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Outpatient Epilepsy Care for the Internist: Part I

Outpatient Epilepsy Care for the Internist: Part I. Michelle Bell, MD Assistant Professor of Neurology Slides created by Michelle Bell, MD and Carl Bazil MD, PhD (Columbia University Comprehensive Epilepsy Center). Epilepsy. Expectations And Objectives. By the end of this lecture you will:

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Outpatient Epilepsy Care for the Internist: Part I

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  1. Outpatient Epilepsy Care for the Internist: Part I Michelle Bell, MD Assistant Professor of Neurology Slides created by Michelle Bell, MD and Carl Bazil MD, PhD (Columbia University Comprehensive Epilepsy Center) Epilepsy

  2. Expectations And Objectives By the end of this lecture you will: Learn basics of seizure and epilepsy epidemiology. Learn the definition of epilepsy. Learn the difference between focal seizures and generalized seizures and learn some common types of both. Learn the clinical presentations of some common focal epilepsy syndromes, generalized epilepsy syndromes and a combined focal and generalized epilepsy syndromes. Epilepsy

  3. Cellular events during a seizure What Is A Seizure? Abnormal synchronous excessive cortical neuronal activity Epilepsy Kandel et al., Principles of Neural Science 5th Ed., Fig. 50-10, pp 1128, 2017.

  4. Introduction

  5. Seizure Propagation Seizures propagate via several pathways. (Reproduced, with permission, from Lothman 1993b.) A. Focal seizures can spread locally from a focus via intrahemispheric fibers (1) and more remotely to homotopic contralateral cortex (2) and subcortical centers (3). The secondary generalization of focal seizure activity spreads to subcortical centers via projections to the thalamus (4). Widespread thalamocortical interconnections then contribute to rapid activation of both hemispheres. B. Primary generalized seizures, such as a typical absence seizure, spread primarily through interconnections between the thalamus and cortex. Source: Seizures and Epilepsy, Principles of Neural Science, Fifth Editon Citation: Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ, Mack S. Principles of Neural Science, Fifth Editon; 2012

  6. Introduction

  7. Seizure Epidemiology Lifetime incidence of having a seizure? • 1% • 10% • 25% • 50% • 75% Epilepsy

  8. Seizure Epidemiology 10% lifetime incidence1 1“Epilepsy.” World Health Organization, World Health Organization, www.who.int/mediacentre/factsheets/fs999/en/. Epilepsy

  9. What Is Epilepsy? 2014 International League Against Epilepsy (ILAE) definition: Disease with either: Two or more unprovoked seizures occurring >24 hours apart OR A single seizure with heightened tendency toward an unprovoked seizure (i.e. with clinical, electrophysiologic, imaging that suggests >60% chance of another seizure over the next 10 years) Epilepsy

  10. Provoked Seizures AKA Acute Symptomatic Seizure Definition: A clinical seizure occurring at the time of a systemic insult or in close temporal association with a documented brain insult. Examples: • Seizures occurring within 1 week of stroke, traumatic brain injury, anoxic encephalopathy, or intracranial surgery. • Seizures occurring in the presence of an active central nervous system (CNS) infection or during an active phase of multiple sclerosis or other autoimmune diseases. • Seizures occurring in the presence of severe metabolic derangements (documented within 24 h by specific biochemical or hematologic abnormalities). • Seizures occurring in the context of drug or alcohol intoxication and withdrawal. • Seizures occurring in the context of exposure to well-defined epileptogenic drugs. Beghi, Ettore, et al. “Recommendation for a definition of acute symptomatic seizure.” Epilepsia, vol. 51, no. 4, 2010, pp. 671–675., doi:10.1111/j.1528-1167.2009.02285. Epilepsy

  11. Epilepsy Epidemiology Lifetime incidence of developing epilepsy? • 1% • 10% • 25% • 50% • 75% Epilepsy

  12. Epilepsy Epidemiology • 1% lifetime incidence (i.e. probability of occurrence) in US. • US Prevalence, i.e. proportion of a population who has epilepsy: 3 million people. • World Prevalence: 50 million people • Neurocysticercosis leading cause of acquired epilepsy internationally. Epilepsy

  13. Epilepsy Can Begin At Any Age Epilepsia. 1993 May-Jun;34(3):453-68. Nature Reviews Neurology5, 380–391 (2009) Epilepsy

  14. New ILAE Epilepsy Classification Seizure types Generalized onset Unknown onset Focal onset Epilepsy Syndromes Etiology Structural Epilepsy types Genetic Infectious Generalized Unknown Focal Combined Generalized & Focal Focal Metabolic Immune Unknown

  15. Epilepsy Types • Focal epilepsy • Generalized epilepsy • Combined generalized and focal epilepsy Epilepsia. 1993 May-Jun;34(3):453-68 Epilepsy

  16. Focal Epilepsy Old terminology • Simple • No impairment in consciousness • Complex • Impairment in consciousness • Secondarily-generalized • Focal symptom followed by generalized seizure New terminology • Focal Aware • Focal with Impaired Awareness • Focal to Generalized Tonic Clonic (GTC) Epilepsy

  17. Temporal Lobe Epilepsy Elements of a temporal lobe seizure? Epilepsy

  18. Temporal Lobe Epilepsy, Symptoms Deja-vu Fear Rising epigastric sensation Speech arrest Auditory hallucinations Epilepsy

  19. Mesial Temporal Sclerosis Epilepsy

  20. Frontal Lobe Epilepsy Elements of frontal lobe seizure Epilepsy

  21. Frontal Lobe Epilepsy, Symptoms Jerking movements Hyper-motor complex movements Vocalizations Smell hallucinations Epilepsy

  22. Cortical Dysplasia Widdess-Walsh, P., Kellinghaus, C., Jeha, L., Kotagal, P., Prayson, R., Bingaman, W., & Najm, I. M. (2005). Electro-clinical and imaging characteristics of focal cortical dysplasia: Correlation with pathological subtypes. Epilepsy Research,67(1-2), 25-33. doi:10.1016/j.eplepsyres.2005.07.013 Epilepsy

  23. Other Focal Epilepsy Seizure Symptoms Parietal Lobe Tingling Perception of movement Occipital Lobe Simple or complex visual hallucinations Epilepsy

  24. Post-traumatic Seizures And Epilepsy Can arise anywhere in the cerebral cortex. Early seizures (within one week) • 6-25% of patients with traumatic brain injury. • 50% occur within the first 24hrs. • Usually the seizure is a generalized tonic-clonic seizure. • Not associated with a significantly elevated risk of epilepsy. • Patients at high risk for early seizures, are usually treated with a one –week anti-epileptic prophylaxis. Epilepsy

  25. Post-traumatic Seizures and Epilepsy, Continued Late seizures (after one week) • 2% 10-year incidence. • More severe the head injury, more likely the risk of seizure (0.5 % for mild injury, 1% of moderate injury, 10% of severe injury). • More likely to be clinically focal in onset. • If a patient has a late seizure, they are started on chronic antiepileptic treatment. Epilepsy

  26. Epilepsy Types • Focal epilepsy • Generalized epilepsy • Combined generalized and focal epilepsy Epilepsy

  27. Generalized Seizures • Absence • Myoclonic • Primary Generalized Tonic Clonic • Atonic/Tonic • Clonic Epilepsy

  28. Generalized Seizures and Epilepsies The Organization of the Epilepsies 2010  (http://www.ilae.org/Commission/Class/documents/ILAE_Organization_of_Epilepsies-2010.ppt) Felton, Elizabeth. “The Genetic Epilepsies: Description, Pathophysiology, Treatment and Prognosis.” The Neurology Report, vol. 8, no. 1, 2015, pp. 11–18. Epilepsy

  29. Childhood Absence Epilepsy Childhood Absence Epilepsy • Epidemiology • Constitutes up to 10% of epilepsy in these age groups. • 90% with typical absence seizures will remit around puberty. • Semiology • Absence seizures • Abrupt impairment in consciousness. • Last on average 10 seconds. • Oral automatisms, eyelid myoclonus. • Later can have GTC seizure. • EEG • 3Hz generalized spike and wave. • Provoke seizure with hyperventilation. Epilepsy

  30. Primary Generalized Seizures • Absence • Myoclonic • Primary Generalized Tonic Clonic • Atonic/Tonic • Clonic Epilepsy

  31. Juvenile Myoclonic Epilepsy Juvenile Myoclonic Epilepsy Syndrome • Epidemiology • 25% of primary generalized epilepsy and 10% of epilepsy. • Onset 12-18 years. • Does not remit but can be less active in adulthood. • Semiology • Myoclonic jerks (AM), GTC seizures, Absence seizures. • EEG • 4-6Hz generalized spike/polyspike and wave, photoparoxysmal response. Epilepsy

  32. Primary Generalized Epilepsies • Absence • Myoclonic • Primary Generalized Tonic Clonic • Atonic/Tonic • Clonic Epilepsy

  33. Epilepsy with GTCs alone Epilepsy with GTCs alone • Epidemiology • Onset can be anywhere from age 5 to 40, though for most patients onset is between age 11 and 23. • Often a family history of epilepsy. • Seizures often occur within 1 to 2 hours of awakening. • Semiology • GTCs alone. • EEG • 3-4 Hz generalized spike and polyspike discharges. Epilepsy

  34. Primary Generalized Seizures • Absence • Myoclonic • Primary Generalized Tonic Clonic • Atonic/Tonic • Clonic Epilepsy

  35. Lennox Gastaut Syndrome, A Combined Generalized and Focal Epilepsy Syndrome Lennox Gastaut Syndrome • Epidemiology • Prevalence of 15/100,000 persons; accounts for 7% of patients with intractable epilepsy. • Semiology - Triad • Multiple Seizures Types (tonic, atonic, myoclonic, atypical absence, focal). • Interictal EEG of diffuse slow spike wave discharges. • Cognitive dysfunction. • EEG • High amplitude 1.5Hz – 2.5Hz generalized and multifocal polyspike and spike wave discharges. • Low voltage frontally predominant 10Hz activity. Epilepsy

  36. Take Home Messages The lifetime incidence of a convulsion is about 10%. The lifetime incidence of epilepsy is about 1%. Epilepsy is defined as: • Two or more unprovoked seizures occurring >24 hours apart OR • A single seizure with heightened tendency toward an unprovoked seizure (i.e. with clinical, electrophysiologic, imaging that suggests >60% chance of another seizure over the next 10 years) Epilepsy

  37. Take Home Messages, continued Epilepsy

  38. Thinking About Treatment (Next Time) Primary generalized v. focal Options • Medications • Surgery • Diet Epilepsy

  39. Outpatient Epilepsy Care for the Internist: Part II Michelle Bell, MD Assistant Professor of Neurology Slides created by Michelle Bell, MD and Carl Bazil MD, PhD (Columbia University Comprehensive Epilepsy Center) Epilepsy

  40. Slide ‹#› Objectives By the end of this lecture you will be able to: Explain the differential diagnosis of epilepsy, particularly other conditions that cause transient loss of awareness List commonly used anti-epileptic drugs (AEDs) for seizures. Describe the basic pharmacology of commonly used AEDs including metabolism, mechanism of action, toxicities and drug-drug interactions. Understand basic factors in choosing AEDs. Describe how an acute seizure is treated. Describe the role of non-medical therapies of epilepsy including resective neurosurgery and neurostimulation. Epilepsy lookalikes and treatment

  41. Slide ‹#› What causes transient behavioral changes? Cardiovascular • Vasovagal syncope • Cardiac syncope • TIA/stroke • Migraine Movement disorders • Tics • Myoclonus • Chorea Toxic-metabolic • Asterixis • Withdrawal syndromes • Drug intoxication Epilepsy lookalikes and treatment

  42. Slide ‹#› Seizure vs. Syncope: Guidelines, not Rules Seizure Longer (1-2 min) Brief aura Rhythmic tonic/clonic Incontinence Tongue-lip biting Postictal confusion Syncope Brief (seconds) Prolonged premonitory symptoms Rare, brief clonic Rare incontinence Rare tongue/lip biting Rapid recovery Epilepsy lookalikes and treatment

  43. Slide ‹#› Seizure: Additional Differential diagnosis Sleep disorders Narcolepsy Night terrors Somnambulism Restless legs syndrome REM behavior disorder Psychiatric disorders Malingering Conversion disorders (e.g. PNES) Panic disorder Epilepsy lookalikes and treatment

  44. Introduction

  45. Slide ‹#› AEDs: Commonly Used Effective Drugs Focal onset and GTCs Carbamazepine/oxcarbazepine Phenytoin Gabapentin/pregabalin lacosamide (may be broad spectrum) Broad spectrum (all seizures) Valproate Lamotrigine Topiramate Zonisamide Levetiracetam Clobazam Ethosuximide: absence seizures only! Epilepsy lookalikes and treatment

  46. Slide ‹#› Trough Peak Clinical pharmacology: Basics Steady-state: requires 4-7 half-lives E.g. if half-life is 24 hours → steady state is ~7 days Same time for elimination if drug stopped High peak can lead to toxicity; low trough to seizure TROUGH Epilepsy lookalikes and treatment

  47. Slide ‹#› Phenytoin Example: Complicated Pharmacokinetics 90% is protein bound → only 10% is free and thus active Thus, decreased binding can lead to toxicity (low albumin, combination with valproate) Metabolized by cytochrome P-450 system, with enzyme induction (affecting other drugs) zero order kinetics at higher doses Epilepsy lookalikes and treatment

  48. Slide ‹#› Zero Order Kinetics At zero order, small increase in dose leads to huge increase in concentration Epilepsy lookalikes and treatment

  49. Slide ‹#› Consequences of Phenytoin Pharmacokinetics Protein binding leads to misleading total level in the presence of other protein binding drugs, low albumin Metabolism affected by many other drugs If in zero-order kinetic zone, small changes in dose lead to large changes in level (and toxicity or seizures!) Epilepsy lookalikes and treatment

  50. Slide ‹#› AEDS: Mechanisms of Action All work on neurotransmission (presumably increasing inhibition and/or decreasing excitation) Multiple suspected mechanisms Drugs with “same” mechanism are not equivalent Mechanisms have rarely been “proven” and may be oversimplification Ideally reverse hyperactivity without affecting normal activity Epilepsy lookalikes and treatment

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