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1. Seizure disorders Medina Fedlu (MD, Neurologist)

2. Out line: Definition Epidemiology Mechanism of seizure Etiologies Classification Patient approach Special situations References

3. Definitions Seizure - A paroxysmal event due to abnormal excessive hyper- synchronous discharges from an aggregate of CNS neurons . Epilepsy (1) at least two unprovoked (or reflex) seizures occurring greater than 24 hours apart, or (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures occurring over the next 10 years, or (3) diagnosis of an epilepsy syndrome

4. Active epilepsy: At least one seizure in the previous 5 year Epilepsy in remission: No seizure in the previous 5 years . Epilepsy syndrome: Disorders in which epilepsy is a predominant feature and there is sufficient evidence to suggest a common underlying mechanism .

5. Epidemiology Overall prevalence = 5-30 person / 1000 Ethiopia -5.2/1000 population Incidence=0.3-0.5% 5-10 % of popn have at least one seizure. Sex : Male: Female=1.5:1 Age: Bimodal distribution-Childhood and late adulthood

6. Classification of Seizures Importance Focused diagnostic approach for etiology Appropriate treatment Prognosis International League Against Epilepsy (ILAE): - based on Clinical Feature & EEG. Partial (focal) Seizure :- - Seizure activity restricted to discrete areas of the cerebral cortex. - cause is usually structural . Generalized Seizures:- - simultaneously involve diffuse regions of the brain . - cellular, biochemical, or structural.

7. 1.Focal seizure Classified into 1.1,Focal aware seizures (FAS ) if awareness is totally preserved for the whole duration of the seizure 1.2,Focal impaired awareness seizures (FIAS ) if there is any alteration of awareness during any part of the seizure. 1.3,focal to bilateral tonic- clonic seizures (FBTCS ). Secondarily generalized seizures

8. 1.1,Focal aware seizures (FAS) Can be 1) Motor Jacksonian march -R epresents the spread of seizure activity over a progressively larger region of motor cortex. Todd’s paralysis - localized paresis for minutes to many hours in the involved region following the seizure. Epilepsia partialis continua - Seizure may continue for hours or days . 2) Non motor -Sensory..( Visual,Auditary,olfactory,gustatary ) - somato sensory ( parasthesia ) -autonomic(flushing, sweating ) -psychic

9. 1.2,Focal impaired awareness seizures (FIAS) Loss of consciousness is characteristic Due to ictal discharge spread to involve the limbic network Begins with aura(Focal aware seizure) Olfactory aura : arises from the uncus hence called uncinate fits. Associated with tumors. Ictal phase often starts with behavioral arrest accompanied by automatism There may be antrograde amnesia or aphasia following seizure Origin : Temporal lobe : 70-80% Frontal lobe Rarely parietal and occipital lobe

10. 1.3,Focal to bilateral tonic clonic seizures Mistaken for primary generalized seizure Ask history suggesting aura-Focal aware seizure Focus is usually frontal lobe Usually tonic- clonic EEG to establish the diagnosis Treatment is different for both primary and secondary generalized

11. 2.Generalized seizure Includes Generalized tonic clonic Absence Atonic Myoclonic Tonic Clonic

12. 2.Generalized seizure . A . GTC (Grand mal) Main seizure type-10% of all epilepsy Common seizure type in metabolic derangements No aura : Vague premonitory symptoms-hours before Tonic- clonic activity . Tonic muscle contraction produces teeth clenching and rigidity (tonic phase ) followed by rhythmic muscular jerking( clonic phase). usually symmetric Strained cry Cyanosis- common

13. b. Absence (petit mal) Brief loss of consciousness-seconds No loss of postural muscle control,No post ictal confusion Motor manifestation: Bilateral blinking of eye lids Chewing movements Coexist with GTC or myoclonic May occur hundreds of times a day EEG:3 Hz generalized spikes-and-wave-a Provoked by hyperventilation Main seizure type in children (4-8 yr )- 15-20% First clue-day dreaming or decreased school performance Treatment response is very good

14. Atypical absence Gradual in onset, longer duration Less abrupt to resolve Localizing findings (motor, autonomic) EEG: generalized slow spike-wave pattern<2.5 sec Less responsive to AED Cause: multifocal structural lesion Seen with mental retardation

15. c. Atonic seizure (drop attack) Loss of postural muscle tone:1-2 sec Quick head drop, nodding, collapse Brief loss of consciousness No post ictal confusion EEG: Brief generalized spike-wave then diffuse slow waves Cause: diffuse encephalopathy Seen in children with developmental delay Uncommon

16. d . Myoclonic seizure Sudden brief muscle contraction Brief, unpredictable jerks Any limb, eyes, head, trunk Sometimes alone; often associated with other generalized seizure types Focal, multi-focal, generalized Predominant feature of JME EEG: Bilateral spikes-wave synchronous with myoclonus Cause: metabolic, degenerative, anoxic brain damage (physiological during sleep)

17. Epilepsy syndromes Distinctive clinical syndromes with common underlying mechanism through clinical, EEG, radiological, or genetic observation. 1.Rolandic (benign partial epilepsy of childhood) Age: 4-13 yr Nocturnal onset EEG : epileptic discharges central and mid temporal region. Subsides mid to late adolescence

18. 2.JME unknown cause GTC (1/3 absence) of early adolescence(8-20 yr) with bilateral myoclonic jerk s Early morning after awakening Provoked by sleep deprivation Consciousness is preserved Family history of epilepsy; polygenic cause. EEG: Poly spike-wave and 4-6 HZ spike-wave Benign; complete remission uncommon. Respond well to appropriate Rx.

19. 3.LENNOX-GASTAUT SYNDROME/LGS/ Common in children Triad: 1.Multiple Seizure types (usually GTC, atonic , & atypical absence). 2.EEG: slow (<3Hz) spike-and-wave. 3.Impaired cognitive function (most cases). Cause: Developmental abnormality Structural lesion Poor prognosis –refractory seizure

20. 4 .MESIAL TEMPORAL LOBE EPILEPSY SYNDROME./MTLE/ Most common epilepsy syndrome in adults (40% of cases of epilepsy) Distinctive clinical, EEG, & pathologic features. Age of onset: late childhood or adolescence Often with History of febrile seizure, family History of epilepsy Focal impaired awarness seizure with some secondary generalization Refractory for medical management Responds well for surgery EEG : Spike on anterior temporal region

21. 5. Post traumatic epilepsy - 1-2 years after injury Type of seizure:2/3 focal or second generalized Early seizure (first 1-2 weeks); acute reaction; Impact seizure Late seizure (after 10-14 days): increased risk Other risk factors: Risk is 40-50% Penetrating injury Depressed skull fracture IC hemorrhage Prolonged coma (>30 min) or amnesia

22. 6.Febrile seizure Increases future seizure risk :2-3% With risk factors: 10-13% Not associated with cognitive or behavioral problem prevalence 3-5%. febrile illness; No CNS infection + family History (febrile seizure/epilepsy) 3mo-5yr(peak incid.:18mo-2yr) generalized, tonic- clonic Seizure or focal

23. Causes and predisposing factors Epileptogenesis : -The process of conversion of normal brain to epilepsy producing one Both genetic or acquired factors influence the seizure threshold .

24. CAUSES ACCORDING TO AGE . Age determines the incidence & likely etiology of seizures. childhood : - Ideopathic [67.6 %] , Congenital[20.0 %], trauma [ 4.7%], infection [ 4.0%], -metabolic , vascular, neoplastic, etc . Febrile seizure

25. Adults : - Ideopathic [ 55.25%] - Vascular [ 15.2%]. - Trauma ( 9.9%). -CNS tumors [ 10.5%] -Degenerative diseases. - Alcohol withdrawal. -Infections, degenerative, etc

26. Broad age range: -Electrolyte imbalance. -Hypo- / hyperglycemia. - Hepatic / renal failure. -Endocrine disorders. -Hematological disorders. - Vasculitides .

27. Patient approach Diagnosis is based on C/F and investigations. History Involve family members Includes: Seizure description by the patient and by the attndant ( ictal phase,pre and post ictal phase) Risk factors: trauma, stroke, tumor,… Predispositions : History of febrile Seizures, family History. Precipitating factors :

28. Physical examination Signs of infection, systemic illness Head trauma :alcohol /illicit drug use CVS: vascular/cardiac disease Limb asymmetry- early brain injury Integumentary CNS: Complete neurologic evaluation: .Mental state –memory, language, Visual , motor , sensor y * Signs of cerebral hemisphere disease. * post- ictal (Todd’s) paralysis. * tonic deviation of the eyes during the Seizure. * Transient cessation of activity & “glassy stare”.

29. INVESTIGATIONS 1.Blood studies: CBC, ESR,Electrolytes Chemistry: Glucose, LFT, RFT Serum or urine drug level / Toxicology screen blood culture 2.Lumbar puncture 3.ECG/echo: if cardiovascular risk factors 4.BRAIN IMAGING. MRI :- superior to CT. 5. Electroencephalography (EEG):

30. Differential diagnosis Syncope Migraine ( basilar artery migraine) Psychogenic seizure: Panic attack/hyperventilation

31. TABLE . Clinical differences between syncope and seizures Feature Syncope Seizure Posture Usually upright Any posture Muscle tone Usually flaccid Increased in some seizures Onset Gradual—visual symptoms common Sudden with or without aura Duration Brief (10–30 seconds) 1–3 minutes Incontinence Rare Often Tongue biting/injury Rare May occur Recovery Seconds Minutes Postictal confusion Rare Common Postictal focal sign (hemi paresis, language) No May be present

32. MANAGEMENT 1.Rx of Underlying Conditions 2. Avoidance of Precipitating Factors 3.Suppression of recurrence:- 4.prevention and Rx of complications

33. INITIATION OF AED THERAPY. Goal: Eliminate or minimize frequency of seizure Avoid side effects Maintain or restore normal vocational or psychological adjustments Educate pt. about the approach to Rx

34. Mechanism of drug action Blocks initiation or spread of seizure by modifying the activity of ion channels and neurotransmitter Na + dependent AP inhibitors : Phenytoin Carbamazepine, Lamotrigine , Topiramate , Zonisamide Ca +2 channel inhibitors : Phenytoin Decreasing glutamate release : Lamotrigine Potentation of GABA receptor function Availability of GABA : Valproate, Gabapentine , Tiagabine Inhibition of T-type Ca +2 channels in thalamus

35. When to start Indications for initiation of antiepileptic drugs: 1. Recurrent seizures of unknown etiology or a known cause that can’t be reversed 2. A single seizure with identified epilepthogenic lesion (e.g. Tumor, Infection trauma) 3.Risk factors associated with recurrent seizures A) an abnormal neurological examination B) Presented as status epilepticus C) Post- ictal Todd’s paralysis D ) Strong Family history of seizures E) Abnormal EEG F) aura and focal onset seizures 4.Issues like employment

36. AED drug selection Factors affecting initial drug selection:- Type of seizure Side effect Ease of dosing Cost Efficacy Availability Optimal dose: trial & error. Introduce slowly with lowest doses. Monitor Seizure control clinically. Monitor side effects.

37. Table . Antiepileptic Drugs of Choice Primary Generalized Tonic- Clonic Focal Absence Atypical Absence, Myoclonic, Atonic   First-Line Valproic acid Lamotrigine Carbamazepine Phenytoin Valproic acid Lamotrigine Ethosuximide Valproic acid Valproic acid   Alternatives Phenytoin Carbamazepine Topiramate Zonisamide b Primidone Phenobarbital Felbamate Gabapentin b Topiramate b Tiagabine b Zonisamide b Levetiracetam b Primidone Phenobarbital Lamotrigine Clonazepam Lamotrigine Topiramate b Clonazepam Felbamate   b As adjunctive therapy.

38. Some idiosyncratic unwanted effects of anticonvulsant drugs Drug Non-dose-related side effects phenytoine Rashes Blood dyscrasias Lympadenopatty Toxic epidermal necrolysis Carbamazepin Rashes Blood dyscrasias , particularly severe Leucopenea Toxic epidermal necrolysi Sodium valproate Anorexia Hair loss Liver damage Lamotrigine Toxic epidermal necrolysis Vigabatrin Retinal damage (visual field constriction) psychological change

39. Monitoring Clinically: Seizure frequency Toxicity Response at 5yr 61%,at 20yr may reach 70% Combination treatment not rational: Structural lesion, multiple seizure type, developmental delay –Not responding to monotherapy (1/3) Drug level: Toxic side effect or if seizure is controlled

40. When to discontinue ~70% of children & 60% of adults with complete medical control Favorable Pt profile for Sz freedom after D/C 1)complete medical control of Sz for 1-5yr, 2)Single Sz type, either focal or generalized 3)Normal neurologic exam, including intelligence 4 ) Normal EEG. -> A patient who fulfills the above all and motivated ,understands risk & benefits can withdraw treatment after two years

41. SPETIAL SITUATIONS Refractory Epilepsy STATUS EPILEPTICUS WOMEN AND EPILEPSY PSYCHOSOCIAL ISSUES

42. A. Refractory Epilepsy seizures persist in: -20% of primary generalized epilepsy -up to 35% of cases of Focal epilepsy. Rigorous attention to: - diagnosis - drug compliance - trials of different drugs -consideration of surgical treatment

43. Rx OF REFRACTORY EPILEPSY: 1. Combination of drugs 2. Surgical 3.VAGUS NERVE STIMULATION.

44. B . STATUS EPILEPTICUS Continuous seizures for > 5min OR repetitive, discrete Szs with impaired consciousness in the interictal period. 50,000-60,000 cases in the U.S. each year. SE is most common at the extremes of age. 135- 155/ 100,000 in infants. 63-86 per 100,000 in those older than 60.

45. Causes:- -anticonvulsant withdrawal or - metabolic disturbances, - drug toxicity, - head trauma, - CNS infection, - CNS tumors, - refractory epilepsy.

46. CLASSIFICATION of SE

47. Dx : Clinical – History of epilepsy - overt tonic- clonic Szs , - automatic mov’ts or myoclonus - paroxysms of ↑ BP, ↑ PR - interictal loss of consciousness. EEG - continuous Sz activity.

48. IMAGING STUDIES Non contrast head CT in the ER is the standard of care for a person presenting with seizures. Imaging can be differed in patients with a known underlying epilepsy. MRI is recommended for a better anatomic detail.

49. TREATMENT of status ABCs of life support: draw blood for serum chemistry , hematologic values, AED concentrations, finger stick for blood glucose level, Administer lorazepam 0.1 mg/kg Start EEG but treatment should not be delayed Monitoring: V/S ,ECG, oximetry , EEG,ABG.

50. C.WOMEN AND EPILEPSY. 1. CATAMENIAL EPILEPSY:. - A marked ↑ in Sz frequency around the menses time. -Due to effects of hormones or altered drug levels. Rx - Acetazolamide 250-500mg/d . - ↑ antiepileptic dosage. - OCP. 2. PREGNANCY: - Sz frequency: unchanged ( 50%), ↑ (30) ↓ (20%). Causes - endocrine effects on the CNS, - Δ in drug pharmacokinetics, - Δ in drug compliance. Frequent evaluation; monitor serum levels

51. . Incidence of fetal abnormalities:- 2-3% ( healthy women ). 5-6% ( epileptic mothers ). Cleft lip, cleft palate, facial dysmorphism , cardiac defects, digital hypoplasia , and nail dysplasia → phenytoin , valproic acid and carbamazepine . Carbamazepine , valproic acid : neural tube defects in1-2% [ baseline: 0.5-1.0% ]. MANAGEMENT . - Mono Rx , at the lowest possible effective dose, if (esp. during the 1 st trimester). - Folate 1-4mg/d. -Oral vit K ,20mg/d last 2wks of pregnancy and for the infant 1mg at birth. .

52. D. Epilepsy in the Elderly Some 25% of new cases of epilepsy develop over the age of 65. Many patients have cerebrovascular disease, neurodegenerative conditions or brain tumor. The onset of seizures commonly leads to loss of independence and to physical injuries and their complications. (e.g. subdural hematomas). With adequate anticonvulsant, control of seizures can be achieved in 70 % of this vulnerable population. Gabapentine and Lamotrigine : well tolerated

53. E.PSYCHOSOCIAL ISSUES STIGMA: social isolation Unemployment DRIVING: -Patients should not drive while anticonvulsant are reduced and for 6 months after stopping them - Careful discussion and full explanation is necessary. Domestic issues are also important: - leaving unlocked the bathroom/lavatory door. -Support groups and information services to patients and their families

54. REFERENCES Harrison: Text book of internal medicine,20 th edition . Bradley's neurology 8 th edition . ILAE 2017 .

55. THANK U!