Epilepsy - Dr. Chandan

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  • Neurotransmitters are substances that are released by the presynaptic nerve terminal at a synapse
    and subsequently bind to specific postsynaptic receptors for that ligand. Ligand binding results in channel
    activation and passage of ions into or out of the cells. The major neurotransmitters in the brain are
    glutamate, gamma-amino-butyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin,
    and histamine. Other molecules, such as neuropeptides and hormones, play modulatory roles that modify
    neurotransmission over longer time periods (Slide 6).
  • Neurotransmitters are substances that are released by the presynaptic nerve terminal at a synapse
    and subsequently bind to specific postsynaptic receptors for that ligand. Ligand binding results in channel
    activation and passage of ions into or out of the cells. The major neurotransmitters in the brain are
    glutamate, gamma-amino-butyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin,
    and histamine. Other molecules, such as neuropeptides and hormones, play modulatory roles that modify
    neurotransmission over longer time periods (Slide 6).
  • Neurotransmitters are substances that are released by the presynaptic nerve terminal at a synapse
    and subsequently bind to specific postsynaptic receptors for that ligand. Ligand binding results in channel
    activation and passage of ions into or out of the cells. The major neurotransmitters in the brain are
    glutamate, gamma-amino-butyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin,
    and histamine. Other molecules, such as neuropeptides and hormones, play modulatory roles that modify
    neurotransmission over longer time periods (Slide 6).
  • Interneurons (e.g., basket cells) are generally considered to be local-circuit cells which influence the activity of nearby neurons. Most principal neurons form excitatory synapses on post-synaptic neurons, while most interneurons form inhibitory synapses on principal cells or other inhibitory neurons. Feed-forward inhibition occurs when an inhibitory neuron receives collateral innervation from an excitatory projection neuron. Since the inhibitory neuron is activated closely in time with the principal cell, feed-forward inhibition serves to inhibit over-activation of the principal cell by the projection neuron. Recurrent inhibition can occur when a principal neuron forms synapses on an inhibitory neuron, which in turn forms synapses back on the principal cells to achieve a negative feedback loop. In this type of feedback inhibition, the excited principal cell recurrently excites interneurons to inhibit the firing of neighboring principal cells, thus preventing the pool of target principal neurons from becoming synchronously over-activated. Slide 4 illustrates schematically both types of inhibition in a local interneuron-granule cell dentate gyrus circuit.
    However, recent work suggests that some interneurons appear to have rather extensive axonal projections, rather than the local, confined axonal structures previously suggested. In some cases, such interneurons mayprovide a very strong synchronization or pacer activity to large groups of neurons.
  • Epilepsy - Dr. Chandan

    1. 1. Epilepsy Presented by : Dr. Chandan
    2. 2. Contents • History • Definition • Mechanism – Neurophysiology • Etiology • C/F • Investigations • Treatment • Epilepsy syndromes • Status and Refractory epilepsy • Epilepsy in Women
    3. 3. History • 400 B.C.: • The Greek physician Hippocrates writes the first book on epilepsy, On the Sacred Disease. • Refuting the idea that epilepsy is a curse or a prophetic power, Hippocrates proves the truth: It's a brain disorder. "It is thus with regard to the disease called Sacred: it appears to me to be nowise more divine nor more sacred than other diseases, but has a natural cause like other affections. . ."
    4. 4. History • 70 A.D.: • In the Gospel According to Mark (9:14-29), Jesus Christ casts out a devil from a young man with epilepsy: "Teacher, I brought you my son, who is possessed by a spirit that has robbed him of speech. Whenever it seizes him, it throws him to the ground. He foams at the mouth, gnashes his teeth, and becomes rigid. I asked your disciples to drive the spirit out, but they could not." (NIV)
    5. 5. History • 1859-1906: • Under the leadership of three English neurologists— • John Hughlings Jackson • Russell Reynolds • Sir William Richard Gowers • the modern medical era of epilepsy begins. In a study, Jackson defines a seizure as "an occasional, an excessive, and a disorderly discharge of nerve tissue on muscles." He also recognizes that seizures can alter consciousness, sensation, and behavior.
    6. 6. History • 1929 • A German psychiatrist named Hans Berger announced to the world • that it was possible to record electric currents generated on the brain, without opening the skull, and to depict them graphically onto a strip of paper. • Berger named this new form of recording as the electroencephalogram (EEG).
    7. 7. DefinitionsDefinitions • Seizure : (Latin sacire, "to take possession of") -paroxysmal event due to – abnormal, excessive, hypersynchronous discharges from an aggregate of CNS neurons. • Epilepsy : ( Greek word epilambanein, meaning to attack or to seize ) – clinical phenomenon rather than a single disease, in which a person has recurrent seizures due to a chronic, underlying process. Harrisons 17th edi
    8. 8. Disease Burden • Epilepsy is affecting at least 50 million people worldwide. • Epilepsy accounts for 1% of the global burden of disease • It knows no geographical, racial or social boundaries.
    9. 9. Mechanism - Neurophysiology • Influx of Na+ and outflow of K+ contribute to membrane depolarization and generation of the action potential • Influx of Ca++ tends to further depolarize the cell • Cl− influx hyperpolarizes the membrane and inhibits action potentials
    10. 10. The dynamic target of seizure control in the management of epilepsy is achieving balance between the factors that influence the excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).
    11. 11. Some antiepileptic drugs stabilize the inactive configuration of the sodium (Na+) channel, preventing high-frequency neuronal firing.
    12. 12. Low-voltage calcium (Ca2+) currents (T-type) are responsible for the rhythmic thalamocortical spike and wave patterns of generalized absence seizures. Some antiepileptic drugs lock these channels, inhibiting the underlying slow depolarizations necessary to generate spike-wave bursts.
    13. 13. The GABA-A receptor mediates chloride (Cl-) influx, leading to hyperpolarizationof the cell and inhibition. Antiepileptic drugs may act to enhance Cl- influx or decrease GABA metabolism.
    14. 14. B-SlideB-Slide 1414 Epilepsy—BasicEpilepsy—Basic NeurophysiologyNeurophysiology  Major Neurotransmitters in the brain: – Glutamate – GABA – Acetylcholine – Dopamine – Serotonin – Histamine – Other modulators: neuropeptides, hormones
    15. 15. B-SlideB-Slide 1515 Epilepsy—BasicEpilepsy—Basic NeurophysiologyNeurophysiology  The brain’s major excitatory neurotransmitter  Two groups of glutamate receptors – Ionotropic—fast synaptic transmission – Metabotropic—slow synaptic transmission Modulation of glutamate receptors by Glycine, polyamine sites, Zinc, redox site
    16. 16. B-SlideB-Slide 1616 Epilepsy—BasicEpilepsy—Basic NeurophysiologyNeurophysiology  The brain’s major inhibitory neurotransmitter Two types of receptors – GABAA— post-synaptic, specific recognition sites, linked to CI- channel – GABAB—presynaptic autoreceptors that reduce transmitter release by decreasing calcium influx, postsynaptic coupled to G-proteins to increase K+ current
    17. 17. B-SlideB-Slide 1717 Basic Mechanisms Underlying SeizuresBasic Mechanisms Underlying Seizures and Epilepsyand Epilepsy  Feedback and feed-forward inhibition, illustrated via cartoon and schematic of simplified hippocampal circuit Babb TL, Brown WJ. Pathological Findings in Epilepsy. In: Engel J. Jr. Ed.Babb TL, Brown WJ. Pathological Findings in Epilepsy. In: Engel J. Jr. Ed. Surgical Treatment of the Epilepsies. New York: Raven Press 1987: 511-540.Surgical Treatment of the Epilepsies. New York: Raven Press 1987: 511-540.
    18. 18. B-SlideB-Slide 1818 Normal CNS FunctionNormal CNS Function Excitation Inhibition glutamate, aspartate GABA Modified from White, 2001
    19. 19. Etiology Harrisons 17th edi
    20. 20. Etiology
    21. 21. International League against Epilepsy (ILAE)-1981 1. Partial seizures a. Simple partial seizures (with motor, sensory, autonomic/ psychic signs) b. Complex partial seizures c. Partial seizures with secondary generalization 2. Primarily generalized seizures a. Absence (petit mal) b. Tonic-clonic (grand mal) c. Tonic d. Atonic e. Myoclonic 3. Unclassified seizures a. Neonatal seizures b. Infantile spasms
    22. 22. GTCS • Initially tonic contraction of muscles throughout the body • Muscles of expiration and larynx at the onset -produce a loud moan or "ictal cry.“ • Respirations are impaired, secretions pool in the oropharynx, and cyanosis develops. • Contraction of the jaw -biting of the tongue • A marked enhancement of sympathetic tone leads to increases in HR, BP and pupillary size. • After 10–20 s, the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction. • The periods of relaxation progressively increase
    23. 23. GTCS – post ictal • The postictal phase - unresponsiveness, muscular flaccidity, and excessive salivation that can cause stridorous breathing and partial airway obstruction. • Bladder or bowel incontinence may occur • Patients gradually regain consciousness over minutes to hours, and during this transition there is typically a period of postictal confusion • Patients subsequently complain of headache, fatigue, and muscle ache that can last for many hours.
    24. 24. There is a patient with H/o Suspected seizure… • Ensure ABC • Is it a seizure ? History and Examination
    25. 25. DD of Seizure
    26. 26. There is a patient with H/o Suspected seizure… • Ensure ABC • Is it a seizure ? History and Examination • Is he a known Epileptic ? On Treatment ? • Proceed with Investigations – as guided by History and Examination, • Blood ( Metabolic / Drug levels ) • EEG, Imaging ( CT / MRI )
    27. 27. You have diagnosed it is a seizure…then ? • If it is First episode of unprovoked seizure ?
    28. 28. Treatment of the first unprovoked seizure • 1. Prolonged focal seizure • 2. First seizure presenting as status epilepticus • 3. Presence of neurological deficit, hemiparesis, mental retardation, cerebral palsy etc. • 4. Family history of seizures among parents, siblings or children. • 5. EEG / CT / MRI abnormality • 6. High risk jobs (Professional or other activities that may endanger life during a seizure) • 7. The individual and family do not accept the expected risk of recurrence ( 35 - 40 % ) •Epilepsy society of India
    29. 29. Antiepileptic Drugs • Which are they • Goal of Treatment • Principels of treatment • Selection of Drug • Duration of Treatment • When to stop • Non medical Treatment
    30. 30. Antiepileptic Drug Therapy • Goals • Completely prevent seizures without causing any untoward side effects • Preferably with a single medication • Dosing schedule that is easy for the patient to follow
    31. 31. Antiepileptic Drug Therapy • Principles • Start with a single conventional antiepileptic drug • Start with a low dose • If ineffective / poorly tolerated, then monotherapy using another AED can be tried • Combination Therapy
    32. 32. Conventional or First line drugs • Phenytoin (PHT) • Phenobarbitone (PHB) • Carbamazepine (CBZ) • Oxcarbazepine (OXC) • Valproate (VPA)
    33. 33. New or Second line drugs • Ethosuximide • Gabapentin • Lomotrigine • Vigabatrin • Topiramate • Tiagabine • Zonisamide • Clonazepam • Clobazam
    34. 34. • Sodium Channel Blockers • Carbamazepine • Phenytoin • Oxcarbazepine • Lamotrigine • Zonisamide • GABA Receptor Agonists • Clobazam • Clonazepam • Phenobarbital • Primidone
    35. 35. GABA Reuptake Inhibitors • Tiagabine GABA Transaminase Inhibitor • Vigabatrin AEDs With a Potential GABA Mechanism of Action • Gabapentin • Pregabalin • Valproate Glutamate Blockers • Felbamate • Topiramate AEDs With Other Mechanisms of Action • Levetiracetam
    36. 36. Selection of Antiepileptic Drugs Harrisons 17th edi
    37. 37. Phenytoin – PHT ( 1938 ) Principal Use Tonic-clonic (grand mal) Focal-onset MOA Block Sodium Channels, also Ca Channels Typical Dose 300–400 mg/d (3–6 mg/kg, adult; 4–8 mg/kg, child); qd-bid Half Life 24 h (wide variation, dose- dependent) Side effects Dizziness,Diplopia,Ataxia,Incoordination,Confusion, Gum hyperplasia,Lymphadenopathy,Hirsutism,Osteomalacia Facial coarsening,Skin rash Interactions Level increased by isoniazid, sulfonamides, fluoxetine Level decreased by enzyme-inducing drugsa Altered folate metabolism
    38. 38. Fosphenytoin ( Pro drug ) Principal Use Tonic-clonic (grand mal) Focal-onset MOA Block Sodium Channels, also Ca Channels Typical Dose IV Preparation, can be given 3 times faster, Half Life Side effects Better Tolerated Interactions
    39. 39. Carbamazepine – CBZ (1974 ) Principal Use Partial Tonic-clonic MOA Block Sodium Channels Typical Dose 600–1800 mg/d (15–35 mg/kg, child); bid-qid Half Life 10–17 h Side effects Ataxia,Dizziness,Diplopia,Vertigo, Aplastic anemia,Leukopenia,GI irritation,Hepatotoxicity Hyponatremia Interactions Level decreased by enzyme-inducing drugsa Level increased by erythromycin, propoxyphene, INH,cimetidine, fluoxetine
    40. 40. Oxcarbazepine - OXC Principal Use Focal-onset MOA Block Sodium Channels Typical Dose 900–2400 mg/d (30–45 mg/kg, child); bid Half Life 10–17 h (for active metabolite Side effects Lessed Side effects Interactions Lesser Interactions
    41. 41. Phenobarbital - PHB Principal Use Tonic-clonic Focal-onset MOA Bind GABA-A receptors,blocks Na, Ca, opens Cl, depress glutamate Typical Dose 60–180 mg/d (1–4 mg/kg, adult); (3–6 mg/kg, child); qd Half Life 90 h (70 h in children) Side effects Sedation.Ataxia,Confusion,Dizziness,Decreased libido, Depression,skin rashes Interactions Level increased by valproic acid, phenytoin
    42. 42. Valproic acid - VPA Principal Use drug of choice for primary GTCS, Absence,Atypical absence,Myoclonic,Focal-onset MOA increase synthesis of GABA , may Block Na channel Typical Dose 750–2000 mg/d (20–60 mg/kg); bid-qid.start 250 mg/d with a maintenance dose of 500-1500 mg/d. Half Life 15 h Side effects Ataxia,Sedation,Tremor Hepatotoxicity,Thrombocytopenia,GI,Weight gain, Transient alopecia,Hyperammonemia, low IQ in infants born Interactions Level decreased by enzyme-inducing drugsa
    43. 43. Lamotrigine - LTG Principal Use Focal-onset,Tonic-clonic,Atypical absence,Myoclonic Lennox-Gastaut syndrome MOA Block Sodium Channels Typical Dose 150–500 mg/d; bid Half Life 25 h,14 h (with enzyme-inducers) 59 h (with valproic acid) Side effects Dizziness,Diplopia,Sedation,Ataxia,Headache, Skin rash,Stevens-Johnson syndrome Interactions Level decreased by enzyme-inducing drugsa and OCP, Level increased by valproic acid
    44. 44. Ethosuximide Principal Use Absence (petit mal) MOA Block Sodium Channels Typical Dose 750–1250 mg/d (20-40 mg/kg); qd-bid Half Life 60 h, adult 30 h, child Side effects Ataxia,Lethargy,Headache Interactions Gastrointestinal irritation,Skin rash Bone marrow suppression
    45. 45. Gabapentin Principal Use Focal-onset MOA Block Sodium Channels Typical Dose 900–2400 mg/d; tid-qid Half Life 5–9 h Side effects Sedation,Dizziness,Ataxia,Fatigue, GI,Weight gain,Edema Interactions No known significant interactions
    46. 46. Tiagabine ( TGB )-1998 Principal Use adjunctive therapy in refractory partial epilepsy MOA GABA uptake inhibitor Typical Dose 32–56 mg/d; bid-qid Half Life 7–9 h Side effects Confusion,Sedation,Depression,Dizziness,Speech or language problems,Paresthesias,Psychosis, Gi Interactions Level decreased by enzyme-inducing drugsa
    47. 47. Topiramate Principal Use Focal-onset,Tonic-clonic Lennox-Gastaut syndrome MOA increase synthesis of GABA , may Block Na channel, inhibit Glutamate, inhibit carbonic anhydrase Typical Dose starting dose 25 mg/d;increased biweekly increments of 25- 50 mg. Maintenance dose is 200-600 mg/d in 2 divided doses. Half Life 20–30 h Side effects Psychomotor slowing,Sedation,Speech or language problems Fatigue,Paresthesias, Renal stones,Glaucoma,Weight loss Hypohydrosis Interactions Level decreased by enzyme-inducing drugsa
    48. 48. Zonisamide - ZNS Principal Use Focal-onset MOA Block Sodium Channels Typical Dose 200–400 mg/d;qd-bid Half Life 50–68 h Side effects Sedation,Dizziness,Confusion,Headache,Psychosis,Anorexia Renal stones,Hypohydrosis Interactions Level decreased by enzyme-inducing drugsa
    49. 49. Levetiracetam Principal Use Focal-onset MOA Block Sodium Channels Typical Dose 1000–3000 mg/d; bid Half Life 6–8 h Side effects Sedation,Fatigue,Incoordination,Psychosis, Anemia Leukopenia Interactions None known
    50. 50. Clonazepam Principal Use Absence,Atypical absence Myoclonic, ( with Anxiety ) MOA GABA-A receptor agonist, May block Na Channels Typical Dose 1–12 mg/d (0.1–0.2 mg/kg); qd-tid Half Life 24–48 h Side effects Ataxia,Sedation,Lethargy Interactions Level decreased by enzyme-inducing drugsa
    51. 51. Vigabatrin - VGB Principal Use Absence,Atypical absence Myoclonic, ( with Anxiety ) MOA Inhibit GABA Transaminase Typical Dose 500 mg twice daily, and is increased by 250-500 mg every 1- 2 weeks to a maximum dose of 4000 mg/d. Half Life 4-8 hrs Side effects Drowsiness,depression (5%), agitation (7%), confusion and, rarely, psychosis. Interactions VGB can reduce plasma concentration of Phenytoin by 25%
    52. 52. Clobazam Principal Use partial epilepsy, Lennox-Gastaut syndrome or primary or secondarily generalized ( as adjunctive ) MOA agonist action at the GABA-A receptor, May Block Sodium and Ca Channels Typical Dose 10-20 mg/d , OD Half Life 10-50 hours Side effects Sedation tolerance, dizziness, ataxia, blurred vision, diplopia, irritability, depression, muscle fatigue Special Indications Catamenial epilepsy, prophylaxis for some situations, such as traveling
    53. 53. When to Discontinue Therapy • 70% of children and 60% of adults who have their seizures completely controlled with antiepileptic drugs can eventually discontinue therapy • Normal IQ / EEG/ CT / MRI / • Seizure free interval / Occupation
    54. 54. Treatment of Refractory Epilepsy • There are currently no clear guidelines for rational polypharmacy • Combine first-line drugs • Later add newer drug such as levetiracetam or topiramate
    55. 55. Women with epilepsy • Proper contraception ( Progest Depots or OCP’s with High Estrogen content ) • Preconceptional counselling • 90 % can have Normal Pregnancy and labour and child • fetal abnormalities in children born to mothers with epilepsy is increased by 5–6% • No preference to any drugs • Avoid Valproate , Carbamazepine • Use Monotherapy • Start Folic acid 10 mg/d
    56. 56. Women with epilepsy • Check AFP, and for Neural tube defects • Vit K 20 mg i.m at 34 and 36 wks • Institutional Delivery • Avoid pptating factors – sleep deprivation, Hypoglycemia, pain, Drug Interactions during labour • Vit K 1 mg i.m to new born • May require reduction in dose postpartally • Contraception • Concentration in breat milk- 80% for ethosuximide, 40–60% for phenobarbital, 40% for carbamazepine, 15% for phenytoin, and 5% for valproic acid
    57. 57. Women with epilepsy • Catamenial Epilepsy : • increase in seizure frequency around the time of menses • Acetazolamide (250–500 mg/d) may be effective as adjunctive therapy in some cases when started 7–10 days prior to the onset of menses and continued until bleeding stops
    58. 58. Morbidity / Mortality • Trauma • Burns • Social Stigma • Most deaths are accidental due to impaired consciousness. However, • Sudden unexpected death in epilepsy (SUDEP) may occur • Mechanism of death is controversial, cardiac arrhythmias, pulmonary edema, and suffocation during an epileptic seizure
    59. 59. Refractory Epilepsy • Options for management of refractory epilepsy: • Future strategies • Second line drugs • Surgery • Gama knife • Seizure prediction and prevention • Neural stimulation (Vagus, TMS, DBS) • Gene therapy • Stem cell therapy

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