Epilepsy 2005 ILAE Report

Transcription

1 1 Seizure & Epilepsy Care Gregory Krauss, MD Johns Hopkins University October 31, Epilepsy 2005 ILAE Report Seizure = a symptom Defined as paroxysmal change in behavior due to abnormal electrical activity in the brain Epilepsy = a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiological, cognitive, psychological, and social consequences of this condition. Fisher et al (2013). Epilepsia

2 2 A practical clinical definition of epilepsy 2013 ILAE Report Epilepsy: a disease of the brain defined by any of the following conditions: 1) At least two unprovoked (or reflex) seizures occurring >24 h apart; 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; 3) diagnosis of an epilepsy syndrome Fisher, R. et al Epilepsia Evidence based medicine: Risks for recurring seizures after medical or surgical treatment for cavernous angioma with seizures Chance of seizure freedom over 5 years of follow-up (3% surgery morbidity) Dammann P. J Neurosurg 2016

3 3 Seizure Classifications Non-Convulsive Generalized Onset Convulsive Partial Onset Simple Complex Secondary Generalization Generalized Tonic-Clonic Convulsions October 31, Complex partial seizure with secondary generalization:

4 4 Causes of focal & generalized epilepsy: Evolving Understanding Thomas and Berkovic. Nature Reviews Neurology 2014; 10: Multiple microdeletions increase risks for GGE + mild intellectual disability (ID) 20 Recurrent Microdeletion Rates in GGE and ID GGE Percentage of Probands Controls GGE ID GGE 16p q q13.3 All 3 Mullen et al. Neurology 2013; 81:

5 5 CNV Inheritance is Complex and Varied in Patients with Both GGE and ID Mullen et al. Neurology 2013; 81: Variable penetrance & expression in genetic generalized epilepsy: Penetrance is defined as the percentage of individuals with a given genotype who exhibit the phenotype associated with that genotype. Expressivity measures the extent to which a given genotype is expressed at the phenotypic level. October 31, 2016 Griffiths AJF. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman;

6 6 Treatment Options Generalized Onset Old Valproate (VPA) Phenobarbital (PHB) New Lamotrigine (LTG) Topiramate (TPM) Zonisimide (ZNA) Levtiracetam (LVT) Perampanel (PER) Mixed (Lennox-Gastaut) Rufinamide Clobazam CBD Partial Onset Old Phenytoin (PHT) Carbamazepine (CBZ) Phenobarbital (PHB) Valproate (VPA) New Tiagabine (TGB) Levtiracetam (LVT) Lamotrigine (LTG) Gabapentin (GBP) Topiramate (TPM) Oxcarbazepine (OXC) Zonisimide (ZNA) Pregabalin (PGB) Lacosamide (LCS) Retigabine (EZB) Eslicarbazepine (ESL) Perampanel (PER) AED Efficacy 1st AED 2nd AED 3rd AED Duotherapy Newly diagnosed epilepsy n=470 Seizure-free 47% Uncontrolled seizures 53% Seizure-free 13% Uncontrolled seizures 40% Kwan P, et al. N Engl J Med. 2000;342: Seizure-free 1% Uncontrolled seizures 39% Seizure-free 3% Uncontrolled seizures 36%

7 7 Quality of life in Epilepsy: Decreases with adverse medication effect & depression Gilliam. Neurology 2002;58:S9-S20 Anti-Seizure Medications Brivaracetam Perampanel Retigabine Eslicarbazepine ASMs 20 Levetiracetam Lacosamide Rufinamide Pregabalin Stiripentol 15 Tiagabine Topiramate Felbamate Oxcarbazepine Fosphenytoin Gabapentin 10 Sodium Valproate Zonisamide Lamotrigine Vigabatrin 5 Bromide Phenobarbital Carbamazepine Ethosuximide Benzodiazepines Phenytoin Primidone Calendar year

8 8 Patient Profile: individualized therapy Patient Factors New onset vs refractory Seizure type G/P Etiology Other meds yes Co morbid conditions yes Age 75 Childbearing age Compliance Drug Factors Side effects Emergent Dose related Idiosyncratic Long term Drug interactions Ease of use Escalation Lamotrigine Levetiracetam Lacosamide Caution with new Antiseizure drugs: Ezogabine/Retigabine > 2 yrs exposure, 10%: sclera, conjunctive, lips, nail beds and scattered Retinal pigment clumping, 30% Urinary retention: 2% Garin S TJAMA Dermatol. 2014

9 9 Quarterly use and cost of AEDs used to treat epilepsy 9,000,000 8,000,000 7,000,000 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000, /2006 1/2007 4/2007 7/ /2007 1/2008 4/2008 7/ /2008 1/2009 4/2009 7/2009 Quarter $900,000,000 $800,000,000 $700,000,000 $600,000,000 $500,000,000 $400,000,000 $300,000,000 $200,000,000 $100,000,000 $0 Epilepsy Dollar Sales Epilepsy TRx Epilepsy Dollar Sales IMS National Prescription Audit (NPA), IMS National Sales Perspective (NSP), and IMS National Drug and Therapeutic Index (NDTI). The Epilepsy Foundation,

10 10 Generic Drug Costs at JHH Price ranges for generic and brand AEDs per pill at Johns Hopkins Outpatient & Moore Clinic Pharmacies AED (Brand Name) Generic Brand Name Carbamazepine 200 mg (Tegretol) $0.14 $1.03 Divalproex 250 mg (Depakote) $0.19 $1.93 Gabapentin 600 mg (Neurontin) $0.35 $3.52 Lamotrigine 25 mg (Lamictal) $0.20 $4.86 Levetiracetam 250mg (Keppra) $0.47 $3.54 Oxcarbazepine 600 mg (Trileptal) $1.18 $6.25 Topiramate 25mg (Topamax) $0.15 $2.85 Zonisamide 100 mg (Zonegran) $0.32 $3.22 Levetiracetam ER (Keppra XR) $1.00 $3.88 Source: accessed May 11, 2010 Case series: seizures after Dilantin substitution Burkhardt RT, Leppik IE, Blesi K, Scott S, Gapany SR, Cloyd JC. Lower phenytoin serum levels in persons switched from brand to generic phenytoin.neurology. 2004;63(8):

11 11 BE study: Taro generic carbamazepine (ANDA ) Bioequivalence Using 400 mg Oral Dose (2x200 mg tablets) of Carbamazepine C max Concentration [ng/ml] AUC CBZ Generic Tegretol 0 0 T max = Time (hr) Cmax, fasting conditions 90% Confidence Intervals (Test/Reference) Cmax, fed conditions 90% Confidence Intervals (Test/Reference) PHT CBZ CBZ - Sprinkle DVP Test/Reference Ratio Test/Reference Ratio Figure 2 (C/D)

12 12 AUC0-t generic/reference products: Fasting & Fed BE studies (hr*ng/ml) 0%-5% Difference >5%-10% Difference >10%-15% Difference >15%-25% Difference % 0.00% CBZ VPA GBP LTG LEV OXC TOP ZON Total (all drugs) Fasting Fed Fasting Fed Fasting Fed Fasting Fed Fasting Fed Fasting Fed Fasting Fed Fasting Fed Fasting Fed Modified release-aeds: Increased Food effects compared to IR 45% 40% 35% Differences in Fed versus Fasting BE Studies (AUC) 45% 40% 35% Differences in Fed versus Fasting BE Studies (Cmax) Percent of Studies 30% 25% 20% 15% 30% 25% 20% 15% Fed Greater Fasting Greater 10% 10% 5% 5% 0% 0-5% 5-10% 10-15% 15-20% >20% Difference Between Fed and Fasting 0% 0-5% 5-10% 10-15% 15-20% >20% Difference Between Fed and Fasting

13 13 Generic lamotrigine versus brand name Lamictal in patients with epilepsy Epilepsia Volume 56, Issue 9, pages , 23 JUL 2015 DOI: /epi Conclusions: generic antiseizure drugs Generic products are typically 75% cheaper than reference products and so should be used by most patients. Individual patients with seizures or possible adverse drug effects after formulation changes can be evaluated with seizure and pilltaking diaries & levels Individual dosing needs often dominate possible product switching effects. A small number of AEDs have complex kinetics (phenytoin) or variable absorption (carbamazepine) it may be best to use single formulations of modified release formulations of these drugs along with careful clinical monitoring

14 14 New Surgical & Stimulation Approaches Laser ablation of amygdala/hippocampus for temporal lobe epilepsy & focal epileptogenic lesions Responsive neural stimulation for nonresectable focal epilepsy (critical motor/language cortex; two foci) Thermal Ablation Stereotactic placement of probe to ablate small targets in brain responsible for seizures Hippocampal sclerosis Periventricular nodular heterotopia Cortical dysplasia

15 15 Ablation 1 Test Dose 3W for 32 sec Laser Doses 10W for 170 sec 12W for 63 sec Final Images Irreversible Damage Estimate 19mm by 13mm Axial Visualase images Treatment Temperature Map Irreversible Damage Estimate Procedure Verification Target Area Irreversible Damage Estimate Ablation Pre procedure Axial images Visualase Image Post procedure

16 16 Patient #2 Principles: Select new AEDs by side-effect and efficacy profile: match to Pt. lamotrigine not potent against seizures, but mild epilepsy few cognitive side-effects appropriate for patient Allergic rx: variation between standard/new AEDs Neurostimulation for Epilepsy 2015 Responsive neurostimulation (RNS, Neuropace) Safety and tolerability demonstrated in unblinded study that suggested efficacy Recruitment 191 patients at 32 sites completed pivotal trial Statistically significant reduction in seizures, 29% reduction in seizures during last 2 months of blinded period FDA approval

17 17 RNS Implant - JHMI 3 subdural strip arrays 1 depth array JH RNS Study Group Heterotopias Implantable RNS Mix signal (analog) chip (takes in signals/digitizes/sends to digital chip Figure 1: Responsive NeuroStimulator implant shown in hypothetical two lead configuration. Digital processor (100 khz) 3.5 cm Memory chip (EEG storage)

18 18 Seizure detection Using proprietary software algorithms Detection of spontaneous seizure triggers stimulation Spontaneous Seizure Electrical Stimulation Seizure Terminated Responsive stimulation Current issues in epilepsy: Epilepsy and the elderly: Most common group newly diagnosed with epilepsy Special treatment considerations Treat underlying vascular & health causes Sudden unexpected death with epilepsy (SUDEP) Sudden death, usually nocturnal during seizures 1/500 risk per year (1% per year if uncontrolled epilepsy) Identifying risks & prevention October 31, 2016

19 19 Incidence of Unprovoked Seizures in Developed Countries Cloyd et al. Epilepsy Res 2006;68(Suppl 1):39-48

20 20 Microvascular disease in young elderly patient with complex partial seizures 39 Exercise training increases size of hippocampus and improves memory in the Elderly *Exercise induced increase in hippocampal volume is correlated with increase in serum BDNF, a mediator of neurogenesis in the dentate gyrus Erickson et al. PNAS. 2011; 108:

21 21 Sudden unexpected death in epilepsy: Cumulative Risk of SUDEP from age of epilepsy onset Thurman, D. J., Hesdorffer, D. C. and French, J. A. (2014), Epilepsia, 55: Sudden unexpected death in epilepsy (SUDEP) Tonic clonic seizures produce: O2 desaturation Post-ictal generalized EEG suppression Peri-ictal autonomic alterations Patients sleeping facedown: Immobility during post-ictal suppression period suffocation & apnea with post-ictal hypoxemia cardiac arrhythmias, need for resuscitation Role for seizure detection devices & intervention October 31,

22 22 EpiWatch research app October 31, 2016 Seizure Detection: Non-EEG seizure detection Alerting and logging (mobile devices) Emergency care delivery, SUDEP intervention Seizure frequency, triggers Medication adherence and side effects Detect clinical manifestations Convulsions, shaking (accelerometer) Falls (gyroscope) Heart rate increase in 80% (PPG) Unresponsiveness (interactive UI)

23 23 US EpiWatch research participants % change between initial HR and max HR 130 % change b/w previous HR & max HR Legend Tonic Clonic (N=73) Complex Partial (N=172)

24 24 Seizure related movements & heart rate changes measured with EpiWatch SUDEP Intervention Nocturnal Convulsion Post-ictal generalized EEG suppression Peri-ictal autonomic alterations Immobility Apnea Post-ictal hypoxemia Cardiac Arrhythmias SUDEP EpiWatch Seizure Detector Alerting Caregiver Interventions: -Turn on side -Stimulate Resuscitate

25 25 Summary: Epilepsy disease has special stigma/social challenges Many new medical & surgical treatments available for 40% with medication resistant epilepsy Changing demographic landscape: elderly Individual risk monitoring: SUDEP