Epilepsy Specialist Symposium Treatment Algorithms in...

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


Bronx, NY


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.


• 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

Agenda

8

First seizure: Diagnosis,

treatment and prognosis November 30th, 2012

Sheryl Haut, M.D. Associate Professor of Clinical Neurology

Director, Adult Epilepsy Montefiore Medical Center



9

Disclosure

Acorda

Vivus

Upsher-Smith

Neuronex


Consultant

Consultant

Consultant

Consultant

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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


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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

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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

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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

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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.

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Incidence and recurrence risk

Incidence Incidence of first unprovoked seizure OR newly diagnosed epilepsy is 50-70/100,000 person years

Recurrence risk across studies

In studies that carefully exclude prior seizures, recurrence risk after a first seizure ranges from 27-52%

Risk factors for recurrence across studies

While recurrence rates vary across studies, risk factors for recurrence are more highly preserved

Role of age 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

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Seizure Description



Medical history


No medical problems


Family history


Results of testing

EEG: Left temporal spikes

MRI: Normal

ETIOLOGY

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Etiology is a significant risk factor for seizure

recurrence after a first seizure

• Seizures without an immediate cause but with an identifiable prior brain injury

Remote symptomatic

• Occurring in otherwise normal individuals with no clear etiology Cryptogenic

• Presumed genetic epilepsy Idiopathic

• The new ILAE classification has revised these terms

Important disclaimer

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PROGNOSIS OF CHILDREN WITH A FIRST UNPROVOKED

SEIZURE

PI Shinnar: 1 April 1988 - 31 March 2005 N=407

0

20

40

60

80

100

120

< 3 3 - 6 6 - 9 9 - 12 12 - 15 > 15

Age Distribution

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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%)

Time (yrs)

0 5 10 15 20

Ris

k o

f S

eiz

ure

Re

cu

rre

nce

0.0

0.2

0.4

0.6

0.8

1.0

Overall

recurrence risk Shinnar et al 05

20

Time (yrs)

0 5 10 15 20

Ris

k o

f S

eiz

ure

Re

cu

rre

nce

0.0

0.2

0.4

0.6

0.8

1.0

Idiopathic/Cryptogenic (n=328)

Remote Symptomatic (n=79)

p < 0.0001

Recurrence Risk Following First Unprovoked Seizure Etiology (N=407)

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Recurrence Risk Following First Unprovoked Seizure Etiology (N=407)

Time (yrs)

0 5 10 15 20

Ris

k o

f S

eiz

ure

Re

cu

rre

nce

0.0

0.2

0.4

0.6

0.8

1.0

Idiopathic (n=75)

Cryptogenic (n=253)

Remote Symptomatic (n=79)

p < 0.0001

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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)

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Seizure Description



Medical history


No medical problems


Family history


Results of testing


MRI: Normal

State of patient

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Sleep state at time

of first seizure

• Higher risk of seizure during sleep, whether daytime nap or nocturnal sleep • 2 year recurrence risk: 53% (asleep) vs 30% awake

Children: Sleep state

• Nocturnal seizures confer a higher recurrence risk, whether asleep or awake

Adults: Time of day

• Results persist after controlling for etiology and EEG

Strength of association

• Many studies have not examined time of day or sleep state Limitation

(Shinnar et al 93,Hopkins et al 88, van Donselaar et al 90,Camfield et al 85, Lindsten 01, MESS Trial 2010)

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Seizure Description



Medical history


No medical problems


Family history


Results of testing


MRI: Normal

EEG abnormalities

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Abnormal EEG and recurrence risk

• All studies in children indicate increased recurrence risk

• Most studies in adults indicate increased risk

Recurrence risk

• Focal spikes

• Generalized spike/wave

• Any epileptiform activity

• Any EEG abnormality

Specifics of abnormalities vary by study

• Risk persists even after controlling for other variables

Strength of association

• Utility of abnormal EEG is higher in non-remote symptomatic cases

• EEGs should include both sleep and awake when possible

Important considerations

(Hauser 82, Camfield 85, , Annegers 86,, van Donselaar 92, FIRST 93, Shinnar 96,Stroink 98, Kim et al 2006, MESS 2010)

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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

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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

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)

Duration of initial seizure

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)

Seizure Classification

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

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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

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FIRST Trial

• 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

Recurrence risk within 24 months

(FIRST1993, Musico et al 1997)

• 2 year remission (79%): 81% treated vs 78% untreated

• 5 year remission (64%): 63% treated vs. 64% untreated)

Long term remission

(Musico et al 1997, Leone et al 2006)

• Treatment reduced early recurrence but did not affect long term remission Conclusions

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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

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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):

Treated group: 14% (CI 10-18%)

Untreated group: 18% (CI 13-23%)

Variables which increased the risk above 20%:

Remote symptomatic with abnormal EEG

Untreated non-remote

symptomatic with either abnormal

EEG and imaging

(Bonnett et al 2010 for MESS trial)

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Risk allocation models

Camfield et al Neurology 1985, Reproduced with permission

Kim et al, Lancet Neurology 2006 Reproduced with permission

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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

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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

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Careful history: Prior seizure?

First unprovoked seizure

YES: Treat

No: Risk factors for recurrence?

No: Don’t treat

YES: Risk of recurrence >50%?

No: Other

considerations?

YES: Treat

YES: Treat

No: Don’t Treat

Sample treatment algorithm

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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

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Acknowledgements

• Dr. Shlomo Shinnar

• Ruth Shinnar

• Montefiore-Einstein Epilepsy

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