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![Acute Vs Chronic epileptogenesis
Acute process initiating a seizure
- [Na+], [K+], [Ca++], GABA, Glutamate
Chronic process converting normal brain in
to epileptic brain
- Changes in gene expression
- Changes in receptors, transporters, ion
channels
- Plasticity
31](https://image.slidesharecdn.com/epilepsy1-230820083036-5afbdca4/85/Epilepsy1-ppt-31-320.jpg)
Epilepsy1.ppt
- 1. Epilepsy One of theoldest Known conditions Dr. Krishna Mohan Rao, MD., D.M Professor of Neurology 1
- 2. History Epilepsy hasbeen known since antiquity. Mention has been made about epilepsy in ancient Indian and Chinese texts. The word epilepsy is derived from the Greek verb epilambanein meaning to be seized, to be taken hold of, or to be attacked. 19th century neurologist Hughlings Jackson suggested “a sudden excessive disorderly discharge of cerebral neurons” as the cause of epileptic seizures 2
- 3. Famous people withe pilepsy Alexander the Great Alfred Nobel Hercules Greek Hero Julius Caesar 3
- 4. Definitions Seizure Paroxysmal neurological dysfunctiondue to abnormal, excessive synchronous discharge of a population of cerebral neurons. (Cerebral dysrhythmia ) Seizures usually brief (< 5 min) and stop spontaneously Convulsion, ictus, event, spell, attack and fit are used to refer to seizures. Commonly generated in cortex and hippocampus, may also b e subcortical Epilepsy Group of neurologic conditions, characterized by recurrent unprovoked seizures with the resultant neurobiological, cognitive, social and psychological consequences. A common operational definition of epilepsy is two or more unprovoked seizures occurring more than 24 hrs apart. 4
- 5. Types of CerebralDysrhythmia Acute Complication of acute CNS insult Self limited Require short term treatment Chronic (recurrent) : Epilepsy Continuous : Status Epilepticus 5
- 6. Definition of Epilepsy Seizures are symptoms, while epilepsy is a disease, so those terms should not be used interchangeably Epilepsy = “seizure disorder” Epilepsy is a syndromic disease Each epilepsy syndrome is determined based on; Type of seizures, age at seizure onset, family history, physical exam, EEG findings, and neuroimaging 6
- 7. Epidemiology of Seizures andEpilepsy Seizures – Incidence: approximately 80/100,000 / yr – Lifetime prevalence: 9% (1/3 benign febrile convulsions) – Almost 1% of the population will develop a single, unprovoked Seizure – 2% will develop Seizures due to acute CNS insults Epilepsy – Incidence: approximately 45/100,000 /yr – Lifetime risk of developing Epilepsy to age 80: 3.4% – Point prevalence: 0.5-1% 7
- 8. Epilepsy is asymptom of numerous disorders, but in the majority of sufferers the cause remains unclear despite careful history taking,examination and investigation! Any process that alters the structure (macroscopic or microscopic) or the function of the brain neurons can cause epilepsy. Etiology of Epilepsy
- 9. Age group by% all first seizures o ccurring in each age group Age groups First seizures occurring - % 0-9 47 10-19 30 20-29 13 30-39 6 40+ 4 9 50% of all cases develop before 10 years of age.
- 10. Hypoxia Hypoglycaemia Hypocalcaemia Febrile Seizures Intracranial Infections Birth trauma Intracranial haemorrhage Congenital anomalies Tuberoussclerosis Storage diseases 1 5 10 0 20 Head Injuries Drugs and alcohol Genetic epilepsies Cerebral tumours 60 Cerebrovascular degenerations Age (years) Causes of Seizures by Age
- 11. Etiology of Seizures Seizures are either provoked or unprovoked Provoked Seizures or Symptomatic : Triggered b y certain provoking factors in otherwise healthy br ain – Metabolic abnormalities (hypoglycemia and hyperglycemia, hyponatremia, hypocalcemia) – Alcohol withdrawal – Acute neurological insult (infection, stroke, trauma) – Illicit drug intoxication and withdrawal – Prescribed medications that lower seizure threshold (theophylline, TCA) – High fever in children Unprovoked Seizures : Occur in the setting of persistent brain pathology 11
- 12. Seizure Precipitants • Metabolicand Electrolyte imbalance (Low less often high blood glucose, low sodium, low calcium, low magnesium) •Stimulant or other proconvulsant toxicity (i.e., cocaine) •Sedative (i.e., valium or alcohol) withdrawal •Sleep deprivation •AED medication reduction or inadequate AED treatment • Hormonal variations • Stress • Fever or systemic infection • Concussion and/or closed head injury 12
- 13. Partial Seizures GeneralizedSeizures Simple Partial Seizures (SPS) Motor oWith march oWithout march oVersive oPostural oPhonatory Sensory oSomatosensory oOlfactory oVisual oAuditory oGustatory oVertiginous Autonomic Psychiatric oDysphasic oDéjà vu or jamais vu oCognitive oAffective oIllusions oStructured hallucinations Complex Partial Seizures (CPS) –With automatism –Without automatism Secondary Generalized Tonic-Clonic Tonic-Clonic (primary tonic-clonic) Absence Myoclonic Clonic Tonic Atonic Atypical Absence Infantile Spasm 13 ILAE Classification of Seizures
- 14. ILAE Classification ofEpilepsy Localization-Related (named by location) Generalized (named by disease) Idiopathic Benign Rolandic epilepsy (Benign childhood epilepsy with centro-temporal spikes) Benign occipital epilepsy of childhood Autosomal dominant nocturnal frontal lobe epilepsy Primary Reading Epilepsy Benign Neonatal Convulsions (+/- familial) Benign myoclonic epilepsy in infancy Childhood absence epilepsy Juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with GTCs on awakening Some reflex epilepsies Symptomatic Temporal lobe Frontal lobe Parietal lobe Occipital lobe (Rasmussen’s encephalitis) (Most Reflex epilepsies) Early myoclonic encephalopathy Early infantile epileptic encephalopathy with suppression- burst (Ohtahara’s syndrome) Cortical abnormalities -malformations -dysplasias Metabolic abnormalities - amino acidurias - organic acidurias - mitochondrial diseases - progressive encephalopathies of childhood West’s Syndrome Lennox-Gastaut Syndrome Cryptogenic (Any occurrence of partial seizures without obvious pathology.) Epilepsy with myoclonic-astatic seizures Epilepsy with myoclonic absence
- 15. Epilepsy - Classification Focal seizures – account for 80% of adult epilepsies - Simple partial seizures - Complex partial seizures - Partial seizures secondarilly - generalised Generalised seizures Unclassified seizures 15 Asynchronous burst firing in some hippocampal and cortical neurons Asynchronous burst firing in abnormal thalamocortical interaction
- 16. Localization of PartialSeizure Focus 70% 10% 20% 16
- 17. Simple Partial Focal onset Aura is commo n No alteration of consciousness May secondaril y generalize
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- 19. Complex Partial Aurais common – Represents the ictal onset – Stereotypical, but may be difficult to describe Absence or alteration of consciousness Automatisms Amnesia Postictal confusion May secondarily generalize 19
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- 21. Absence seizures (Petit-mal seizures) Brief stare with unresponsiveness May have associated eye flutter or simple automatisms Sudden onset with arrest of activity No aura or postictal confusion Generalized 3 per second spike and wave 80% will experience resolution with age 20% will have convulsive seizures. 21
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- 23. Absence Seizure 3 Hzspike and wave 23
- 24. Primary Generalized Convulsive No warning; abrupt onset Tonic, clonic, tonic-clonic or clonic-tonic- clonic activity Bowel and bladder incontinence common Postictal unresponsiveness or confusion Generalized spike and wave 24
- 25. Generalized Tonic-Clonic Seizures Stages(Grandmal) Prodrome Aura Tonic Phase Clonic phase Postictal unconsciousness and hypotonia Postictal neurological deficit (Todd’s paralysis) Sleepiness Return to normal functioning. 25
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- 28. Myoclonic seizures Brief contraction of a muscle, muscle group, or several muscle groups caused by cortical discharge Can be single or repetitive Severity range from imperceptible twitch to severe jerking (may result in propulsion of hand-held objec ts/ fall) Recovery is immediate and conciousness is not lost Myoclonus can be induced by action, noise, startle, photic stimulation or percussion If occuring as part of idiopathic generalised seizure s, myoclonus occurs on waking or on drop ping off to sleep May occur at any age EEG: generalised spike/ spike and wave/ polyspike and wave, often assymmetrical and irregular, frequently predominant in frontal area. Interictal EE G varies depending on underlying epil epsy aetiology.
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- 30. Pathophysiology Genetic causes ofepilepsy Gene defects affecting neuronal excitability - Ion channel defects Genes encoding development - Neuronal Migrational disorders Genes encoding cerebral energy metabolism - Mitochondrial disorders Genetic neurodegenerative disorders - Progressive myoclonic epilepsies 30
- 31. Acute Vs Chronicepileptogenesis Acute process initiating a seizure - [Na+], [K+], [Ca++], GABA, Glutamate Chronic process converting normal brain in to epileptic brain - Changes in gene expression - Changes in receptors, transporters, ion channels - Plasticity 31
- 32. Basic Mechanisms ofEpilepsy In epileptic tissue there is an imbalance between excitation and inhibition that enhances and allows for a prolonged discharge. There is also augmentation of mechanisms that synchronize neuronal discharges. 32
- 33. Evaluation of aFirst Seizur e History & physical exam. Blood tests: CBC, electrolytes, glucose, Calcium, Magnesium, phosphate, hepatic and renal function Lumbar puncture only if meningitis or encephalitis suspected and potential for brain herniation is ruled out Blood or urine screen for drugs Electroencephalogram CT or MR brain scan 33
- 34. EEG 34 Discovered by Hans Berger1929 Electrical activity recorded by electrodes placed on the scalp
- 35. EEG Ictal vsinterictal Distinguish from epileptiform convulsions from non-ictal behavioural manifestations 50 % epilepsy patients show interictal epileptiform discharges in the first EEG 10% will not show any significant abnormality 0.5% healthy individuals can have abnormal recordings Frequent seizures more likely to have a positive yield EEG within 24 hours can have a yield of 50% 35
- 36. EEG 36 To increase yield: Sleep Hyperventilation Photicstimulation Repeat recordings increases yield to 69-77%
- 37. EEG Abnormalities Backgroundabnormalities: significant asymmetries and/or degree of slowing inappropriate for clinical state or age Interictal abnormalities associated with seizures and epilepsy – Spikes (< 70 m sec) – Sharp waves (~70 – 200 msec) – Spike-wave complexes May be focal, lateralized, generalized 37
- 38. Neuroimaging Detects abnormalitiesin 21-37% pts with epilepsy MRI is modality of choice when there is a suggestion of an underlying focal process If not available or contraindicated, CT is adequate to assess for gross pathology 38
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- 40. Single Photon EmissionCT (SPECT) Positron Emission Tomography (PET) MRI spectroscopy Functional MRI Functional cerebral changes Useful adjuncts in candidate epileptic surgery
- 41. Other tests Prolactin(PRL) Elevated PRL measured within 20 min of a suspected event, should be considered a useful adjunct to differentiate GTC / CPS from psychogenic non-epile ptic seizure among adults A normal PRL should not be used to distinguish seizure from syncop e. 41
- 42. Follow-on tests Measuringdrug levels Toxicity vs non-compliance Avoid ‘treating’ drug levels 42
- 43. First Aid Tonic-Clonic Seizure Turn person on side with face turned toward ground to keep airway clear, protect from nearby hazards Transfer to hospital needed for: – Multiple seizures or status epilepticus – Person is pregnant, injured, diabetic – New onset seizures DO NOT put any object in mouth or restrain 43
- 44. Medical Treatment of FirstSeizure Whether to treat first seizure is controversial 16-62% will recur within 5 years Relapse rate might be reduced by antiepileptic drug treatment Abnormal imaging, abnormal neurological exam, abnormal EEG or family history increase relapse risk Quality of life issues are important 44
- 45. When to initiateAED treatment? General Principles Usually after two or more unprovoked seizur es Risks – benefit considerations Likelihood of recurrence - CNS structural abnormality - Specific epilepsy syndromes e.g. JME Social consequence of recurrence Infrequent seizures Precipitating lifestyle factors Anticipated poor compliance TREAT after 1 seizure WAIT-and-SEE after 1 or 2 seizures
- 46. Strategies for managingnewly diagnosed epilepsy Newly diagnosed epilepsy First drug Second drug Refractory Rational duotherapy Surgical assessment Seizure-free Seizure-free 47% 13% 40%
- 47. Ten commandments inthe pharmacological treatment of epilepsy Choose the correct drug for the seizure type or epilepsy syndrome Start at low dosage and increase incrementally Titrate slowly to allow tolerance to central nervous system side-effects Keep the regimen simple with once- or twice-daily dosing, if possible Measure drug concentration when seizures are controlled or if control is not readily obtained (if possible)
- 48. Counsel thepatient early regarding the implications of the diagnosis and the prophylactic nature of drug therapy Try two reasonable mono-therapy options b efore adding a second drug When seizures persist, combine the best tolerated first-line drug with one of the newer agents depending on seizure type and mechanism of action Simplify dose schedules and drug regimens as much as possible in patients receiving poly-pharmacy Aim for the best seizure control consistent with the optimal quality of life in patients with refractory epilepsy
- 49. Non-Drug Treatment/ Lifestyle Modifications Adequate sleep Avoidance of alcohol, stimulants, etc. Avoidance of known precipitants Stress reduction - specific techniques 49
- 50. Therapy of epilepsy Current antiepileptic drugs are effective in controlling seizures in about 75% of patients In 50% of patients we obtain nearly complete eliminations of seizure occurrence In additional 25% of patients we can significantly reduce the frequency and severity of seizures The choice of drugs is based on type of seizures, tolerabilit y of a drug and response to therapy (empiric part) The therapy is often started with the lower dose and the do se is “titrated” gradually thereafter The use of antiepileptics is often limited by their adverse effects 50
- 51. Choosing Antiepileptic Drugs Seizure type / Epilepsy syndrome Comorbid conditions Adverse side effects or events Interactions / other medical conditions Pharmacokinetic profile Cost Efficacy ALL FEMALES (and also consider in males): • Folate 1 - 4 mg/day • MVI • Calcium (1200-1330 mg per day) 51
- 52. Antiepileptic Drug Interactions Drugs that induce metabolism of other drugs: carbamazepine, phenytoin, phenobarbital Drugs that inhibit metabolism of other drugs: valproate, felbamate Drugs that are highly protein bound: valproate,phenytoin, tiagabine, carbamazepine Other drugs may alter metabolism or protein binding of antiepileptic drugs 52
- 53. Classification of Anticonvulsants Classicalor older generation Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Trimethadione Newer generation Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin Others 53
- 54. Classification of Anticonvulsants Actionon Ion Channels Enhance GABA Transmission Inhibit EAA Transmission Na+: Inhibition Phenytoin, Carbamazepine Lamotrigine Topiramate Valproic acid Ca++: Inhibition Ethosuximide Valproic acid Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate Felbamate Topiramate Na+: For general tonic-clonic and partial seizures Ca++: For Absence seizures Most effective in myoclonic but also in tonic-clonic and partial seizures Clonazepam: for Absence 54
- 55. FDA Indications forAEDs: Monotherapy and/or Add-On Therapy Monotherapy Carbamazepine Divalproex ER Ethosuximide Oxcarbazepine Phenobarbital Phenytoin Primidone Lamotrigine1 Felbamate1 Topiramate 1Approved for conversion to monotherapy. Add-On Therapy Carbamazepine Levetiracetam Divalproex ER Gabapentin Ethosuximide Phenytoin Oxcarbazepine Tiagabine Phenobarbital Zonisamide Primidone Physician’s Desk Reference, 2004. 55
- 56. Choices of antiepilepticdrugs in childhood seizure disorders SEIZURE TYPE INITIAL CHOICE SECOND THIRD Tonic-clonic Valproate, carbamazepine Lamotrigine oxcarbazine Phenytoin Myoclonic Valproate Lamotrigine Phenobarbital, clobazam Absence Valproate Lamotrigine, ethosuximide Clobazam Partial Carbamazepine, phenytoin Valproate, gabapentin, oxcarbazine Lamotrigine, vigabatrin, topiramate Infantle spasms Vigabatrin, corticosteroids Valproate Lamotrigine Lennox-Gastaut Valproate Topiramate, lamotrigine Felbamate 56
- 57. Choices of antiepilepticdrugs by type of ad ult seizure disorder Seizure Type Initial Drug Therapy Alternative or Adjunctive Partial (Simple, Complex, secondarily generalized ) Carbamazepine, Phenytoin Valproate Felbamate, Gabapentine Lamotrigine, Zonisamide, Oxacarbazepine Topiramate, Leveteracetam Primary generalized Tonic-clonic Carbamazepine, Phenytoin Valproate Gabapentin, Lamotrigine, Topiramate, Leveteracetam Myoclonic Valproate Clonazepam, Lamotrigine, Leveteracetam Atonic Valproate Clonazepam, Lamotrigine Felbamate Absence Ethosuximide,Valproate Clonazepam, Lamotrigine 57
- 58. Combination antiepileptic regimens forrefractory seizures COMBINATION INDICATION Valproate and lamotrigine or levetiracetam Partial or generalized seizures Valproate and ethosuximide Generalized absence Carbamazepine and valproate Complex partial seizures Vigabatrin and lamotrigine or tiagabine Partial seizures Topiramate and lamotrigine or levetiracetam Numerous types 58
- 59. GENERIC NAME USUAL DOSE CHILDREN, ADULTS mg/Kgmg/day INDICATIONS SERUM HALF LIFE, Hrs EFFECTIVE BLOOD LEVEL, µg/mL Valproic acid 30-60 1000 to 3000 GTC, partial, absence, myoclonic 6-15 50-100 Phenytoin 4-7 300-400 GTC, partial 12-36 10-20 CBZ 20-30 600-120 0 Generalized tonic-clonic, partial 14-25 4-12 Phenobarbital 3-5 90-200 Generalized tonic-clonic, partial 40-120 15-40 Lamotrigine 5-15 300-500 Generalized 15-16 59
- 60. GENERIC NAME USUAL DOSE CHILDREN, ADULTS mg/Kgmg/day INDICATIONS SERUM HALF LIFE, Hrs EFFECTIVE BLOOD LEVEL, µg/mL Topiramate 5-9 100 to 500 GTC,partial, Atypic al absence, myoclonic 20-30 2-25 Gabapentine 30-60 900- 3600 Sec.GTC, partial 5-7 2-20 Levetiracetam 20-30 1000- 3000 Generalized tonic-clonic, partial 6-8 20-60 OXCBZ 8-10 900- 2400 Generalized tonic-clonic, partial 8-10 12-24 Zonisamide 4-8 200-600 Generalized, refractory partial, infantile spasms, Lennox-gastaut 49-69 10-40 60
- 61. GENERIC NAME USUAL DOSE CHILDREN, ADULTS mg/Kgmg/day INDICATIONS SERUM HALF LIFE, Hrs EFFECTIVE BLOOD LEVEL, µg/mL Tiagabine 0.3-1.0 30-45mg/k g GTC, partial, Adjunctive therapy 5-9 5-70 Clobazam 5-10 10-20mg Adjunctive to GTC, partial 10-77 Clonazepam 1-3 0.5 to 4 Adjunctive to GTCS partial , infantile Spasms, LGS, SE 20-80 0.01-0.07 ACTH 40-60 Units/da y Infantile spasms Vigabatrin 40-100 1000-3000 Generalized, refractory partial, infantile spasms, Lennox-gastaut 4-7 7-40 felbamate 45-80 1200-3600 Adjunctive to GTCS, Refractory partial and Lennox Gastaut 20 40-100 61
- 62. Therapeutic drug monitoring Indications for use: Uncontrolled seizures despite administration of greater-than-average doses. Seizure recurrence in a previously controlled patie nt. Documentation of intoxication. Assessment of patient compliance. Documentation of desired results from a dose change or other therapeutic maneuver. Assessment of therapy in patients with infrequent seizures. When precise dosage changes are required. 62
- 63. Duration of therapy& Discontinuing AEDs Seizure freedom for 3 years implies overall >60% chance of successful withdrawal in some epilepsy syndromes. withdrawal of each AED over at least 6 weeks would seem to be a safe approach. Favorable factors Control achieved easily on one drug at low dose – No previous unsuccessful attempts at withdrawal – Normal neurologic exam and EEG – Primary generalized seizures except JME – “Benign” syndrome Consider relative risks/benefits (e.g., driving, pregnan cy) 63
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- 66. Mechanisms governing excitability Basic mechanism of neuronal excitability is the action potential Hyperexcitable state can result from: – Increased excitatory synaptic transmission – Decreased inhibitory neurotransmission – Alteration in voltage-gated ion channels – Alteration in intra or extracellular ion concentrations (favoring depolarization) – Summation of synchronous subthreshold excitatory stimuli 66
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- 69. Seizure-precipitating factors. Seizure Precipitating factors Nonepileptic patients Patients with epilepsy Systemicor Cerebral insults Provoked seizures Acute symptomatic seizures Provocative factors , sleep deprivation Stress, Alcohol, Noncompliance Fatigue Fever Metabolic Menses Specific Trigger Reflex Epilepsies 69
- 70. Juvenile Myoclonic Epilepsyof janz (JMEJ) Myoclonic seizures with onset in late childhood or adolescence May develop generalized convulsive or absence seizures Interictal EEG shows normal back- ground with polyspike-wave bursts Autosomal dominant inheritance – Chromosome 6 70
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- 72. Juvenile Myoclonic Epilepsy Diagnosis often delayed Patients rarely report myoclonic jerks Absence seizures occur in 25% Myoclonic seizures precede tonic-clonic seizures by 2-3 years Tonic-clonic seizures typically occur when patient reaches 10-17 years 72