Prescribing and Monitoring Anti-Epileptic Drugs€¢Gamma knife •Laser ablation •Device therapy...
Transcript of Prescribing and Monitoring Anti-Epileptic Drugs€¢Gamma knife •Laser ablation •Device therapy...
Prescribing and Monitoring Anti-Epileptic Drugs
Mark Granner, MD
Clinical Professor and Vice Chair for Clinical Programs
Director, Iowa Comprehensive Epilepsy Program
Department of Neurology
University of Iowa Hospitals and Clinics
Disclosure
• I have no actual or potential conflicts of interest in relation to the content of this lecture.
Iowa Comprehensive Epilepsy Program
Basic Premise
• Epilepsy is an ideal condition to manage in an integrated care delivery model• Emergency care
• Primary care
• Secondary care (Community Neurology)
• Tertiary care (Epilepsy Center)
Iowa Comprehensive Epilepsy Program
Definitions
• Seizure• A paroxysmal alteration in behavior associated with
hyperexcitability of a population of neurons
• Provoked seizure• A seizure occurring in the setting of some systemic provoking
factor
• Epilepsy• At least 2 unprovoked seizures at least 24 hours apart• One unprovoked seizure and a probability of further seizures equal
to above (60%)• First degree family history
• Abnormal EEG
• Abnormal MRI
Iowa Comprehensive Epilepsy Program
Epidemiology of EpilepsyUnited States Number
Epilepsy total 3,000,000
New cases per year 150,000
Refractory epilepsy 1,000,000
Potential surgical candidates
200,000
Surgery per year 1,500
Iowa Number
Epilepsy total 30,000
New cases per year 1,500
Refractory epilepsy 10,000
Potential surgical candidates
2,000
Surgeries per year 25
Diagnosis of Epilepsy: History
• History• Events
• Duration, responsiveness, movements• Risk factors
• Febrile seizures• TBI, CNS infection, stroke, neoplasm• Family history• Autoimmune disease
• Provoked by• Alcohol, sleep deprivation, stress, lights
Iowa Comprehensive Epilepsy Program
Diagnosis of Epilepsy: Tests
• MRI
• EEG
• In the ED consider• CBC, electrolyte panel• Urine drug screen• CT• Lumbar puncture
Iowa Comprehensive Epilepsy Program
Tonic
Clonic
Tonic-clonic
Atonic
Myoclonic
Absence
Secondary Generalized
GeneralizedPartial
Previous Classification of Seizure Types
Unclassified
Simple Complex
MotorTonic-clonic
Other motor
Non-Motor (Absence)
Unknown Onset
Motor
Non-Motor
Focal to bilateral tonic-clonic
Generalized OnsetFocal Onset
Motor
Tonic-clonic
Other motor
Non-Motor
ILAE 2017 Classification of Seizure Types Basic Version
Unclassified
Aware Impaired
Awareness
Fisher RS, et al. Instruction Manual for the ILAE 2017 Operational Classification of Seizure Types. Epilepsia 2017.
First vs Second Generation AEDs
• No significant difference in efficacy
• Significant difference in toxicity• Generally wider therapeutic windows
• Fewer (or no) drug interactions, hepatic enzyme induction
• Less adverse effect on bine density
• More “broad spectrum” options
• Allow for more individually tailored therapy
Pharmacotherapy of Epilepsy
First Generation (1900-1978)
Generic Name Brand Name
Phenobarbital
Phenytoin Dilantin
Primidone Mysoline
Ethosuximide Zarontin
Carbamazepine Tegretol
Valproic acid Depakote
Second Generation (1993-2009)
Generic Name Brand Name
Gabapentin Neurontin
Lamotrigine Lamictal
Topiramate Topamax
Oxcarbazepine Trileptal
Levetiracetam Keppra
Zonisamide Zonegran
Pregabalin Lyrica
Rufinamide Banzel
Lacosamide Vimpat
Iowa Comprehensive Epilepsy Program
Pharmacotherapy of Epilepsy:Effective For Partial SeizuresTeratogenicity < 3%Minimal/No Averse Effect on Bone DensityGeneric Formulation AvailableExtended-Release Formulation Available (or long half-life)
First Generation (1900-1978)
Generic Name Brand Name
Second Generation (1993-2009)
Generic Name Brand Name
Lamotrigine Lamictal
Oxcarbazepine Trileptal
Levetiracetam Keppra
Zonisamide Zonegran
Iowa Comprehensive Epilepsy Program
Epilepsy Medication in Primary CareMedication (Brand) Use Disadvantages
Ethosuximide (Zarontin)
Absence epilepsy. Will not treat GTC, focal seizures.
Levetiracetam(Keppra)
Any seizure type. IV form for emergency use.
No significant.
Lorazepam (Ativan)
Acute repetitive seizures, status epilepticus.
Short half-life. Tolerance to chronicuse.
Phenytoin (Dilantin)
Status epilepticus.Partial sz or GTC.
Side effects, drug interactions.(e.g. osteoporosis)
Iowa Comprehensive Epilepsy Program
Monitoring Considerations
Medication(Brand)
Considerations
Lamotrigine(Lamictal)
Metabolism increased with CYP450 inducersphenytoin, carbamazepine, phenobarbital
Metabolism decreased by valproic acidLevels fall (up to 50%) through pregnancy
Measure plasma concentrations at least twice per trimesterAdjust dose as neededReturn to previous dose after delivery
Initial titration must be slow (add 25 mg per week)SJS, TEN, other rashes
Levetiracetam(Keppra)
Not liver metabolizedRenal excretion
Adjust dosing in chronic or acute kidney disease
Levels fall through pregnancyMeasure plasma concentrations at least twice per trimesterAdjust dose as neededReturn to previous dose after delivery
When To Check Blood Levels
• Doing well baseline
• Pregnancy
• Adherence
• Drug interactions
• Breakthrough seizure
• NOT annually or per routine
Emergencies in Epilepsy: Status Epilepticus• Diagnosis
• Recurrent seizures without recovery to baseline• Single prolonged seizure (5-10 min)
• Incidence• 18.31-412 patients / 100,000• 55,000 - 125,000 SE cases / year in U.S.
• Mortality = 19-22%• 11,000 - 25,000 deaths per year in U.S.• Would rank #14 on CDC’s mortality list
• 12% of new onset epilepsy present with SE
Iowa Comprehensive Epilepsy Program
1 Hesdorffer, et al. 19982 DeLorenzo, et al. 1995
Treatment of Convulsive Status Epilepticus
• Benzodiazpine• IV lorazepam 0.1 mg/kg• IV diazepam 0.15 mg/kg • IV midazolam 0.2 mg/kg
• Long-acting AED• IV phenytoin/fosphenytoin 20 mg/kg• IV lacosamide 200 mg• IV valproate 30 mg/kg• IV levetiracetam 2000-6000 mg
• Refractory• pentobarbital 12 mg/kg; 0.2-0.4 mg/kg/hr• propofol 3-5 mg/kg; 1 mg/kg/hr• midazolam 0.2 mg/kg; 0.1-0.25 mg/kg/hour
Iowa Comprehensive Epilepsy Program
Drug Resistant Epilepsy: Definition
• Failure to completely control seizures despite trials of 2 anti-epileptic drugs (AEDs)• Appropriately chosen for seizure type
• Patient adherent
• Efficacy rather than tolerability failure
• 1/3 of epilepsy patients
• Only 4-6% will later achieve 1 year of seizure freedom
• $15,500,000,000 a year in U.S. (all epilepsy)• 76% ($11,780,000,000) by DRE patients
Iowa Comprehensive Epilepsy Program
Sudden, unexpected death in epilepsy (SUDEP)
• Leading cause of premature death in epilepsy patients
• Sudden death risk 20 times greater than in general population
• Risks• Severity of epilepsy
• Frequent generalized tonic clonic seizures• Polytherapy
• Male gender• Non-adherence (low drug levels)• Young age of onset and long duration of epilepsy
• Possible mechanisms• Respiratory + arousal depression• Cardiac arrhythmia• Autonomic dysfunction
Iowa Comprehensive Epilepsy Program Shorvon, Tomsen. Lancet, 2011.
Reducing the Risk of SUDEP
Now
• Optimize seizure control, especially GTCs• Referral to epilepsy center
• Educate patients and families
• Good adherence to therapy
• Alerting systems
• Not yet FDA-approved
Future?
• Predicting risk
• The search for a biomarker
• UI Center for SUDEP Research
• Detection/alerting/response systems
• Pharmacotherapy?
Iowa Comprehensive Epilepsy Program
Drug Resistant Epilepsy: Treatment OptionsPrimary
• Surgery• Resection• Disconnection• Minimally invasive
• Gamma knife• Laser ablation
• Device therapy• Vagus nerve stimulator
(VNS)• Responsive
Neurostimulating System (RNS)
Adjunctive
• Investigational drug trials
• Cannabidiol (CBD)
• Diet• Ketogenic• Modified Atkins
Iowa Comprehensive Epilepsy Program
EmergencyDepartment
Primary CareCommunityNeurologist
Epilepsy Center
First seizure
Integrated Epilepsy Management
Iowa Comprehensive Epilepsy Program
Seizures controlled Seizures not controlled/diagnosis in question
Initial consultation
Seizures not controlled/diagnosis
in question
Medication withdrawal
0
1
12
3
36+
Month
Seizures controlled
Modified from:
National Association of Epilepsy Centers, 2010
Resources• Epilepsy Foundation
• http://www.epilepsy.com/• www.epilepsyiowa.org• www.epilepsy.com/accelerating-new-therapies/new-
therapies-pipeline
• SUDEP resources• www.sudepaware.org• csr.case.edu
• University of Iowa resources• https://www.uihealthcare.org/epilepsy/• https://www.medicine.uiowa.edu/neurology/research/s
udep-research-program