Staging of Seizures According to

Current Classification Systems

December 10, 2013

Elinor Ben-Menachem, M.D.,Ph.D,

Instituet of Clinical Neuroscience and

Physiology,

Sahlgren Academy, Goteborg University,

Sweden

American Epilepsy Society | Annual Meeting

1

Disclosure

Name of Commercial

Interest

American Epilepsy Society | 2013 Annual Meeting

Type of Financial

Relationship

UCB

Eisai

Bial

Lundbeck

Electrocore

Biocontrol

Acta Neurologica

Scnadinavica

Research Grant, Consult

Research Grant, Consult

Research Grant

Consult

Consult

Consult

Chief Editor

Learning Objectives

1. To understand the previous staging attempts for new-onset epilepsies that might be applied to patients with refractory epilepsies.

2. To use staging to determine if antiseizure drugs should be started in new patients or withdrawn in seizure free patients

3. Understand how a staging process might work in determining refractoriness

American Epilepsy Society | 2013 Annual Meeting

Impact on Clinical Care and

Practice • The physician, by staging refractory

epilepsy, can help define prognosis and

make management decisions based on this

assessment for the individual patient.

• Help patients understand his/her condition

which will also facilitate decision making

Purposes of Staging

• Staging describes the extent or severity of a person’s epilepsy. Knowing the stage of disease helps the doctor plan treatment and estimate prognosis.

• Staging systems for epilepsy should continually evolve over time and continue to change as knowledge about the epilepsies advances

• Lacking a measure of the severity of epilepsy("staging"), prognosis cannot be established

For Cancer (National Cancer

National Cancer Institute: http://www.cancer.gov/cancertopics/factsheet/detect

ion/staging

• The staging system is based on the size and/or extent (reach) of the primary tumor (T), whether cancer cells have spread to nearby (regional) lymph nodes (N), and whether metastasis (M), or the spread of the cancer to other parts of the body, has occurred.

• Physical exams, imaging procedures, laboratory tests, pathology reports, and surgical reports provide information to determine the stage of a cancer

Previous Attempts at a Scoring

System to Predict Seizure freedom

and Success of Withdrawal

7

Berg AT, Shinnar S. Neurology. 1991;41(7):965-972.

No aetiology, normal EEG

No aetiology, abnormal EEG

Symptomatic, normal EEG

Symptomatic, abnormal EEG

0 20 40 60 80 100

Percentage Recurrence

Recurrence Following

a First Seizure

MESS Trial (Multicentre Study of

Early Epilepsy and Single Seizures)

• Multicenter study of early epilepsy and single seizures

• Randomized controlled trial comparing policies of – Immediate AED treatment

– Deferred AED treatment

• 1443 patients over 5 years were recruited where the clinician and patient were uncertain about the need for AED treatment – 56% with a single seizure

– 44% with 2 or more seizures

• Immediate treatment – 45% carbamazepine

– 45% valproate

– 10% other AEDs

Marson A, et al. Lancet. 2005;365(9476):2007-2013.

Predicting Recurrence

Risk For Individuals

Prognostic Index

Starting Value

Single seizure 0

2 or 3 seizures 1

4 or more seizures 2

Add if Present

Neurological disorder

of deficit 1

Abnormal EEG 1

Risk Classification Group Final score

Low risk 0

Medium risk 1

High risk 2-4

Kim LG, et al. Lancet Neurol. 2006;5(4):317-322.

Treatment

Policy

1-Year

Recurrence

Risk (%)

3-Year

Recurrence

Risk (%)

5-Year

Recurrence

Risk (%)

Low Risk Start

Delay

26

19

35

28

39

30

Medium Risk Start

Delay

24

35

35

50

39

56

High Risk Start

Delay

36

59

46

67

50

73

Recurrence Risk

MESS Study

Kim LG, et al. Lancet Neurol. 2006;5(4):317-322

Newly diagnosed epilepsy Categories of treatment outcome (N= 1098)

Non responders

24,7% Relapse

6,9 %

Immediate

Responders

28,7%

Remission

68,4%

Responders 75,3%

Refractory

31,7%

Brodie et al. Epilepsia 2009;50 (Suppl 11):411-2

Epilepsy Surgery Seizure free at 5 years postsurgery

Type of surgery No. of patients

(studies)

% seizure free at 5

years (95% CI)

Temporal 3895 (40) 66 (62 – 71)

Temporal +

extratemporal

2334 (25) 59 (56 – 62)

“Extratemporal” 169 (2) 34 (28 – 40)

Frontal 486 (7) 27 (23 – 30)

Parietal 82 (1) 46 (56 – 62)

Occipital 35 (1) 46 (29 – 63)

Téllez-Zenteno et al. Brain 2005; 128:1188-1898 13

Discontinuation of AED Therapy

in Children

Dooley J et al. Neurology 1996:4:969-974

Points # of patients Seizure free

at 24 months

0 1 100%

1 15 95%

2 32 80%

3 35 45%

4 10 5%

Multivariate predictors of recurrence

Female 1 point

Abnormal neuro exam 1 point

Age of onset <120 months 1 point

Focal seizures 2 points

Dooley J et al.

Neurology 1996;

46:969-974

Predicitng Long-Term Outcome of Childhood

Epilepsy in Nova Scotia Canada and Turku

Finland. Sillanpåå M, Camfield P, Camfield C. Arch Neurol 1995:52:589-592

• Scoring system to predict remission in

childhood epilepsy ( n=486) developed in

Canada and tested and validated in Turku,

Finland (n=141) and followed for 30 years

• Nova Scotia scoring system predicted

outcome in 61% of Finnish cases with

positive predictive value of 84%, sensitivity

43%, specificity 88%).

Scoring System

• Variable Score

Age at first seizure, mo

<12 99

12-144 142

>144 0

Intellignece

Normal 111

Retardation 0

Previous Neonatal Seizure

No 218

Yes 0

# seizures before treatment

1 or 2 72

3 to 20 123

>20 0

Sillanpåå M, Camfield P, Camfield C.

Arch Neurol 1995:52:589-592

Prediction

• A score of 495 will predict remission of epilepsy

• Seven of the cases were incorrectly predicted to remit at 10 years

• 166 cases, which were predicted NOT to remit, did so at 10 years

• Limitations:

Children with absence seizures were not included

The Turku Cohort included very few cases <12 years of age

Sillanpåå M, Camfield P, Camfield C. Arch Neurol 1995:52:589-592

• Remarkable that 4 predictors available on

the day of diagnosis could be so strong

predictors of outcome 30 years later.

• EEG did not contribute

• Predictors of persistent epilepsy were: Fine

motor deficiets , neonatal asphyxia, poor

coordination, high freq of initial seizures,

status epilepsticus, poor mental

development

Sillanpåå M, Camfield P, Camfield C. Arch Neurol 1995:52:589-592

Unfavorable Prognostic Factors

for Antiepileptic Drug Withdrawal • Age at onset >12 y • Symptomatic vs idiopathic etiology • Mental retardation • Abnormal neurologic examination • Family history of epilepsy • Poor initial response to treatment • More than 1 drug being used at time of withdrawal • Epileptiform EEG changes • Slowing on EEG • Emergence of EEG abnormalities during drug withdrawal • Juvenile myoclonic epilepsy

J.Britton. Antiepileptic drug withdrawal. Mayo Clin Proc. 2002;77:1378-1388

Withdrawal of AEDs in Adults:

Medical Research Council (MRC)

Antiepileptic Drug Withdrawal Study

• 409 patients who were seizure free for 2 years or more.

• Randomized to withdrawal or staying on AED

• At the time of randomization 83% of patients were

receiving monotherapy with carbamazepine (237 patients),

phenobarbitone/primidone (72 patients), phenytoin (184

patients) or valproate (228 patients)

Chadwick D et al: Epilepsia. 1996, Lancet 1991; 337: 1177.).

Withdrawal of AEDs in Adults:

Medical Research Council (MRC)

Antiepileptic Drug Withdrawal Study

• By 3 years after a seizure, 95% of patients have

experienced a further 1-year remission of their epilepsy

and by 5 years 90% of patients have experienced a further

2-year remission.

• Most important factors contributing to the risk of further

seizures after a first seizure after randomization were:

• 1. Previous seizure-free interval

• 2. Partial seizures at recurrence

• 3. Previously experienced seizures while receiving

treatment.

Chadwick D et al: Epilepsia. 1996, Lancet 1991; 337: 1177.).

AED Withdrawal: what is the chance

of success? 1994 AAN Practice

Parameter

• 52 Class 11 studies, 1 Class 1 study

• Pooled estimates (weighted average) –

Children 69% are successful; 31% will

recur.

Adults 61% are successful; 39% will

recur.

American Academy of Neurology quality standards

subcommittee. Practice parameter: a guideline for

discontinuing antiepileptic drugs in seizure-free patients.

American Academy of Neurology Practice Parameters 1994.

When to discontinue (AAN

Practice Parameter • Seizure freedom >2 years implies 60% chance of success

in certain epilepsy syndromes

Favorable factors :

1. Control easily achieved on a low dose of one drug

2. No previous unsuccessful attempts at withdrawal

3. Normal neurological exam and EEG

4. Primary generalized epilepsy except JME

5. Benign syndromes

Considerations: driving, pregnancy, work, family

Conclusion

• Very few studies have attempted to use

staging as a means for prediciton or

information

• Only helpful for determing risk for seizure

recurrence if AEDs are withdrawn or risk of

remaining seizure free after intiating drug

therapy in new onset patients

How to apply Cancer Staging to

Epilepsy

Proposal: The FEDS staging system could be based on

• The size and/or extent (reach) of the primary focus or foci

(F)

• Pathological EEG and the extent of interictal pathology (E)

• Whether the patient is drug resistant in a true sense (D), or

has not had or is able to have successful epilepsy surgery

• A history of refractory status epilepticus (S).

How to apply Cancer Staging to Epilepsy

• Neurological exams, imaging procedures,

genetic tests, EEGs, pathology reports, and

surgical reports would provide information

to determine the stage of epilepsy.

Advantages of Staging – Staging helps to plan the appropriate treatment.

– Epilepsy stage can be used in estimating prognosis .

– Knowing the stage of EPILEPSY would be important in identifying clinical trials that may be a suitable treatment option for a patient.

– Staging would help health care providers and researchers exchange information about patients; it provides common terminology for evaluating and comparing the results of clinical trials and different treatment approaches.

Hot Topics Symposium

Conclusions

Elinor Ben-Menachem, M.D.,Ph.D,

Instituet of Clinical Neuroscience and

Physiology,

Sahlgren Academy, Goteborg University,

Sweden

American Epilepsy Society | Annual Meeting

31

Conclusions

• Staging of epilepsy can bring us to a new level in understanding epilepsy severity and prognosis.

• This is a first initiative to try to jumpstart a process which could be successfully implented to aid in better understanding epilepsy and stimulate focused research