1. One Size Does Not Fit All: Personalized Treatment of Patients with Epilepsy
Vikram R. Rao, MD, PhD
University of California, San Francisco, Epilepsy Center, San Francisco, California
A REPORT FROM THE 67TH ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY (AES 2013)
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2. Personalized Treatment in Epilepsy
Epilepsy: enduring tendency for recurrent seizures
4th most common neurological disorder; lifetime prevalence is 1 in 26 individuals.
Evidence for superiority of one antiepileptic drug (AED) over another is often lacking.
AEDs are chosen based on patient-specific factors:
Genetic information
Physical characteristics and comorbid conditions
Concurrent medications
Individualizing treatment may maximize tolerability, adherence, and efficacy
Chang BS, Lowenstein DH. N Engl J Med. 2003;349:1257; Fisher RS et al. Epilepsia. 2005;46:470; Institute of Medicine, 2012; Glauser T et al. Epilepsia. 2013;54:551; French JA, Gazzola DM. Continuum. 2013;19:643
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3. Pharmacogenomics in Epilepsy
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4. Pharmacogenomics: Overview
Pharmacogenomics: use of biomarkers related to a patient’s genome to guide drug therapy
Chan A et al. Ann Neurol. 2011;70:684
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5. Pharmacogenomics: To Avoid Adverse Drug Reactions
HLA-B*1502 allele predicts carbamazepine (CBZ)-induced Stevens-Johnson syndrome in patients of Han Chinese and South Asian ancestry; pre-treatment testing recommended in these patients.
HLA-A*3101 allele may be a marker of CBZ-induced drug reactions in other patient populations.
Avoid sodium channel blockers, such as lamotrigine (LTG), in syndromes with SCN1A mutation (eg, Dravet syndrome).
Research is ongoing for markers of valproate (VPA)-induced weight gain and vigabatrin retinopathy.
Chung WH et al. Nature. 2004;428:486; McCormack M et al. N Engl J Med. 2011;364:1134; Ozeki T et al. Hum Mol Genet. 2011;20:1034; Belcastro V et al. Epilepsy Res. 2013;107:1; Kinirons P et al. Epilepsy Res. 2006;70:144
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6. Pharmacogenomics: To Predict Favorable Treatment Responses
Some previously medically refractory patients can achieve seizure freedom with levetiracetam (LEV).
Genetic basis of these “dramatic responders” is elusive.
Functional variants of cytochrome P-450 enzymes affect phenytoin (PHT) metabolism.
SCN1A polymorphisms may influence maximum dose and serum levels of CBZ and PHT.
A patient’s genetic profile may eventually be used to determine optimal medical therapy, but ethical, financial, and legal issues abound.
Nicolson A et al. Neurology. 2004;63:568; Lynch JM et al. Epilepsy Res. 2009;83:44; Dibbens et al. Epilepsy Res. 2012;101:277; Aynacioglu AS et al. Br J Clin Pharmacol. 1999;48:409; Chaudhry AS et al. J Pharmacol Exp Ther. 2010;332:599; Tate SK et al. Proc Natl Acad Sci U S A. 2005;102:5507; Tate SK et al. Pharmacogenet Genomics. 2006;16:721; Zimprich F et al. Epilepsia. 2008;49:1108
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7. Personalizing Drug Delivery
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8. Personalizing Drug Delivery: Formulation
Extended-release (ER) AED formulations allow more gradual systemic absorption vs immediate-release
ER formulations offer several advantages:
Less variability in serum drug levels
Lower incidence of peak-dose toxicity
Increased patient convenience (may favor compliance)
Benefit directly demonstrated for LTG vs ER CBZ
Potential disadvantages of ER formulations:
Higher cost
High peak serum levels may be desired when treating seizures with predictable diurnal variation
Shorter “forgiveness period”
Bialer M. CNS Drugs. 2007;21:765; Canger R et al. Acta Neurol Scand. 1990;82:9; Brodie MJ et al. Epilepsy Res. 1999;37:81; Saetre E et al. Epilepsia. 2007;48:1292; Guilhoto LM et al. Epilepsy Behav. 2011;20:334
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9. Personalizing Drug Delivery: Route of Administration
Rectal diazepam in solution leads to a more rapid increase in serum drug levels than rectal suppositories (basis for Diastat®)
RAMPART study: Intramuscular midazolam is superior to intravenous (IV) lorazepam for pre-hospital treatment of status epilepticus
Higher rate of seizure freedom on arrival to hospital:
Lower rates of hospital/ICU admission
Issues: difficulty obtaining IV access; shorter half-life of lorazepam out of refrigeration
Sublingual lorazepam associated with higher rates of treatment failure compared with rectal diazepam
Knudsen FU. Acta Paediatr Scand. 1977;66:563; Kriel RL et al. Pediatr Neurol. 1999;20:282; Silbergleit R et al. N Engl J Med. 2012;366:591; Silbergleit R et al. Epilepsia. 2013;54(suppl 6):74; Malu CK et al. J Child Neurol. 2013
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10. Personalizing Drug Delivery: Dosing Considerations
Setting (eg, pre-hospital vs hospital; household vs ambulance)
Clinical urgency (eg, status epilepticus vs self-limited seizure)
Ease of obtaining IV access
Logistical considerations of particular medications and formulations (eg, availability, storage requirements, cost)
Regulatory approval status and extent of data supporting clinical efficacy
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11. Cutaneous Drug Reactions
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12. Cutaneous Drug Reactions: Epidemiology
Among treatment-related side effects underlying AED intolerance, rash is one of the most common.
Adverse cutaneous drug reactions (ACDRs) affect 2% of hospitalized patients.
With AEDs, 15% of patients will develop a rash within 4 weeks of drug initiation.
Risk factors for ACDRs:
Age
Number of comorbid conditions
Polypharmacy
Immunosuppression
Female gender (?)
Chung S et al. J Br Epilepsy Assoc. 2007;16:296; Arndt KA, Jick H. JAMA. 1976;235:918; Porter J, Jick H. JAMA. 1977;237:879; Blaszczyk B et al. Pharmacol Rep. 2013;65:399; Liao PJ et al. Int J Clin Pract. 2013;67:576; Todd G. Dermatol Clin. 2006;24:459
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13. Cutaneous Drug Reactions: Clinical Manifestations
Broad spectrum of severity:
Mild, diffuse, morbiliform rash life-threatening multisystem illness
Key factors for initial evaluation:
Need to determine chronicity, distribution, pattern, organization, morphology, probable anatomic depth, and mucosal membrane involvement
Reactions that are likely immunologic:
Activated T lymphocytes and macrophages can be found in areas of damaged skin.
Caproni M et al. Br J Dermatol. 2006;154:319
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14. Cutaneous Drug Reactions: DRESS
Drug reaction with eosinophilia and systemic symptoms (DRESS):
Morbiliform cutaneous eruption involving the face, trunk, and limbs, along with fever, lymphadenopathy, hematologic abnormalities, and organ dysfunction (especially the liver)
Mortality ~ 10%
Aromatic AEDs, particularly CBZ, and sulfonamides are the most common inciting agents.
Typically develops 2–6 weeks after treatment initiation
Several formal diagnostic criteria exist
Husain Z, et al. J Am Acad Dermatol. 2013;68:693; Kardaun SH et al. Br J Dermatol. 2013;169:1071; Bocquet H et al. Sem Cutan Med Surg. 1996;15:250; Kelly JP et al. J Clin Epidemiol. 1995;48:1099
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15. Cutaneous Drug Reactions: SJS/TEN
Stevens-Johnson syndrome (SJS): less than 10% body surface area (BSA) skin detachment
Toxic epidermal necrolysis (TEN): differs from SJS only in severity; greater than 30% of BSA involvement, higher mortality
Usually 1–3 weeks after drug initiation, prodromal phase of flu-like symptoms
PHT, PHB, CBZ, and LTG are most often associated with SJS/TEN; estimated incidence: 1–10/10,000 new users; case reports exist of other AEDs causing SJS/TEN
Tartarone A, Lerose R. Ther Drug Monit. 2010;32:669; Mockenhaupt M et al. Neurology. 2005;64:1134; Zou LP et al. Seizure. 2012;21:823; Duong TA et al. JAMA Dermatol. 2013;149:113; Naveen K et al. Int J Crit Illness Injury Sci. 2012;2:44
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16. Cutaneous Drug Reactions: Treatment
Prompt withdrawal of the offending agent and initiation of aggressive supportive care remain the mainstays of treatment
Topical corticosteroid therapy is common.
Systemic corticosteroids and other immunosuppressive agents are controversial.
Intensive care or burn unit needed for management of systemic complications and to optimize fluid status, nutrition, analgesia, and infection control
Husain Z et al. J Am Acad Dermatol. 2013;68:709; Tas S, Simonart T. Dermatology. 2003;206:353
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17. Epilepsy in Women
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18. Epilepsy in Women: Catamenial Epilepsy
Estrogen: proconvulsant
Progesterone: neuroinhibitory
One-third of women with focal epilepsy demonstrate a catamenial pattern.
Seizures occur at times during menstrual cycle when estrogen level exceeds progesterone level or when levels of either hormone are changing rapidly.
Cyclic progesterone therapy may be beneficial for a subset of women with catamenial epilepsy.
Less robust evidence for acetazolamide and clobazam
Pennell PB. Continuum. 2013;19:697; Herzog AG et al. Neurology. 2012;78:1959; Harden CL, Pennell PB. Lancet Neurol. 2013;12:72
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19. Epilepsy in Women: Contraception
Enzyme-inducing AEDs lead to increased clearance—and thus decreased contraceptive efficacy—of sex hormones.
Estrogen-containing contraceptives induce hepatic enzymes and may decrease the serum concentration of certain AEDs such as LTG.
Best options for women with epilepsy are long-acting reversible contraceptives:
Progestin implants
Intrauterine devices (IUDs)
Davis AR et al. Epilepsia. 2011;52:243; Reimers A et al. Epilepsia. 2005;46:1414.
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20. Epilepsy in Women: Risk of Congenital Malformations
~3.5% of women in their reproductive years may be taking an AED for epilepsy or other indications (eg, headache, pain, or a mood disorder).
AED use increases the risk of major congenital malformations to 3%–9%, about two- to threefold higher than the risk in the general population.
Fetal exposure to valproate has been associated with dose-dependent impairment in cognitive abilities during childhood.
LTG is often considered the drug of choice during pregnancy.
Pennell PB. Continuum. 2013;19:697; Meador KJ et al. Neurology. 2008;71:1109; Harden CL et al. Neurology. 2009;73:133; Holmes LB et al. N Engl J Med. 2001;344:1132; Tomson T, Battino D. Lancet Neurol. 2012;11:803; Meador KJ et al. Lancet Neurol. 2013;12:244
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21. Epilepsy in Women: Risk of Congenital Malformations
Rates of major congenital malformations at one year after birth in relation to exposure to AED monotherapy
Tomson T, Battino D. Lancet Neurol. 2012;11:803; Tomson T et al. Lancet Neurol. 2011;10:609
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22. Epilepsy in Women: Managing Epilepsy During Pregnancy
20%–33% of women with epilepsy experience an increase in seizure frequency during pregnancy.
Optimize seizure control before pregnancy; seizure freedom for at least 9 months prior to pregnancy is associated with an 84%–92% chance of remaining seizure-free during pregnancy.
Avoid polytherapy if possible
Monitor therapeutic drug levels, especially of LTG and LEV, monthly.
Folic acid supplementation, 0.4–5.0 mg/d
Anon. Neurology. 2006;66:354; Harden CL et al. Neurology. 2009;73:126; Pennell PB et al. Neurology. 2008;70:2130; Pennell PB, Hovinga CA. Int Rev Neurobiol. 2008;83:227; Harden CL et al. Neurology. 2009;73:142; Thomas SV. Neurol India. 2011;59:59
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23. Epilepsy in Patients with HIV
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24. Epilepsy and HIV: Treatment Issues in Patients with HIV
Multiple considerations in the personalized treatment of epilepsy in patients infected with human immunodeficiency virus
ARV = antiretroviral therapy AED = antiepileptic drug
From a presentation made by Gretchen L. Birbeck, MD, PhD, at AES 2013
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25. Epilepsy and HIV: Drug Interactions
Concurrent use of AEDs with antiretroviral medications (ARVs) is common, and the potential interactions between these drug types are extensive, for example:
Avoid saquinavir in patients on potentially arrhythmogenic AEDs, such as ezogabine or lacosamide
Rilpivirine and etravirine are contraindicated with CBZ, oxcarbazepine, PHB, and PHT
Avoid enzyme-inducing AEDs in patients taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors
Most benzodiazepines are contraindicated with ARVs due to the risk of prolonged sedation.
AED/ARV interactions have clinical implications for disease progression and emergence of ARV resistance.
Birbeck GL et al. Neurology. 2012;78:139; Siddiqi O, Birbeck GL. Curr Treat Options Neurol. 2013;15:529
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26. Epilepsy and HIV: Management of Epilepsy
Treatment with ARVs is recommended for all HIV-positive patients, so potential drug-drug interactions should be anticipated before starting AEDs in an HIV-positive patient
The AED of choice in HIV-positive patients is LEV, due to its broad-spectrum activity, ease of use, minimal drug interactions, and favorable side-effect profile.
Alternatives: pregabalin, gabapentin, lacosamide
Valproate is also favorable because it will not induce ARV metabolism, but its side-effect profile may be somewhat worse than that of other therapeutic options.
Siddiqi O, Birbeck GL. Curr Treat Options Neurol. 2013;15:529
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