonvulsant therapy Start with one first-line drug Start at a low dose; gradually increase dose until effective control of seizures is achieved or side-effects develop (drug levels may be helpful) Optimize compliance (use minimum number of doses per day) If first drug fails (seizures continue or side-effects develop), start second first-line drug whilst gradually withdrawing first If second drug fails (seizures continue or side-effects develop), start second-line drug in combination with preferred first-line drug at maximum tolerated dose (beware interactions) If this combination fails (seizures continue or side-effects develop), replace second-line drug with alternative second-line drug If this combination fails, check compliance and reconsider diagnosis (is there an occult structural or metabolic lesion or are seizures truly epileptic?) If this combination fails, consider alternative, non-drug treatments (e.g. epilepsy surgery, vagal nerve stimulation) Do not use more than two drugs in combination at any one time

39. 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

40. Summary of Serious and Non-serious Adverse Events of the Newer AEDs AEDSerious Adverse EventsNonserious Adverse Events GabapentinNoneWeight gain, peripheral edema, behavioral changes LamotrigineRash, including Stevens Johnson and toxic epidermal necrolysis (increased risk for children, also more common with concomitant valproate use and reduced with slow titration); hypersensitivity reactions, including risk of hepatic and renal failure, DIC, and arthritis Tics and insomnia LevetiracetamNoneIrritability/behavior change OxcarbazepineHyponatremia (more common in elderly), rashNone TopiramateNephrolithiasis, open angle glaucoma, hypohidrosis (predominantly children) Metabolic acidosis, weight loss, language dysfunction ZonisamideRash, renal calculi, hypohidrosis (predominantly children) Irritability, photosensitivity, weight loss

41. 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

42. Withdrawing anticonvulsant therapy Withdrawal of medication may be considered after apatient has been seizure-free for more than 2 years. Childhood-onset epilepsy, particularly classical absenceseizures, carries the best prognosis for successful drug withdrawal. Other epilepsy syndromes, such as juvenile myoclonic epilepsy, have a marked tendency to recur after drug withdrawal. Seizures that begin in adult life, particularly those with partial features, are also likely to recur, especially if there is an identified structural lesion. Overall, the recurrence rate after drug withdrawal depends on the individual's epilepsy history. Patients should be advised of the risks of recurrence, to allow them to decide whether or not they wish to withdraw. If undertaken, withdrawal should be slowly, reducing dose gradually over weeks or months. Withdrawal may necessitate precautions around driving or occupation.

43. Discontinuation of AED  Discontinuation of AED is not recommended: Earlier unsuccessful AED withdrawal Earlier refractoriness to treatment Known brain lesion Juvenile myoclonic epilepsy

44. contraception AEDs induce hepatic enzymes that metabolise synthetic hormones, increasing the risk of contraceptive failure. This is most marked with carbamazepine, phenytoin and barbiturates, but clinically significanteffects can be seen with lamotrigine and topiramate. If the AED cannot be changed, this can be overcome by giving higher-dose preparations of the oral contraceptive. Sodium valproate and levetiracetam have no interaction with hormonal contraception.

46. Risks of Congenital Abnormalities  Congenital malformations Most common: orofacial clefts, heart defects Less common: microcephaly, neural tube defects  Major malformations General population: 2% to 4% Newborns prenatally exposed to AEDs: 4% to 8% Multiple AEDs and higher doses may substantially increase malformation rate  Minor malformations

47. Epilepsy and breast feeding  Breast feeding is not contraindicated with women on AEDs.  Sleep deprivation can provoke seizures.

48. 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

49. AEDs and Bone Health

50. Status Epilepticus 1-10 mg IV Diazepam or 4 mg IV lorazepam bolus, can repeated once Stage of Established status(SZ continue after 30 min) 1-Phenobarbit infusion 10mg/kg at 100 mg/min 2-phenytoin infusion 15mg/kg at 50mg/min or Fosphenytoin 15mg/kg at 100mg/min.Can repeate another 5-10mg/kg of phyentoin 3-if SZ continue after 30-60min (refractory)

51.  Propofol 2mg/kg----1-3 mg/kg/hr  Thiopental 100-250mg given once 20 sec—-----3- 5mg/kg/hr  Midazolam 0.1-0.3 mg/kg—NOT exceeding 4mg/min slowly IV infusion----0.05-0.4 mg/kg/hr  SZ control—300mg/day phenytoin or 400-1200 mg/day by nasogastric tube  When seizure control for 12 hr,then the anaesthetic drugs withdrawn slowly over 12 hrs,if recure again 12 hrs