Epilepsy for the General Internist

Transcription

1 Epilepsy for the General Internist William O. Tatum DO, FAAN, FACNS Professor of Neurology Mayo College of Medicine Senior Consultant, Mayo Clinic Florida Director, Epilepsy Center and Monitoring Unit Jacksonville, Florida USA 14th Annual Internal Medicine Conference March 26, MFMER slide-1

2 Confluence of Interest Professional Affiliations American Clinical Neurophysiology Society EFA and ILAE American Board of Clinical Neurophysiology Financial Disclosure Demos Publishers Inc., Springer Publishers Epilepsy & Behavior Case Report journal: Editor-in-Chief Grant support Mayo Clinic Brain Sentinel Consultant: SK Life Science 2016 MFMER slide-2

3 An 18 y/o female with migraine experienced her first grand mal seizure after partying the night before. In the ED, she was loaded with IV PHT and begun on PHT 200 mg PO BID (15 ug/dl). An increase in morning jerks occurred. Following a normal MRI and abnormal EEG with GSW, she was begun on VPA ER and titrated to 1000 mg PO q HS. She had no further seizures but she was dizzy, had blurry vision & an unsteady gait. VIDEO Does she have epilepsy? 2016 MFMER slide-3

4 The First Seizure Recurrence greatest in 1 st 2 years (21-45%). Response to the 1 st ASD predicts control. 1 + risk factors double the likelihood & treatment with ASDs halves it. 2 Prior brain insult (level A) Epileptiform EEG (level A) Abnormal MRI/nocturnal Sz (level B) ASD treatment renders 65-85% seizure free 3 SE occur in 7-31% (level B) Brodie MJ et al. Neurology 2012;78: Krumholz A et al. Neurology 2015;84: Hakami T, et al. Neurology 2013;81(10): Her EEG demonstrated epileptiform discharges 2016 MFMER slide-4

5 Epilepsy Definition: Epilepsy exists after a single unprovoked seizure when the risk of a recurrence is >60%. 1 Nearly 3 million people in U.S. One epileptic seizure/life-time occurs in 1/10 people. 70% of adults with new-onset epilepsy have focal seizures. 2 The cause is unknown in 62%. In the rest, stroke 9%, trauma 9%, alcohol 6%, neurodegenerative 4%, static encephalopathy 3.5%, brain tumor 3%, and infection in 2%. PCP in the US see 83% of new-onset cases; 40% with epilepsy Fisher R et al. Epilepsia 2014;55(4): French JA, Pedley TA. N Engl J Med 2008;359: Smith MC, Buelow J. Epilepsy. Dis Mon 1996;42(11): Yes, she does have epilepsy 2016 MFMER slide-5

6 Seizures are a Symptom An age-related predisposition exists that reflects cause. Brain malformations and infection during childhood Trauma and brain tumor in mid-life Stroke and dementia in later life Annegers JF. The Epidemiology of Epilepsy. In: Wyllie E, ed. The treatment of epilepsy: principles & practice. Philadelphia: LWW. 2001: MFMER slide-6

7 The Impact of Epilepsy Mental & physical QoL worse. Memory and cognitive impairment worse. Neurotoxicity due to ASDs and seizures. Co-morbidities are more common (DM, smoking, obesity, stroke, and depression greater). Injury, unemployment, household and lifetime income reduced, and health care overutilization is more common MFMER slide-7

8 Driving State-specific driving laws exist. Epilepsy increases the risk of MVAs (up to 7x). 1 Fatalities rare (<0.2%). 2 Most patients with epilepsy are controlled with ASDs and drive. 3 Inform the patient & document. 1. Lings S. Neurology 2001;57(3): Sheth S et al. Neurology 2004;63(6): Tatum WO et al. Epilepsy & Behav 2012;23(1): She must be seizure free 6 months to drive in Florida 2016 MFMER slide-8

9 Pharmacologic Management Classification is the foundation for ASD selection; focal or generalized? When unclear or unknown Broad spectrum ASDs VPA, LTG, TPM, LEV, ZNS Treatment should be a hierarchy Efficacy, safety, tolerability ASD monotherapy if possible Scheffer I et al. Epilepsia 2017:8 MAR 2017 DOI: /epi With myoclonus & GTC seizures she needs a broad spectrum ASD MFMER slide-9

10 Genetic Generalized Epilepsy Absence, myoclonic, (clonic)-tonic-clonic Genetic influence Common in children Normal neuroimaging and intelligence Treatment responsive ETH for CAE 1,3 VPA 1,3 (JAE, JME, GTC) LEV, LTG, TPM, ZNS 1.Nadkarni S et al. Neurology 2005;64(suppl3):S2-S11. 2.Nicolson A et al. JNNP 2004;75: Karceski S et al. Epilepsy & Behavior 2005;7:S1-S64. Our patient has Juvenile Myoclonic Epilepsy 2016 MFMER slide-10

11 Focal Epilepsy Most common type in adults > 60% of epilepsies Temporal lobe epilepsy is most common Focal seizures with and without impaired consciousness, focal evolving to convulsion Due to focal CNS lesion EEG may clarify seizure classification. Treatment *Initial: CBZ, LTG, OXC Alternate: LEV *Karceski S et al. Epilepsy & Behavior 2005;7:S1-S64. Up to 50% of JME manifest lateralized features MFMER slide-11

12 Encephalopathic Epilepsy Clinical features Mixed seizure types & cognitive impairment EEG abnormalities West s Syndrome Epileptic spasms Lennox-Gastaut syndrome Tonic-atonic Atypical absence Refractory to treatment; recurrent injury Broad spectrum ASDs Surgical procedures Winesett SP, Tatum WO. In: Wyllie s Treatment of Epilepsy Principles and Practice. 6th edition: Wolters Kluwer. Philadelphia, PA MFMER slide-12

13 Treatment Antiseizure Drugs 1 Seizure freedom No side-effects Epilepsy Surgery 2 Neurostimulation 3 Ketogenic Diet 4 1.Kwan P, Brodie MJ. Neurology 2003;60(Suppl 4):S2-S12. 2.Wiebe S et al. NEJM 2001;345: Cascino GD. Epilepsia 2008;49(Suppl 9): Sirven J et al. Epilepsia 1999;40: MFMER slide-13

14 Anti-Seizure Drugs None alter the course of the disease process ( AEDs ). All current ASDs provide symptomatic treatment. Effective in focal seizures 2/3rds of the time in generalized seizures 80-85% of the time. The response to ASD treatment has been stable over time. All ASDs potentially have adverse events and none treat the non-seizure symptoms (e.g. neurocognitive, psychosocial). No ASDs are truly prophylactic for prevention of epilepsy (due to trauma, stroke, brain tumor etc.). Mohanraj R, Brodie MJ. Eur J Neurol 2006;13: Kwan P, Schachter SC, Brodie MJ. N Engl J Med 2011;369: MFMER slide-14

15 Consider Treatment after a First Seizure If it really wasn t the first seizure and other seizure types were present (our patient). Prolonged seizure or status epilepticus A neurological deficit or abnormality on examination + immediate family history Abnormality on CT/MRI or on the EEG High risk jobs or patient/family opinion 2016 MFMER slide-15

16 Consider the Individual Seizure type and epilepsy syndrome Age Gender Pregnancy potential Comorbidities Co-medications Lifestyle Scheffer I, Epilepsy Currents Chung, JAMA MFMER slide-16

17 The Elderly >60 is fastest growing segment of population. Most have focal seizures. 3.3% in nursing homes on ASD 1. More concurrent medical disorders 2. Stroke, hepatic, renal disease Osteopenia/osteoporosis PHT is the most common ASD but LEV, LTG, GBP are a better choice 3. 1Garrad et al. Ann Neurol 2003;54: Ramsay RE, Rowan AJ, Pryor FM. Neurology 2004;9(suppl 5):S Rowan AJ et al. Neurology 2005;64: MFMER slide-17

18 Women of Childbearing Potential Childbearing potential 9-51 years old Contraception Pregnancy Vitamin supplementation Precautions Harden CL, Hopp J, Ting TY, et al. Practice parameter update: management issues for women with epilepsy: focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73: Tomson et al. Epilepsia. 2015;56(7): Folate 1-2 mg daily was recommended MFMER slide-18

19 What about ASDs and Pregnancy? Globally 15 million WWE are of child-bearing age. Uncontrolled GTC Sz can have devastating consequences (> 5 associated with lower IQ). 10-fold increase of SUDEP in pregnancy. VPA impairs cognitive development 6 years post-partum Lower IQ (~ 10 IQ points) Dose-dependence > 800 mg/day Baker GA et al. IQ after in utero exposure to AEDs: a controlled cohort study. Neurology 2015;84: Meador KJ et al. NEAD Sutdy Group. A prospective observational study. Lancet Neurol 2013;12: Adab N et al. The long term outcome of children born to mothers with epilepsy. JNNP 2004;75: N American Pregnancy Registry Fall 2014 Alternatives to VPA were recommended MFMER slide-19

20 Consider Co-morbidities Mental Health issues Select: LTG, VPA, OXC, PGB Avoid: PB, TPM, LEV, ZNS, PER Pain Select: GBP, PGB, TPM, CBZ Eating disorder: avoid drugs that impact weight Weight gain: VPA, GBP, PGB, CBZ, OXC, PER, EZO Weight loss: TPM, ZNS, FBM Hyponatremia (elderly, on diuretics) Avoid: CBZ, OXC, ESLI (CBZ derivatives) Cardiovascular risks (e.g. high cholesterol) Avoid: CBZ, PHT (P450 enzyme inducers) 2016 MFMER slide-20

21 Antiseizure Drugs The mainstay of epilepsy management in >90% of patients. 1 Choices are based on seizure type and epilepsy syndrome 2 Focal Epilepsy: Essentially all ASDs Generalized Epilepsy: VPA, LTG, TPM, LEV,? LCS, ETH (absence) Advantages of newer ASDs include tolerability and advantages of conventional ASDs is cost. 3 1.Marson A et al. The Lancet 2007;369: Tatum WO. Current Treatment Neurology French JA, et al. Neurology. 2003;60: Levetiracetam is a great option in JME. Eslicarbazepine acetate (Aptiom) $650 for a 30-day supply of 400 mg brand name Divalproex sodium (Depakote ER) $165 for a 30-day supply of 500 mg brand name $107 for 30-day supply of 500 mg generic Phenytoin (Dilantin) $28 for a 30-day supply of 100 mg brand name $18 for 30-day supply of 100 mg generic Perampanel (Fycompa) $712 for a 30-day supply of 4 mg brand name Levetiracetam (Keppra) $435 for a 60-day supply of 500 mg brand name $158 for 60-day supply of 500 mg generic Lamotrigine (Lamictal) $310 for a 30-day supply of 100 mg brand name $115 for 30-day supply of 100 mg generic Pregabalin (Lyrica) $153 for a 30-day supply of 75 mg brand name Gabapentin (Neurontin) $109 for a 30-day supply of 300 mg brand name $25.33 for 90-day supply of 300 mg generic Carbamazepine (Tegretol) $117 for a 60-day supply of 200 mg brand name $19 for 60-day supply of 200 mg generic Topiramate (Topamax) $506 for a 30-day supply of 100 mg brand name $147 for 30-day supply of 100 mg generic Oxcarbazepine (Trileptal) $193 for a 30-day supply of 300 mg brand name $90 for 30-day supply of 300 mg generic Zonisamide (Zonegran) $458 for a 60-day supply of 100 mg brand name $120 for 60-day supply of 100 mg generic 2016 MFMER slide-21

22 ASD Interactions Some ASDs (e.g. PHT, VPA) are highly protein bound and interact increasing free unbound drug concentrations. Some ASDs (i.e. PHT) induce the P450 enzyme system and increase the metabolism of lipid soluble drug clearance. Therefore, dose increases of other drugs may be required. e.g. contraception and anticoagulation compromised. Some ASDs (i.e. VPA) inhibit hepatic enzymes and reduce metabolism of other ASDs/drugs and cause toxicity requiring dose reductions. Some ASDs do both (e.g. TPM, ZNS)-variable effects. Levetiracetam has no drug-drug interactions 2016 MFMER slide-22

23 Consider Safety Steven-Johnson Syndrome: most of the ASDs Aplastic Anemia: carbamazepine, oxcarbazepine, felbamate Organ Failure (e.g. hepatic): valproate, felbamate Depression: phenobarbital, perampanel, leviteracetam, zonisamide topiramate, lacosamide Nephrolithiasis: topiramate, zonisamide Visual loss: vigabatrin, ezogabine Weight Loss: felbamate, topiramate, zonisamide Weight Gain: gabapentin, pregabalin, valproate, carbamazepine, perampanel, vigabatrin Teratogenesis: all ASDs 2016 MFMER slide-23

24 Sudden Unexpected Death in Epilepsy SUDEP is 24 times > the population involving /1000 person years. Young people years Males: females 7:4 Substance abuse Epilepsy > 10 years GTC seizures Unattended/prone position MR/Symptomatic epilepsy (1/100) VIDEO 2016 MFMER slide-24

25 Drug-resistance: A Treatment Approach Newly Diagnosed 1 st Monotherapy 2 nd Monotherapy 3 rd Mono or Polytherapy No Video-EEG Seizure reduction Minimize ASD side effect Optimize quality of life Seizure freedom No Side effects ASDs (Polytherapy) Neurostimulation Ketogenic Diet (children) Monitoring Epilepsy Surgery Drug Resistant In: Wheless JW, Willmore LJ, Brumback RA, eds. Advanced Therapy in Epilepsy. Hamilton, Ontario: BC Decker, Inc MFMER slide-25

26 Quality Indicators in Epilepsy 1. Seizure frequency & intervention noted each encounter. 2. Etiology, seizure type/syndrome noted each encounter. 3. Ask about side-effects to ASDs each visit. 4. Personalize safety issues/education yearly. 5. Screen for psychiatric health each visit. 6. Counsel women of childbearing yearly. 7. Refer drug-resistant patients to a CEC after 2 years. Fountain NB et al. Quality Improvement in Neurology: Epilepsy Update Quality Measurement Set. Neurology 2015;84(14): MFMER slide-26

27 Conclusions The treatment approach to epilepsy requires a definitive diagnosis and classification of seizure/epilepsy type. Management is individualized and a shift toward the new ASDs has been based upon Pks and tolerability. Drug-resistance is a problem and VEM and non-medical therapies should be considered a standard of care. The future promises better diagnosis and treatment for patients with epilepsy though the PCP plays a primary role for access to care MFMER slide-27

28 THE END 2016 MFMER slide-28