Epilepsy Specialist Symposium Treatment Algorithms in the Diagnosis and Treatment of Epilepsy

Epilepsy Specialist Symposium Treatment Algorithms in the Diagnosis and Treatment of Epilepsy November 30, 2012 Fred Lado, MD, Chair Montefiore Medical Center Albert Einstein College of Medicine Bronx, NY American Epilepsy Society Annual Meeting

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Epilepsy Specialist Symposium Treatment Algorithms in the Diagnosis and Treatment of Epilepsy November 30, 2012 Fred Lado, MD, Chair Montefiore Medical Center Albert Einstein College of Medicine Bronx, NY American Epilepsy Society Annual Meeting

Disclosure Nothing to disclose American Epilepsy Society Annual Meeting 2012

Learning Objectives Manage patients with first seizure by applying risk/benefit analysis using prediction of seizure recurrence based on presentation and ancillary tests Evaluate patients for epilepsy surgery weighing the advantages/disadvantages of different approaches and understanding the rationale for selecting a specific approach Appropriately refer patients for implantation of and will successfully treat them with neurostimulator devices Discuss SUDEP with patients/families utilizing knowledge of both indications for discussion and understanding of pathophysiology of SUDEP. American Epilepsy Society Annual Meeting 2012

Agenda Diagnosis and treatment of a first seizure Sheryl Haut, MD Debate surgical planning for extratemporal non-lesional surgery? Ashesh Mehta, MD and Francois Dubeau, MD Patient selection for treatment by devices (VNS, DBS) to palliate seizures Barbara Jobst, MD Discussing SUDEP Jeff Buchhalter, MD, PhD

First seizure: Diagnosis, treatment and prognosis November 30 th, 2012 Sheryl Haut, M.D. Associate Professor of Clinical Neurology Director, Adult Epilepsy Montefiore Medical Center Albert Einstein College of Medicine American Epilepsy Society Annual Meeting 8

Disclosure Acorda Vivus Upsher-Smith Neuronex Consultant Consultant Consultant Consultant American Epilepsy Society Annual Meeting 2012 9

Learning Objectives To become familiar with the epidemiology of a first seizure, including definitions and incidence To understand factors related to recurrence risk after a first seizure To recognize the role of treatment on recurrence risk and integrate this role into clinical practice American Epilepsy Society Annual Meeting 2012 10

7 year old girl presents after a first convulsive seizure noted by her parents Seizure Description Nocturnal, during sleep Self limited after 2 minutes Medical history Normal birth and early development No medical problems No recent infections Family history One first cousin with epilepsy 11

Definitions First unprovoked seizure A seizure occurring in a person >1 month of age with no prior history of unprovoked seizures Excludes neonatal seizure; febrile seizure; acute symptomatic seizure Newly diagnosed epilepsy Second unprovoked seizure First presenting unprovoked seizure, history of prior events 12

Seizure or epilepsy? Epilepsy: Two or more unprovoked seizures Is the definition of epilepsy changing? ILAE conceptual definition: Disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure (Fisher 2005). What time frame of 2 seizures constitutes epilepsy? Experts Split on Whether Chief Justice Roberts Has Epilepsy 13

Epidemiology of first seizure Challenges Most studies do not distinguish first seizure from newly diagnosed epilepsy The majority of patients do not present for medical attention after a first seizure unless the seizure was a convulsion Overall, only one-third to one half of children and adults with seizures present after a first unprovoked seizure. 14

Incidence and recurrence risk Incidence Recurrence risk across studies Risk factors for recurrence across studies Role of age Incidence of first unprovoked seizure OR newly diagnosed epilepsy is 50-70/100,000 person years In studies that carefully exclude prior seizures, recurrence risk after a first seizure ranges from 27-52% While recurrence rates vary across studies, risk factors for recurrence are more highly preserved Recurrence risk and risk factors are remarkably similar for children and adults Hauser 82, Hirtz 84, Annegers 86, Stroink 98, Shinnar 90, Berg 91, Hauser 93, First Seizure Trial Group 93, Lindsten 01, others 15

7 year old girl presents after a first convulsive seizure noted by her parents Seizure Description Medical history Family history Nocturnal, during sleep Self limited after 2 minutes Normal birth and early development No medical problems No recent infections One first cousin with epilepsy ETIOLOGY Results of testing EEG: Left temporal spikes MRI: Normal 16

Etiology is a significant risk factor for seizure recurrence after a first seizure Remote symptomatic Cryptogenic Seizures without an immediate cause but with an identifiable prior brain injury Occurring in otherwise normal individuals with no clear etiology Idiopathic Presumed genetic epilepsy Important disclaimer The new ILAE classification has revised these terms 17

PROGNOSIS OF CHILDREN WITH A FIRST UNPROVOKED SEIZURE PI Shinnar: 1 April 1988-31 March 2005 N=407 120 100 80 60 40 20 0 < 3 3-6 6-9 9-12 12-15 > 15 Age Distribution 18

All 10yr F/U Number of Children 407 368 Mean Age at First Seizure (yrs) 6.8 6.8 Recurrent Seizures 185 (45%) 175 (48%) Total Number of Seizures to Date 1 (no recurrences) 222 (55%) 193 (52%) 2 (one recurrence) 49 (12%) 45 (12%) 3 20 ( 5%) 19 ( 5%) 4 14 ( 3%) 14 ( 4%) 5 15 ( 4%) 15 ( 4%) 6-9 27 ( 7%) 24 ( 7%) 10 60 (15%) 58 (16%) Overall recurrence risk Shinnar et al 05 Risk of Seizure Recurrence 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 Time (yrs) 19

Recurrence Risk Following First Unprovoked Seizure Etiology (N=407) 1.0 Risk of Seizure Recurrence 0.8 0.6 0.4 0.2 Idiopathic/Cryptogenic (n=328) Remote Symptomatic (n=79) 0.0 0 5 10 15 20 Time (yrs) p < 0.0001 20

Recurrence Risk Following First Unprovoked Seizure Etiology (N=407) 1.0 Risk of Seizure Recurrence 0.8 0.6 0.4 0.2 Idiopathic (n=75) Cryptogenic (n=253) Remote Symptomatic (n=79) 0.0 0 5 10 15 20 Time (yrs) p < 0.0001 21

Remote symptomatic etiology is associated with a uniformly higher risk of recurrence (Hauser 90, Shinnar 96, Stroink 98, Lindsten 01, FIRST trial, MESS trial, others) 22

7 year old girl presents after a first State of patient convulsive seizure noted by her parents Seizure Description Medical history Family history Nocturnal, during sleep Self limited after 2 minutes Normal birth and early development No medical problems No recent infections One first cousin with epilepsy Results of testing EEG: Left temporal spikes MRI: Normal 23

Sleep state at time of first seizure Children: Sleep state Adults: Time of day Strength of association Limitation Higher risk of seizure during sleep, whether daytime nap or nocturnal sleep 2 year recurrence risk: 53% (asleep) vs 30% awake Nocturnal seizures confer a higher recurrence risk, whether asleep or awake Results persist after controlling for etiology and EEG Many studies have not examined time of day or sleep state (Shinnar et al 93,Hopkins et al 88, van Donselaar et al 90,Camfield et al 85, Lindsten 01, MESS Trial 2010) 24

7 year old girl presents after a first convulsive seizure noted by her parents Seizure Description Medical history Family history Nocturnal, during sleep Self limited after 2 minutes Normal birth and early development No medical problems No recent infections One first cousin with epilepsy EEG abnormalities Results of testing EEG: Left temporal spikes MRI: Normal 25

Abnormal EEG and recurrence risk Recurrence risk All studies in children indicate increased recurrence risk Most studies in adults indicate increased risk Specifics of abnormalities vary by study Focal spikes Generalized spike/wave Any epileptiform activity Any EEG abnormality Strength of association Risk persists even after controlling for other variables Important considerations Utility of abnormal EEG is higher in non-remote symptomatic cases EEGs should include both sleep and awake when possible (Hauser 82, Camfield 85,, Annegers 86,, van Donselaar 92, FIRST 93, Shinnar 96,Stroink 98, Kim et al 2006, MESS 2010) 26

Prognosis Following First Unprovoked Seizure EEG Abnormalities and Recurrence Risk Idiopathic/Cryptogenic Cases (N=328) EEG N Recurred (%). Number of Subjects 328 129 (39%) EEG Available 305 126 (41%) Abnormal EEG 124 (41%) 71 (57%) Epileptiform Abnormalities 97 (31%) 61 (64%) Focal Spikes (No Slowing) 60 (20%) 35 (58%) Benign Rolandic 35 (11%) 20 (57%) Slowing and Focal Spikes 10 ( 3%) 5 (50%) Generalized Spike and Wave 34 (11%) 25 (74%) Nonepileptiform Abnormalities 27 ( 9%) 10 (37%) Slowing (No spikes) 20 ( 7%) 8 (40%) Nonspecific Abnormalities 10 ( 3%) 4 (40%) Normal EEGs 181 (59%) 55 (30%) No EEG Available 23 3 (13%) Shinnar et al 2005 Shinnar et al 2005 28

Other risk factors History of febrile seizure Appears to increase the recurrence risk in remote symptomatic epilepsy only (Shinnar et al 2005) Multiple seizures at first presentation Duration of initial seizure Seizure Classification Seizures in a cluster are not independent (Haut et al 1997) Results for recurrence risk differ among studies (Hauser 90, Shinnar 96, Ramos et al 2000, Camfield et al 2000, Kho et al 2006) Prolonged first seizure or status epilepticus does not increase recurrence risk If seizure recurs, it is likely to be of similar duration however (Shinnar 05) Partial > generalized (Hirtz 84, Shinnar 90, Camfield 85, Annegers 88) Family history Family history of unprovoked seizures is generally not significant Significant for siblings in the setting of idiopathic epilepsy 29

Treatment after a first seizure: What is the evidence? First Seizure Trial Group (FIRST) Randomized subjects within 7 days after a first witnessed tonic-clonic seizure with or without partial onset: Immediate treatment (carbamazepine, phenytoin, phenobarbital, or sodium valproate) vs. treatment with the same drugs only after seizure recurrence. Multicenter study of early Epilepsy and Single Seizures (MESS): Pragmatic trial which randomized subjects presenting with one or more seizures, where both clinician and patient were uncertain whether to proceed with treatment: Treatment was immediate vs. deferred; Medication choice was made by clinician At least four other studies: Camfield 89, Chandra 92, Gilad 96, Das 2000 30

FIRST Trial Recurrence risk within 24 months (FIRST1993, Musico et al 1997) 22% treated vs.41% untreated had a recurrence (more than half within 6 months) Treatment reduced recurrence but more than 50% of untreated did not recur Long term remission (Musico et al 1997, Leone et al 2006) 2 year remission (79%): 81% treated vs 78% untreated 5 year remission (64%): 63% treated vs. 64% untreated) Conclusions Treatment reduced early recurrence but did not affect long term remission 31

MESS Trial Immediate treatment increased the time to first recurrence, second recurrence and first GTC seizure Immediate treatment reduced the time to achieve 2 year remission, but this effect is lost after 2 years Adverse effects 8% higher in immediate vs. deferred group # to treat: 14 patients after a single seizure to prevent 1 recurrence within 2 years Reproduced with permission, The Lancet 32

Recurrence risk and implications for driving Emerging European regulations allow driving after a single unprovoked seizure after six months if recurrence risk is below 20% Risk of recurrence within 12 months starting at the six month point after a presenting seizure (if seizure free): Variables which increased the risk above 20%: Treated group: 14% (CI 10-18%) Untreated group: 18% (CI 13-23%) Remote symptomatic with abnormal EEG Untreated nonremote symptomatic with either abnormal EEG and imaging (Bonnett et al 2010 for MESS trial) 33

Risk allocation models Camfield et al Neurology 1985, Reproduced with permission Kim et al, Lancet Neurology 2006 Reproduced with permission 34

Other treatment considerations Anxiety Patient may be very anxious about seizure recurrence; early treatment may alleviate anxiety Injury Even a single seizure can cause injury Children are generally supervised at all times; risk of injury may be lower Adults may live alone, risk of injury may be higher Duration of initial seizure If first seizure was prolonged or status epilepticus, recurrent seizure is more likely to be of similar duration 35

How long to treat? Medication withdrawal following treatment of a first seizure has not been well studied Studies of medication withdrawal in epilepsy demonstrate certain features reliably: More successful in children than adults Success is higher when etiology is idiopathic; lowest when etiology is remote symptomatic Other Factors related to higher recurrence include lifetime # of seizures and presence of an abnormal EEG Available studies do not show an advantage of waiting more than 2 years of remission to withdraw AEDs Recommended rate of taper is typically 4-6 weeks Gross- Tsur et al, 2004 36

First unprovoked seizure Sample treatment algorithm Careful history: Prior seizure? No: Risk factors for recurrence? YES: Treat No: Don t treat YES: Treat YES: Risk of recurrence >50%? YES: Treat No: Other considerations? No: Don t Treat 37

Conclusions At least half of patients who present with a first seizure actually have newly diagnosed epilepsy Recurrence rates after a true first seizure in careful studies range from 27-52% Remote symptomatic etiology, abnormal EEG and seizure during sleep/night are among the strongest risk factors for recurrence Most recurrences occur during first 6 months Treatment after a first seizure reduces the rate of recurrence within the first 2 years but does not alter the long term prognosis Risk stratification modeling may help clinicians decide whom to treat 38

Acknowledgements Dr. Shlomo Shinnar Ruth Shinnar Montefiore-Einstein Epilepsy 39