A 29-year-old woman came for evaluation.

1. A 29-year-old woman came for evaluation. • The previous evening, her husband, who was in the next room, heard unusual sounds and found her lying on the bed looking dazed. She was confused for a few minutes but quickly returned to normal. • On questioning, she recalls an unwitnessed event about 1 month previously; at that time, she awoke feeling mildly confused, had sore muscles, and discovered she had bitten her tongue. • How should she be evaluated and treated? NEJM 2008;359:166

2. What is epilepsy?

3. What is epilepsy? • Epilepsy is a disorder in which the person two or moreepileptic seizures.

4. Classification of Epileptic Seizures

5. Classification of seizures (International League Against Epilepsy ILAE) Partial seizures 57% Generalized seizures 40% 3% Unclassified seizures

6. I. Partial seizures II. Generalised A. simple partial B. complex partial C. partial seizures evolving to generalised seizures (sometimes called secondarily generalised seizures) A. absence B. myoclonic C. clonic D. tonic E. tonic-clonic F. atonic Classification of epileptic seizures (ILAE) • III. Unclassified Epileptic Seizures • Includes all those seizures that cannot be classified • because of incomplete data or because they defy • classification into the above categories

7. LEG LEG TRUNK TRUNK ARM ARM FACE FACE Simple partial seizures Central fissure Somatosensory.Tingling ofcontralateral limb, face, or side of body Focal motor. Tonic-clonic movementsof upper (or lower) limb. Postcentral gyrus Precentral gyrus Contraversive. Head and eyesturned to opposite side Visual.Sees flashes of light, scotomas, unilateral or bilateral blurring Auditory.Hears ringing, hissing or noises Autonomic. Sweating, flushing or pallor, and/or epigastric sensations

8. Complex partial seizures Impairment of consciousness: cognitive, affective symptoms Formed auditory hallucinations. Hears music, etc FRONTAL PARIETAL LOBE LOBE POSTERIOR TEMPORAL Formed visual hallucinations. Sees house, trees that are not there GYRUS Dreamy state; blank, vacant expression; déjà vu; jamais vu; or fear OCCIPITAL LOBE d Ž j ˆ Bad or unusual smell Superiortemporalgyrus Dysphasia Psychomotor phenomena. Chewing movements, wetting lips, automatisms (picking at clothes)

9. Absence seizure Between seizurespatient normal Seizure:Vacant stare, eyes roll upward, eyelids flutter (3/sec), cessation of activity, lack of response

10. Tonic-clonic seizures A. Tonic phase B. Clonic phase C. Post-ictal confusional fatigue Incontinence Cyanosis Epileptic cry Clonic jerks of limbs, body and head Cyanosis Generalised stiffening of body and limbs, back arched Eyes blinking Limbs and body limp Salivary frothing

11. Status epilepticus • A condition characterized by an epileptic seizure that is so frequently repeated or prolonged as to create a fixed and lasting condition • A medical emergency that requires prompt and appropriate treatment

12. Some epilepsy triggers In rare cases patients may have one specific trigger that brings on a seizure, for example: Flashing visual stimuli Looking at a particular kind of pattern Hearing a particularpiece of music Reading

13. Epilepsy Syndromes: Examples • Benign epilepsy of childhood with centrotemporal spikes: • Localization-related, idiopathic epilepsy • Age of onset: 3-13 years • Simple partial onset and generalizing to tonic-clonic seizures • No associated illnesses • EEG findings are diagnostic. • Aetiology is genetic. • Prognosis is excellent.

14. Epilepsy Syndromes: Examples • Juvenile myoclonic epilepsy • Generalized, idiopathic with age-related onset • Onset during teenage years • Consists of myoclonic, absence and generalised tonic-clonic seizures • Specific gene locus in chromosome 6p21.2-p11 has been proposed • Treatment is very specific: valproate

15. Epilepsy Syndromes: Examples • Infantile spasms (West’s syndrome) • Generalised, symptomatic and/or Idiopathic • Ages of 4-12 months • Characterized by a quick spasm that consists of flexion at the neck, waist, arms and legs. May occur a hundred times a day • Impairment in psychomotor development • 20% die before 5 years of age; of the survivors 75%-93% are mentally retarded; 25% of these will develop Lennox-Gastaut syndrome

16. Epilepsy Syndromes: Examples • Lennox-Gastaut Syndrome • Generalized, idiopathic and/or symptomatic • Devastating disorder in children (1-8 years) with mixed types of seizures and progressive mental retardation • Seizures include tonic, tonic-clonic, atypical absence, myoclonic and atonic seizures • Cognitive deficit is present and may be associated with behavioural problems • Prognosis is poor and response to AED therapy generally unsatisfactory

17. Incidence of seizure types Generalised tonic-clonic 23.0% Complex partial 36.0% Other generalised 8.0% Absence 6.0% Simple partial 14.0% Myoclonic 3.0% Unclassified 3.0% Partial unknown 7.0%

18. Causes of epilepsy ?

19. Disruption of the balance between excitation and inhibition Lack of inhibition Excess excitation epileptic seizures epileptic seizures

20. Formation of epileptic seizures Hughlings Jackson An abnormal synchronous and sustained activity (overexcitation) in a group of nerve cells Epileptogenic focus Interictal activity Recruitment of surrounding, normal nerve cells into a synchronous pattern of larger abnormal activity Ictal activity Epileptic seizure

21. Predisposing factors • Disturbed levels of body water/electrolytes:– ‘water intoxication’/hyponatraemia– dehydration/hypernatraemia– hypocalcaemia– hypomagnesia • Disturbed levels of blood glucose:– hypoglycaemia • Altered blood gases:– reduction in oxygen supply to the brain, via e.g. asphyxia, heart attack, head injury, stroke • Raised body temperature:– febrile convulsions

22. Predisposing factors • Altered sleep patterns:– sleep deprivation • Hormonal disturbance:– thyroid disturbance– sex hormones • Toxicity:– accumulation of toxic waste due to renal failure– congenital metabolic disorders e.g. phenylketonuria– poisoning or drug overdose

23. Etiological categories of epilepsy • Idiopathic – No identifiable cause, assumed to have a probable genetic basis • Cryptogenic – No cause is found, but there may be an undiscovered physical cause which has yet to be found • Symptomatic – A cause for the condition can be found (e.g. head injury, scarring due to infections in the brain, stroke, brain tumor).

24. Aetiology of epilepsy Degenerative brain disorder 3.5% Infection 2.5% Neoplasm 4.1% Idiopathic and cryptogenic epilepsy 65.5% Vascular injury 10.9% Trauma 5.5% Congenital causes 8.0%

25. 100 Others 90 80 Degenerative 70 Cerebrovascular 60 Proportion of cases (%) Brain tumour 50 40 Trauma 30 Infection 20 10 Development 0 0–4 5–14 15–24 25–44 45–64 65+ Symptomatic seizures in different age groups

26. Diagnosis of epilepsy

27. Diagnosis/evaluation of a seizure • History taking • Electroencephalography (EEG) • Brain images (CT scan, MRI)

28. K-complex • Lambda complex • Mu rhythm • Spike • Sharp waves • Repetitive spike- and-wave activity • Sleep spindle • Vertex sharp wave • Polyspike discharge Normal Specific EEG wave types EEG morphologies

29. EEG activation techniques • Hyperventilation • Photic stimulation • EEG during sleep/awakening • EEG after sleep deprivation • Ambulatory EEG monitoring • Other sensory stimuli

30. Epidemiology

31. Prevalence of epilepsy is approximately 6 to 8 per 1000 population in the United States. • Affects about 45 million people worldwide.

32. Epidemiology: prognosis effect of treatment

33. Epidemiology: prognosis Predictors of remission: • young age at onset • young age at diagnosis • generalized seizures • normal neurological examination • idiopathic etiology

34. Epilepsy and quality of life • Burden of epileptic seizures • Chronic drug treatment • Pregnancy • Employment • Driving

35. Treatment

36. Treatment of underlying causes • Not to treat • Trigger avoidance • Drug therapy • Surgery • Vagus nerve stimulation • Ketogenic diet • Complementary therapies

37. Procedure Indication Hemispherectomy Children with severe unilateral epilepsy syndromes such as Rasmussen’s syndrome; such epilepsies usually have some pre-existing loss of motor function on the contralateral side. Subpial transection Partial-onset seizures arising from a region of cortex that is non-resectable. Common surgical procedures

38. Focal resection 1. Sub-dural grid used to localise the site of seizure onset 2. Frontal lobectomy of non-dominant hemisphere (red area indicates the extent of resection)

39. Vagus nerve stimulation VNS lead transmits signals from the generator to the vagus nerve Generator is implanted under the skin in the upper left chest

40. Ketogenic diet • A high fat/low carbohydrate diet • Tried occasionally in children with severe epilepsy syndromes such as Lennox-Gastaut syndrome and generalised myoclonic seizures. The aim is to achieve a state of body chemistry called ‘ketosis and acidosis’.

41. Complementary therapies • Relaxation • Many complementary therapies involve relaxation. Yoga, meditation or other relaxation therapy might help some people to avoid seizures being brought on by stress. • Aromatherapy • Aromatherapy massage can be very relaxing and is liked by many people. Finding a qualified therapist is important as some of the essential oils used can be dangerous.

42. Complementary therapies • Acupuncture • Probably not effective in the control of seizures, but it can be effective in reducing stress and anxiety. Again, a qualified therapist would be recommended. • Biofeedback • Some people can learn a technique which may delay a seizure or prevent them from happening • People with partial seizures are able to learn and use it to prevent the initial seizure from spreading to become generalised. It is most appropriate for people with the kind if partial seizures that start with ‘aura’-type symptoms • E.g. Someone whose simple partial seizures take the form of tingling in the arm may find that rubbing the arm can sometimes stop the seizure developing into a tonic-clonic type

43. Drug therapy

44. 1857 Bromides 1912 Phenobarbital Ethosuximide 1937 Phenytoin 50ies Carbamazepine 1960 Benzodiazepine 70’s Valproate 1989 Zonisamide Vigabatrin 1990 Lamotrigine Oxcarbazepine 1991 Felbamate 1993 Gabapentin 1995 Topiramate 1996 Tiagabine 1999 Levetiracetam AED - History

45. Standard New Phenytoin (PHT), Pfizer (Dilantin) Felbamate (FBM), Carter-Wallace Carbamazepine (CBZ), Novartis (Tegretol) Vigabatrin (VGB), Aventis(Sabril) Sodium valproate (VPA), Sanofi Synthelabo (Depakine) Lamotrigine (LTG), GSK(Lamictal) Gabapentin (GBP), Pfizer(Neurontin) Ethosuximide (ESM), Pfizer Topiramate (TPM), Janssen-Cilag(Topamax) Barbiturates Phenobarbital (PB) Primidone (PRM) Tiagabine (TGB), Sanofi Synthelabo(Gabatril) Oxcarbazepine (OCBZ), Novartis(Trileptal) Benzodiazepines Clonazepam (CZP) Clobazam (CLB) Zonisamide (ZNS), Athena Generations of AEDs

46. Agent Partial 2o gen-eralised Tonic-clonic Absence Myo-clonic Lennox-Gastaut Infantile spasms CBZ + + + – – 0 0 VPA + + + + + + + PHT + + + – – 0 0 ESM 0 0 0 + 0 0 0 PB + + + 0 ?+ ? ? PRM + + + 0 ? ? ? CZP + + + ? + ?+ ?+ CLB + + + ? + + ?+ Standard AEDs: efficacy against common seizure types and syndromes Seizure type Key: + proven efficacy, ?+ probable efficacy, 0 ineffective, – worsens control ? effect unknown

47. Agent Partial 2o gen-eralised Tonic-clonic Absence Myo-clonic Lennox-Gastaut Infantile spasms LTG + + + + + + ?+ GBP + + ?+ 0 ?– ? ? VGB + + ?+ – – ? + OCBZ + + + – – 0 0 TPM + + + ? + + ? TGB + + ? ? ? ? ? FBM + + ?+ ?+ ? + ? New AEDs: efficacy against common seizure types and syndromes Seizure type Key: + proven efficacy, ?+ probable efficacy, 0 ineffective, – worsens control, ? effect unknown

48. Tolerability • Dose-related side effects • Idiosyncratic side effects • Chronic side effects • Drug interactions • Teratogenicity

49. Modes of action • Decreased excitation – via blockade of sodium channels, interaction with voltage-sensitive calcium channels or blockade of glutamate receptors. • Increased inhibition – via an increase in the concentration of GABA in the synaptic cleft.

50. Na + Na + Ca Ca 2+ 2+ Ca 2+ Na Ca + 2+ Na + Blocking presynaptic glutamate release Treated epileptic neurone Untreated epileptic neurone AED blocks Na+ and Ca2+ channels Synaptic vesicle (glutamate neurotransmitter) Na+ Na+ Ca2+ Ca2+ Presynaptic neurone Presynaptic neurone Glutamate released in response to Na+ and Ca2+influx into the presynaptic neurone Stabilised presynaptic neurone