1. Prof Akram M Al-Mahdawi CABM,MRCP,FRCP,FACP,FAAN
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
Psychiatric-based events
Syncope
TIA
TGA
Sleep disorder
Dizziness/vertigo
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
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
Duration
10-20 seconds
Few minutes
Postictal confusion
Yes
Perspiration
Pronounced
Not 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
20%
10%
70%

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 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,1st 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 yrs, less frequent abcence,polyspike and wwave.R Na valproate,levetiracetam.80% develop GTCs,80% seizyre free in adulthood

25. Diagnostic steps Epilepsy is a clinical diagnosis. 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 New 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 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

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
Gabapentin
None
Weight gain, peripheral edema, behavioral changes
Lamotrigine
Rash, 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
Levetiracetam
Irritability/behavior change
Oxcarbazepine
Hyponatremia (more common in elderly), rash
Topiramate
Nephrolithiasis, open angle glaucoma,
hypohidrosis (predominantly children)
Metabolic acidosis, weight loss, language dysfunction
Zonisamide
Rash, 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
The potential risk of congenital abnormalities is an important consideration among women with epilepsy and their treaters.
Congenital malformations associated with AED use include:
Most common: orofacial clefts, hear defects.
Less common: microcephaly, neural tube defects.
Major malformations are seen in approximately 2% to 4% of the general population compared with 4% to 8% among newborns prenatally exposed to AEDs.
Multiple AEDs and higher doses may substantially increase malformation rate.
Minor malformations are increased 2 to 3 fold (10% to 30%) with AED use.
References
So EL. Update on epilepsy. Med Clin North Am. 1993;77:
Foldvary N. Treatment issues for women with epilepsy. Neurol Clin. 2001;19:
Schachter SC. Antiepileptic drug therapy: general treatment principles and application for special patient populations. Epilepsia. 1999;40(suppl 9):S20-S25.
Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344:

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 Slide: AEDs and Bone Health in the Elderly
There has been increasing interest in the impact of AEDs on bone health overall. Although no studies have been done to assess impact of AEDs on fracture rates, studies on bone mineral density have demonstrated some consistent trends.
AEDs strongly associated with a decrease in bone mineral density include:
Carbamazepine.
Phenobarbital.
Phenytoin.
Primidone.
Conflicting findings on bone mineral density have been noted for:
Divalproex.
Lamotrigine.
To date, there are limited information on newer AEDs with regard to bone mineral density.

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 mg given once 20 sec— mg/kg/hr
Midazolam mg/kg—NOT exceeding 4mg/min slowly IV infusion mg/kg/hr
SZ control—300mg/day phenytoin or 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