Excess mortality and hospitalized morbidity in newly treated epilepsy patients Chen Z, Liew D, Kwan P Published in Neurology online before print 07/15/2016 doi: 10.1212/WNL.0000000000002984 Presented by Kurt Qing, MS4

Outline Epilepsy overview Study overview Study methods Study results Study discussion Study Limitations Ponderings

Epilepsy overview Definition: Two or more (24 hours apart) unprovoked epileptic seizures Types Partial (focal) : simple vs complex Partial with secondary generalization Generalized Worldwide stats: prevalence: 2.7 – 17.6 per 1000 incidence: 16 – 51 per 100,000 per year (WHO & Epilepsy Foundation similar numbers) Banerjee PN, Filippi D, Hauser WA, The descriptive epidemiology of epilepsy—A review. Epilepsy Research. 85(1) July 2009: 31-45.

Study overview “Quantify the burden of mortality and hospitalized morbidity” in patients with newly diagnosed and treated epilepsy Exposure to CYP450-inducing AED Retrospective cohort Mortality, hospitalizations, new comorbidities Baseline comorbidities, mono vs multi AED, CYP450-inducing AED

Study Methods Hong Kong Hospital Authority (HKHA) In-patient records Public health care Covers >90% of population In-patient records Discharge summaries 9/16/2005 – 9/15/2010 Followed until 9/15/2011 ICD-9-CM No previous epilepsy diagnosis or treatment

Study Methods Standardized mortality ratio (SMR) Obs/Exp (Census 2006 – 2011) Standardized hospitalization rate (SHR), length of stay ratio (SLR), and SLR per admission (SLRA) Obs/Exp (HKHA 2006 – 2011)

Study Methods Standardized incidence ratios (SIR) Statistics w/ STATA Obs/Exp (HKHA+ 2006 – 2011) Only in patients w/o prior comorbidity >30 days after starting AED Statistics w/ STATA Byar approximation for 95% CIs Glm w/ log-binomial regression Photo from Wikipedia

Study Results

Study Results

Study Results

Study Results low n Cohort SMR 5.09 (4.88 – 5.31) Supplementing table e-3 data

Study Results

SMR also higher with psych and physical + psych comorbidities Study Results Multi AEDs, SMR = 5.98 (5.53 – 6.47) Single AEDs, SMR = 4.80 (4.56 – 5.05) SMR also higher with psych and physical + psych comorbidities

Study Results

Study Results

63% non-seizure-related Study Results 63% non-seizure-related Physical only

Study Results

Study Results Overall RR mono vs multi 1.02 (0.85 – 1.23) Age >35 SIR acute stroke 4.96 (4.19 – 5.84), esp in age 35-44 Overall RR enzyme vs none 1.48 (1.19 – 1.85) Total SIR cancer 1.97 (1.56 – 2.46), higher in men only Total SIR MI 4.18 (3.54 – 4.91), female > men

Study Results (summary) Higher SMR in… Hong Kong overall Young age Pts with baseline comorbidities Pts taking multiple AEDs Higher SHR Higher SIR for stroke, cancer, and ischemic heart disease

Study Discussion/Conclusions Epilepsy and cancer may have common etiology factors No association b/w AED and cancer EIAEDs may increase stroke and coronary disease by affecting cholesterol metabolism Bidirectional relationship between epilepsy and psychiatric disorders

Study Limitations Surveillance bias e.g. occult cancer Public hospitals records only – underestimating Older, sicker patients Starting AED Requiring hospitalization No cause of death data (future)

Study Limitations (critique) Varying length of follow-up (1 to 6 years) Study population not representative Mean onset age 20 in HK in general (Fong 2003) Median onset age 60 in study Control M&M data for hospitalized patients Comparing standardized ratios indirectly rather than relative risks (only table 4) No data on seizure control (refractory?) Fong GCY, et al. "A prevalence study of epilepsy in Hong Kong." Hong Kong Med J. 9(4) 2003: 252-257.

Study Limitations (critique) Exposure to other enzyme-inducing agents (i.e. for comorbidities) EIAED and liver disease No data on adverse effects or toxicity EIAED and stroke Ischemic, embolic, hemorrhagic

Study Limitations (critique) Olesen JB et al. Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study. Pharmacoepidem Drug Safe. 20 (2011): 964–971. 

Ponderings Multiple logistic regression (n = 7,461) Relationships among age, specific baseline and new comorbidities, AED use, mortality, morbidity Quickly determine predictive factors and interactions Predictive factors plus cause of death Ex: young health patients on mono-AED tend to die of sudden death whereas older patients tend to die of stroke.

Thank you!