Neuro B3.pdf - IDD2 Neurology Lecture Notes

PHR 936: IDD2 – Neurology Objectives & Outline OBJECTIVES...

PHR 936: IDD2 – Neurology Objectives & Outline OBJECTIVES Recognize definitions and terminology in the epilepsy field Summarize causes and mechanisms of seizures/epilepsy Describe the most common types of seizures Epilepsy Pathology Explain methods to diagnose epilepsy Identify therapy options for epilepsy Thomas E. Prisinzano, PhD OUTLINE [email protected] Epilepsy Pathology Introduction Definitions, Numbers & Facts Causes, Pathophysiology, Seizures Diagnosis: EEG, Brain Imaging Therapy: First Aid, Lifestyle, Diet, Surgery, Neurostimulation 1/27 Historic figures: Julius Caesar, Alexander the Great 2/27 Definitions Definitions Prodrome Symptoms hours or days before a seizure (e.g., agitation, depression, Epilepsy (“The Sacred Disease”) disorientation, euphoria, headache, ill-temper, insomnia, irritability, Greek, ἐπιλαμβάνειν, epilepsia, “to seize” Latin: sacire, “to take possession of”, “to be possessed” photosensitivity); different from aura Chronic disease characterized by recurrent, unprovoked seizures Aura Beginning of seizure; symptoms seconds to minutes before a seizure Epilepsy Diagnosis (e.g., deja-vu, dreamlike experience, hallucination, strange light, fear, stomach At least two unprovoked seizures occurring more than 24 hours apart sensations, tingling, changes in smell/taste/sound, confusing thoughts) Seizure Ictus (ictus = blow, stroke) Abnormal and excessive cerebral neuronal discharge with or without a Actual seizure, time from first symptoms (including aura) to the end of seizure change in the level of consciousness Brain firing irregularly Interictal Uncontrolled Period between seizures; may be absent, brief or last hours to days; may Convulsion Can be in distinct brain regions or brain-wide include deep sleep, headache, tiredness, irritability, vomiting, confusion, Abnormal, involuntary muscle contraction seen with certain seizure disorders balancing problems. For most people with epilepsy, the interictal state corresponds to more than Fisher et al., Epilepsia, 2014: ILAE Official Report International League Against Epilepsy, 1981 4/27 99% of their life. 5/27  Numbers & Facts Epilepsy Etiology Related to Age Etiology Age of Epilepsy Onset 3-3.5M in US ($18B/Year) 70 Million Perinatal Injury First few years Metabolic Defect First few years 4th most common CNS disorder Congenital Malformation First few years Infection Most common years 2 to 10 > 44 new cases per 100,000 people each year Genetic Most common years 4 to 20 1 % of people in the US will have epilepsy by the age of 20 years Postnatal Trauma Most common years 3 to 30 10% of a population will have a seizure in their lifetime Brain Tumor Most common > 20 years of age Over 2/3 of all seizures begin in childhood Vascular Disease Most common > 30 years of age Epilepsy is among the most common pediatric neurological disorders Age Age > 65 Incidence increases again after age 60 years 300 65 > 500,000 people in the USA have uncontrolled epilepsy 250 Diet - neurotransmitters, nutrition Incidence/100,000 Unprovoked Idiopathic Seizures Mortality rate 2-3-times higher 200 Acute Symptomatic Seizures Drug therapy Surgery Risk of SUDEP 24-times higher 150 100 sudden unexpected death in epilepsy (SUDEP) 50 0 www.who.int; www.cdc.gov; www.epilepsyfoundation.org 0 20 40 60 80 Hauser et al., Epilepsia, 34:453-468, 1993; Annegers et al., Epilepsia, 36:327-333, 1995 6/27 www.who.int; Annegers et al., Epilepsia, 36:327-333, 1995 Age [Years] 7/27 Causes Pathophysiology 30% Symptomatic Cannabinoids: 11% CVD (Secondary) Excitation Inhibition N/V chemo 5% Developmental Intracranial pressure glaucoma Medication resistant epilepsy Glutamate GABA 4% Head Injury Alterations in excitation or inhibition can lead to seizures Too much Glutamate, too little GABA Synchronous discharge of neurons, triggered from epileptic neurons (foci) 4% Brain Tumors Most seizures start in small groups of injured, hyper-excitable neurons (foci), 3% Infection where either local chemical changes or distorted synaptic input causes abnormal 2% Degenerative Disorders high frequency discharges 1% Others 70% Idiopathic Normal EEG (Primary) Seizure Disorders Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Hypothalamic Hamartoma Reflex Epilepsies Benign Occipital Epilepsy of Childhood Interictal Dysphoric Disorder Rolandic Epilepsy Childhood and Juvenile Absence Epilepsy Juvenile Myoclonic Epilepsy Rasmussen's Syndrome/Encephalitis Doose Syndrome Landau-Kleffner Syndrome Ring Chromosome 20 Syndrome Seizure EEG Dravet Syndrome Lennox-Gastaut Syndrome Temporal Lobe Epilepsy Epilepsy in Females with Mental Retardation Ohtahara Syndrome Tuberous Sclerosis Febrile Infection-Related Epilepsy Syndrome Progressive Myoclonic Epilepsis West Syndrome/Infantile Spasms Frontal Lobe Epilepsy Annegers et al., Mayo Clin Proceed, 71:570-575, 1996 8/27 Steriade et al., Journal of Neurophysiology 80(3): 1456-1479, 1998 9/27  ILAE Classification of Seizures Focal Seizures Affect only part of the brain Seizures Focal seizures can turn into generalized seizures Classified according to whether they alter consciousness Affect only part of the brain Focal (Partial) Generalized Simple Focal Seizures Patient retains consciousness affect small region of the brain (frontal or temporal lobes and/or hippocampus) may exhibit motor, somatosensory, autonomic, or psychic symptoms duration 15 sec - 3 min retains consciousness Simple Focal Seizure (click link in PPTX slide show modus) Simple Focal Tonic-Clonic Grand Mal Complex Focal Seizures Patient consciousness impaired partial consciousness Petite Mal Begin as simple focal seizures, progress to complex seizures with impaired consciousness Complex Focal Absence may involve unconscious repetition of simple actions, gestures or verbal utterances, or simply a blank stare and apparent unawareness of the seizure, followed by no memory of the seizure Secondarily may include an aura (“breeze”, breeze before the storm) impaired consciousness Myoclonic duration 15 sec - 3 min Generalized Complex Focal Seizure (click link in PPTX slide show modus) Tonic Focal Seizures evolving to Secondarily Generalized Seizures Consciousness impaired Focal Seizure with Secondarily generalized Seizures (click link in PPTX slide show modus) Atonic International League Against Epilepsy, 1981 10/27 International League Against Epilepsy, 1981 11/27 Generalized Seizures Epilepsies and Epilepsy Syndromes International Classification of Epilepsies and Epilepsy Syndromes Involve entire brain: 1) Localization-Related Epilepsies and Epilepsy Syndromes both hemispheres, bilaterally symmetrical without local onset Idiopathic (age-related onset) Symptomatic Loss of consciousness Benign childhood epilepsy Temporal lobe epilepsy Primary reading epilepsy Frontal lobe epilepsy Parietal lobe epilepsy Muscle stiffening (tonic phase) which may involve 2) Generalized Epilepsies and Epilepsy Syndromes tongue biting, urinary incontinence and the absence Generalized Tonic-Clonic 30-60 sec of breathing, followed by rhythmic muscle Idiopathic (age-related onset) Symptomatic (Grand Mal) contractions (clonic phase) Benign familial neonatal seizures Epilepsy with myoclonic seizures Generalized Tonic-Clonic Seizure Juvenile myoclonic epilepsy West Syndrome (click link in PPTX slide show modus) Childhood absence epilepsy Lennox-Gastaut Syndrome Interruption of consciousness, person becomes Absence (Petit Mal) 3-30 sec unresponsive for a short period of time ( < 30 sec) 3) Epilepsies and Epilepsy Syndromes undetermined whether focal or generalized Abscence Seizure (click link in PPTX slide show modus) Neonatal seizures Brief muscle contractions, jerky movements Myoclonic epilepsy in infancy Myoclonic sec Myoclonic Seizure (click link in PPTX slide show modus) Landau-Kleffner Syndrome (acquired epileptic aphasia) Muscle stiffening, muscles are tense, extremities Tonic sec pulled towards body or rigidly pushed away from it 4) Special Syndromes Tonic Seizure (click link in PPTX slide show modus) Situation-Related Seizures Loss of muscle tone, causing person to fall Febrile convulsions Atonic sec Atonic Seizure (click link in PPTX slide show modus) Seizures due to factors such as alcohol, drugs, eclampsia International League Against Epilepsy, 1981 12/27 International League Against Epilepsy, 1985 13/27  Epilepsy Diagnosis Epilepsy Diagnosis: EEG Observation EEG Placements Multiple Electrode Cap Right Hemisphere Neurological Examination Left Hemisphere behavior, motor ability, mental function Mid Line F: Frontal Lobe T: Temporal Lobe Neuropsychological Tests C: Central Lobe P: Parietal Lobe O: Occipital Lobe Blood Test FePsy Z: Mid Line genetic conditions Normal EEG Generalized Seizure EEG Electroencephalography (EEG) Brain Imaging Computerized tomography (CT) Magnetic resonance imaging (MRI) Functional MRI (fMRI) Positron emission tomography (PET) Single-Photon Emission Computerized Tomography (SPECT) www.mayoclinic.org; www.google.com; www.fepsy.com 14/27 www.google.com 15/27 Epilepsy Diagnosis: EEG Epilepsy Diagnosis: EEG Electroencephalography (EEG) 8-13 hz (cycles/sec) Guyton and Hall, Textbook of Medical Physiology, 13e, Fig 59-3 awake but quiet 14-80 hz awake, attentive asynchronous Generalized Seizures (Tonic-Clonic) 4-7 hz sleep, emotional stress some disorders Absence Seizures 60h INDICATION: focal, tonic-clonic seizures metabolized partially by CYP3A4 PK: t1/2: 12-16h ADV EFF: dizziness aromatic ring N-acetylation metabolized by CYP2C19 ataxia somnolence / Insomnia ADV EFF: dizziness, headache, fatigue cognitive problems not very acidic ataxia rash (fatal) abnormal vision diplopia DDI: Phenytoin, Carbamazepine (CYP3A4 inducers) cardiac problems (increase in P-R interval of ECG) Valproic Acid, Cimetidine, Erythromycin (CYP3A4 inhibitors) euphoria-related adverse events (6-9%) MISC: contraindicated in patients with sulfonamide hypersensitivity DDI: low potential for DDIs 23/45 24/45 Excitatory, GLUtamatergic Synapse Voltage-Gated Ca2+ Channel Blocker – MoA Extra cellular Excitatory GLUtamatergic Synapse 1 Gabapentin Presynaptic Targets Pregabalin Ethosuximide 2 1: Voltage-Gated Na+ Channels 3 Phenytoin, Carbamazepine, Oxcarbazepine, Valproic Acid, Lamotrigine, Topiramate, Zonisamide, Lacosamide 2: Voltage-Gated Ca2+ Channels Gabapentin, Pregabalin, Ethosuximide 3: SV2A (synaptic vesicle protein) Levetiracetam 4 Postsynaptic Target 4: AMPA Receptors Perampanel Katzung, Masters, Trevor, Basic and Clinical Pharmacology, 11th Edition 25/45 Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition, McGraw Hill, 2011 26/45  Voltage-Gated Ca2+ Channel Blocker – MoA Gabapentin (Neurontin®, Gralise®) Utilized in pain CHEMISTRY: 1-(aminomethyl)cyclohexaneacetic acid Advantages of targeting these channels, avoid opiate type controlled substance in KY MECHANISM: voltage-gated Ca2+ channel blocker → Glu release↓ GABAergic → GABA release ↑ INDICATION: focal seizures PK: t1/2: ~ 6h T-type Ca2+ channel 0% PPB L-type Ca2+ channel hardly metabolized excreted mostly unchanged in urine ADV EFF: sedation, somnolence, dizziness, fatigue nystagmus ataxia DDI: none (based on PK) Bialer et al., Nature Reviews, 2010 27/45 28/45 Pregabalin (Lyrica®) Ethosuximide (Zarontin®) CHEMISTRY: (3S)-3-(aminomethyl)-5-methylhexanoic acid CHEMISTRY: (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione federally controlled substance MECHANISM: voltage-gated Ca2+ channel blocker MECHANISM: voltage-gated Ca2+ channel blocker → Glu release↓ → Glu release↓ salts INDICATION: focal seizures INDICATION: absence seizures PK: t1/2: ~ 6h 0% PPB PK: t1/2: ~ 60h hardly metabolized metabolized: CYP3A4, CYP2E1 renal elimination ADV EFF: sedation, somnolence, dizziness ADV EFF: nausea, anorexia headache mood changes weight gain headache dry mouth blurred vision DDI: common (ethosuximide levels affected by co-medication) DDI: low potential for DDis 29/45 30/45  Excitatory, GLUtamatergic Synapse SV2A Modulator Excitatory GLUtamatergic Synapse 1 Glutamatergic Synapse GABAergic Synapse Presynaptic Targets 2 1: Voltage-Gated Na+ Channels 3 Phenytoin, Carbamazepine, Oxcarbazepine, Valproic Acid, Lamotrigine, Topiramate, Zonisamide, Lacosamide 3 3 2: Voltage-Gated Ca2+ Channels Gabapentin, Pregabalin, Ethosuximide 3: SV2A (synaptic vesicle protein) Levetiracetam 4 Postsynaptic Target 4: AMPA Receptors Perampanel Katzung, Masters, Trevor, Basic and Clinical Pharmacology, 11th Edition 31/45 32/45 Levetiracetam (Keppra®) Excitatory, GLUtamatergic Synapse CHEMISTRY: (S)-2-(2-oxopyrrolidin-1-yl)butanamide Excitatory GLUtamatergic Synapse 1 MECHANISM: binds to SV2A Presynaptic Targets → alters release of GABA & Glu 2 1: Voltage-Gated Na+ Channels 3 Phenytoin, Carbamazepine, Oxcarbazepine, Valproic Acid, Lamotrigine, Topiramate, INDICATION: focal, generalized tonic-clonic, myoclonic seizures Zonisamide, Lacosamide 2: Voltage-Gated Ca2+ Channels Gabapentin, Pregabalin, Ethosuximide PK: t1/2: ~ 6-8h < 10% PPB 3: SV2A (synaptic vesicle protein) minimally metabolized Levetiracetam 4 ADV EFF: sedation, somnolence, dizziness, asthenia Postsynaptic Target dose needs to be lowered in renal insufficiency & elderly 4: AMPA Receptors DDI: no significant DDI with ASDs or other drugs Perampanel 33/45 Katzung, Masters, Trevor, Basic and Clinical Pharmacology, 11th Edition 34/45  AMPA Receptor Blocker – MoA Perampanel (Fycompa®) CHEMISTRY: 5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H)-one federally controlled substance CIII MECHANISM: AMPA-R blocker (non-competitive antagonist) INDICATION: tonic-clonic seizures PK: t1/2: ~ 70-105h slower metabolic process 95% PPB Perampanel metabolized by CYP3A4 ADV EFF: dizziness (falls), drowsiness, fatigue weight increase FDA Black Box Warning aggression, hostility, irritability, anger, homicidal ideation DDI: CYP3A4 inducers/inhibitors → Perampanel clearance ↑/↓ Bialer et al., Nature Reviews, 2010 35/45 increased clearance of levonorgestrel 36/45 OVERVIEW: Anti-Seizure Drugs Inhibitory, GABAergic Synapse Excitatory GLUtamatergic Synapse Inhibitory GABAergic Synapse Molecular Targets for ASDs at Inhibitory, GABAergic Synapse Presynaptic Targets Postsynaptic Target Inhibitory GABAergic Synapse Postsynaptic Target 1: Voltage-Gated Na+ Channels 1: GABAA receptor Phenytoin, Carbamazepine, Oxcarbazepine, Barbiturates: Valproic Acid, Lamotrigine, Topiramate, Phenobarbital, Primidone 1: GABAA receptor Zonisamide, Lacosamide Barbiturates: Benzodiazepines: Phenobarbital, Primidone Diazepam, Clonazepam, Lorazepam, Midazolam 2: Voltage-Gated Ca2+ Channels Benzodiazepines: Gabapentin, Pregabalin, Ethosuximide Diazepam, Clonazepam, Lorazepam, Midazolam 3: SV2A (synaptic vesicle protein) Levetiracetam 1 Postsynaptic Target 4: AMPA Receptors Perampanel 1 Katzung, Masters, Trevor, Basic and Clinical Pharmacology, 11th Edition 37/45 Katzung, Masters, Trevor, Basic and Clinical Pharmacology, 11th Edition 38/45  GABAA Receptor Modulator – MoA Phenobarbital (Luminal®) CHEMISTRY: 5-Ethyl-5-phenyl-1,3-diazinane-2,4,6-trione 6 carbons federally controlled substance CIII MECHANISM: GABAA receptor modulator (positive allosteric) INDICATION: focal, tonic-clonic seizures PK: 80-100% bioavailability t1/2: > 60h 40-60% PPB renal excretion of non-metabolized drug Zombie dust, puffer fish strong CYP2C and CYP3A inducer ADV EFF: sedation – tolerance develops Nystagmus Ataxia Learning difficulties DDI: induces metabolism of other drugs (e.g., warfarin) 39/45 40/45 Primidone (Mysoline®) GABAA Receptor Modulator – MoA CHEMISTRY: 5-ethyldihydro-5-phenyl-4,6(1H,5H)-pyrimidinedione MECHANISM: GABAA receptor modulator (positive allosteric) depresses glutamate excitability affects Na+, K+, Ca2+ conductance INDICATION: focal seizures, generalized tonic-clonic seizures essential tremor PK: ~100% bioavailability t1/2: 3-22h depending on co-medication 25% PPB metabolized by CYP2C9/19 (phenobarbital: active metabolite) strong CYP2C and CYP3A inducer ADV EFF: largely those of phenobarbital (less well tolerated) sedation – tolerance develops Nystagmus, ataxia DDI: common; induces metabolism of other drugs 41/45 42/45  Sedative and muscle relaxation Benzodiazepines Benzodiazepines Federally controlled substances if has hydroxyl group CHEMISTRY: dealkylation in 3 position it is MECHANISM: GABAA receptor modulators (positive allosteric modulation) shorter acting Diazepam 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one INDICATION: all seizure types including Status Epilepticus (Valium®, Diastat®) Diazepam Status Epilepticus Clonazepam long-acting (also absence seizures) Lorazepam Status Epilepticus Midazolam Acute management of seizures including SE Clonazepam 5-(2-chlorophenyl)-7-nitro-2,3-dihydro-1,4-benzodiazepin-2-one (Klonopin ®) PK: t1/2: 20-50h 85-99% PPB Lorazepam (RS)-7-Cl-5-(2-chlorophenyl)-3-OH-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Ativan®) ADV EFF: tolerance (50%, 1-6 months) – limits long-term use CNS depression, strong sedation, lethargy aggressiveness (25%) withdrawal syndrome Midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (Dormicum®) DDI: common, induction of CYPs - can cause DDIs also has Benzoic position hydroxylation and 43/45 44/45 oxidation PHR 936: IDD2 – Neurology PHR 936: IDD2 – Neurology Epilepsy Questions? Anti-Seizure Drug Pharmacokinetics https://ukhealthcare.uky.edu/sites/default/files/clinical-pks-anticoagulation-manual.pdf Thomas Prisinzano, Ph.D. [email protected] 45/45 1/20  Fosphenytoin (Cerebyx®) Prodrug of phenytoin Designed for i.v. administration Used for status epilepticus & seizures occurring during neurosurgery HN O Phosphatase O N in Blood HN HN O O O N O O N P O H O OH Na O Na Phenytoin 47/45 Carbamazepine/ Oxcarbazepine Antiseizure Drugs Used for Various Seizures O HO OH Epoxide 3A4 Hydrolyase N Inactive N N O NH2 O NH2 O NH2 Active Carbamazepine Metabolism Loss Ÿ Induces 3A4, 1A2, of 2B6, 2C19, 2C8, 2C9 H2O Ÿ Autoinducer (induces UGT) Ÿ Epoxide is more toxic O HO than carbamazepine N N O NH2 O NH2 Active 49 48/45  Barbiturates In 1958, American physicians prescribed about three to four R1 R 2 Antiepileptics: billion doses of barbiturates, which were widely used drugs for O X Nomenclature of Drugs Related to inducing sleep. O O N 5 Barbiturate Structure O HN 1 3 NH Ureide Structure Barbiturates have a number of deleterious side effects O Class of Compounds X including lethargy, confusion, and depression. R1 R 2 O O O Barbiturates NH N NH Chronic use of barbiturates is associated with a potential for Hydantoins NH O addiction involving both physical and psychological R1 R 1 R1 R 1 R1 R 1 dependence. O O O Oxazolidinediones O NH O – Major symptoms of withdrawal (seizures, delirium, and N N N hypothermia) that can persist for up to 2 weeks after O O O discontinuation. Succinimides CH2 – Tolerance to barbiturates can develop within 2 weeks of treatment because of induction of hepatic microsomal enzymes © Dept. MDCM Ÿ KU 2015 adapted from Figure 17.4 in Foye 7th Ed. They are lethal at about 10 times the hypnotic dose. 50 51/45 Barbiturates – Physiochemical Properties Barbiturates – SAR Two substituents are required at the 5-position. O O About 5 - 7 carbon atoms (total) are optimal in the two R OEt H 2N O Base R NH O substituents at position 5. R' OEt H 2N R' NH O O If one of the 5-substituents is a phenyl group, the duration of Urea action is increased. O O O O O O O O Replacement of the 2-oxo group with a 2-thio (change the HN NH N NH N NH HN N oxygen to a sulfur) results in a significant loss in the duration of O OH O OH action (ultra-short duration of action). Barbituric Acid Enol Form Enolate Ion – No thiobarbiturate is currently available in the U.S. 52/45 53/45  Barbiturates – SAR Barbiturates – SAR Two substituents are required at the 5-position. About 5 - 7 carbon atoms (total) are optimal in the two substituents at position 5. Lipophilic Important to cross the BBB O O O O O O O O HN NH HN NH HN NH HN NH O O O O O O O O HN NH HN NH HN NH HN NH O O O O O O O O 54/45 55/45 Barbiturates – SAR Barbiturates – SAR If one of the 5-substituents is a phenyl group, the duration of Replacement of the 2-oxo group with a 2-thio (change the action is increased. oxygen to a sulfur) results in a significant loss in the duration of action (ultra-short duration of action). OH – No thiobarbiturate is currently available in the U.S. CYP 2C19 O O O O HN NH HN NH O O O O O O HN NH HN NH Aromatic hydroxylation is relatively slow O S Sulfa derivative more lethal cLogP 2.1 3.0 pKa 8.1 7.5 Generally, barbiturates have a long duration (> 6 h) Ionized at pH 7.4 17% 44% Duration 3–4h 10 – 30 min 56/45 57/45  Barbiturates – Metabolism Benzodiazepine – Metabolism O-Conj. O-Conj. H 3C H 3C Thiopentylbarbital O O O O O O N N + HN NH HN NH OH O Oxidative desulfurization O O Cl N Cl N Glu Phase II OH O OH O O-Conj. H 3C OH O N O O Phase I O O O O Phase I O O Phase II O O H O Oxidation + Oxidation N N HN NH HN NH HN NH HN NH HN NH Cl O Pentobarbital O O O O Valium Cl N OH O-Conj. Aromatic Conj. = glucuronide or sulfate O O hydroxylation O O Phase II O O HN NH Phase I HN NH HN NH O O O Phenobarbital 58/45 59/45  Objectives Select appropriate therapy for individual patients with epilepsy Recognize and manage common risks and concerns associated with anti-seizure drug use Assess and manage anti-seizure drug rash Epilepsy Therapeutics Recognize and treat common therapeutic issues in people with epilepsy of childbearing potential (PWECP) Anna Pfeiffer, PharmD, BCPS To determine if anti-seizure medications (ASMs) can be discontinued in a patient with epilepsy Medical Treatment of First Seizure Controversial Up to 50% recur within 5 years; highest risk in first 2 years Abnormal imaging, abnormal EEG, How many antiepileptic drugs are on the market right now? prior stroke or trauma, or nocturnal seizures increase recurrence risk Treatment reduces risk by ~ 35% Quality of life issues are important Krumholz A, et al. Neurology 2015; 84: 1705-13. Choosing an ASM Drugs of Choice by Seizure Type Is there a risk of Treat underlying Efficacy repeated seizures? No condition Concomitant conditions Yes PK/PD Generalized Focal Drug interactions Carbamazepine Phenobarbital Formulation Tonic-clonic Absence Atonic/Tonic Myoclonic Gabapentin Phenytoin Lacosamide Pregabalin Adverse effects Carbamazepine Ethosuximide Lamotrigine Lamotrigine Lamotrigine Topiramate Lacosamide Lamotrigine Oxcarbazepine Levetiracetam Cost Lamotrigine Valproic acid Phenobarbital Phenobarbital Levetiracetam Valproic acid Phenytoin Topiramate Oxcarbazepine Zonisamide Levetiracetam Personal preferences Oxcarbazepine Valproic acid Valproic acid Zonisamide Eslicarbazepine Perampanel Perampanel Phenobarbital Brivaracetam Phenytoin Topiramate Valproic acid General ASM Management Monotherapy preferred Slow titration improves tolerability Adjustments made on clinical response TDM can be helpful When would therapeutic drug If polytherapy required, select different mechanism of action if possible monitoring be helpful? Documentation of previous medication trials Therapeutic Drug Monitoring Strategies for Cross-titrating ASMs Situations where it can be helpful It depends on a few factors: Suspected toxicity Why are we making the switch? Breakthrough seizures with appropriate ASM dosing How sensitive is the patient to medication changes? Adherence Is the new medication in the same drug class as the old medication? Suspected drug interactions Most often, we want to reach goal dose of new ASM before we It it’s phenytoin taper old ASM Pregnancy Reduces risk of breakthrough seizure Formulation or generic substitution Sometimes increases risk of side effects Critical illness But remember…treat the patient not the number! Documenting ASM Trials ASM-Resistant Epilepsy ASM Status Max Daily Efficacy Started Stopped Notes Not Seizure-Free Dose LTG active 400 mg 400 mg 4/2024 35% Non-Responders Seizure-Free 3rd drug LEV active 4000 mg 3000 mg 10/2023 Agitation at 2000 mg BID, 5% can tolerate 3000 mg/day 10% OXC d/c 1200 mg 1200 mg 3/2021 10/2023 Obtained seizure control Seizure-Free 2rd drug but experienced symptomatic 50% hyponatremia (125 Responders Seizure-Free 1st drug mEq/L) ZNS d/c 200 mg Not reached 1/2021 3/2021 Intolerable sedation prior to seizure control Kwan and Brodie, N Engl J Med 342:314-319, 2000  Side Effect Management Rash Peak – related Can consider switching to extended – release formulation 3% of all ASMs 7 Split – dosing Biggest risk = rash with 6 5.9 another ASM 4.8 New start or increased dose Carbamazepine 5 4.6 Depending on SE, may need slower titration 4 3.7 Percent Patients with HLA-B*1502 (usually Asian); testing recommended Morning vs. nighttime dosing Patients with HLA-A*3101 3 2.5 (Japanese, Native American, Dose – dependent Southern Indian, Han Chinese, 2 May need reduction of first ASM and introduction of second ASM Korean, European, Latin 1 American) Lamotrigine 0 High initial dose Phenytoin Lamotrigine Zonisamide Carbamazepine Rapid dose increases Oxcarbazepine Co-administration with valproic acid Arif H, et al. Neurology 2007;68:1701-9. Maculopapular (morbilliform) Urticarial (Hives) Begins 3-20 days after Wheals with pale centers starting drug and red borders Itchy Migratory Resolves within weeks of Change shape, size, location stopping Anaphylaxis or angioedema may be associated Bahrani E, et al. CNS Drugs 2016;30:245-67. Bahrani E, et al. CNS Drugs 2016;30:245-67.  Stevens Johnson Syndrome/Toxic Epidermal Erythema Multiforme Necrolysis 7-21 days after starting medicine Targetoid lesions Sheet-like skin and mucosal May involve mucous sloughing membranes 30% BSA is Self-limiting TEN, 10-30% is SJS/TEN Mortality rate 10-30% Bahrani E, et al. CNS Drugs 2016;30:245-67. Bahrani E, et al. CNS Drugs 2016;30:245-67. Drug-induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Rash Treatment Symptoms If SJS/TENS/DIHS/DRESS - discontinue immediately Usually hospitalization with systemic corticosteroids 2-6 weeks after starting medicine Burn unit Fever, generalized rash, lymphadenopathy, facial edema, Non life threatening rash multiorgan failure Discontinue quickly 10% mortality Start new ASM with rapid titration or load in hospital Use benzodiazepines to cover for breakthrough seizures, if necessary Bahrani E, et al. CNS Drugs 2016;30:245-67.  Bone Health Fractures & ASMs Osteopenia or osteoporosis in 38-60% of patients in tertiary Increased risk with increased treatment duration epilepsy clinics Dose-relationship with fractures Increase in fractures in people with epilepsy and with ASMs Most associated: carbamazepine, clonazepam, phenobarbital, Adverse effect of ASM on bone phenytoin, valproic acid Inhibition of osteoblasts or activation of osteoclasts Increased vitamin D metabolism Risk factors: Inhibition of calcium absorption Treated > 2 years, high doses, polytherapy, co-morbidities that increase osteoporosis risk, low physical activity Instability or poor coordination due to ASD Injury due to seizure Monitoring vitamin D and bone mineral density Andersen NB, Jorgensen NR. Best Pract Res Clin Rheum 2022;36:101755. Andersen NB, Jorgensen NR. Best Pract Res Clin Rheum 2022;36:101755. Treatments Safety Precautions in Epilepsy Vitamin D supplementation Heavy machinery High-dose (4000 IU/day for adults; 2000 IU/day for children) improved BMD compared to low dose (400 IU/day for adults and children) Heights Only study in patients with epilepsy Swimming/bathing Estrogen - may trigger seizures in some women Driving In one retrospective study, both antiresorptive and anabolic All states restrict driving for people with active seizures medications appeared to work as well in people with epilepsy as Seizure free for 3-12 months in those without epilepsy Some states have mandatory reporting Kentucky driving laws? Seizure first aid Mikati MA, et al. Neurol 2005;67:2005-14. Whitney DG. Epilepsia 2020;61;2583-92.  Suicidality Suicidality Analysis of 199 placebo-controlled clinical trials of eleven drugs Risk increased at 1 week and continued through week 24 (n=43,892 patients > 5 years) Patients with epilepsy (RR=3.6), psychiatric disorders (RR=1.6), Patients receiving antiepileptic drugs had ~ twice the risk of or other conditions (RR=2.3) were all at increased risk for suicidal behavior or ideation (0.43%) compared to patients suicidality receiving placebo (0.22%) No differences between drugs 4 completed suicides in treatment group vs. 0 in placebo group No differences among age groups FDA requires black box warning for all ASMs More recent studies have differing outcomes Sudden Unexplained Death in Epilepsy Patients (SUDEP) Issues in PWECP with Epilepsy Catamenial epilepsy – 1/3-1/2 of women Abrupt death in patients with Progesterone – antiseizure epilepsy without an apparent medical cause Estrogen – proseizure Treatment: ASMs, benzodiazepines, acetazolamide, progesterone Incidence 1 in 1000 (adults) – 4,500 (children) Menstrual cycle dysfunction Risk factors Polycystic ovary syndrome associated with valproic acid Tonic-clonic seizures Decreased fertility Frequency of seizures More anovulatory cycles Not being seizure-free Nocturnal seizures Prolactin can decrease libido No one else in bedroom Not adding additional therapy Friedman, et al., J Clin Invest 2013;123:1415-6. Harden C, et al. Neurology 2017;88:1674-80. Sveinsson O, et al. Neurology 2023;ahead of print. Bangar S, et al. Funct Neurol 2016;31:127-34.  Contraception and ASMs Pregnancy and Post-Partum Enzyme inducing AS can Most women have no change in seizure frequency decrease the effectiveness of If a woman is seizure-free for at least 9 mo prior to pregnancy, she has oral contraceptives a >84% chance of being seizure-free during pregnancy Not all contraception is for Caution regarding pharmacokinetic changes during and after pregnancy prevention