This presentation looks at current information regarding various aspects of AED withdrawal that a neurologist has to deal with on a day to day basis..

1. Withdrawal of Anti-epileptic drugs
Dr Pramod Krishnan, MD (Int Med), DM Neurology (NIMHANS)
Fellowship in Epilepsy (SCTIMST) (LMU, Munich)
World Sleep Federation Certified Sleep Medicine Specialist.
Consultant Neurologist and Epileptologist
Head of the Department of Neurology,
Manipal Hospital, Bengaluru.

2. “The ideal objective of treating a person with epilepsy is to induce
remission by usage of antiepileptic drugs (AEDs) and ultimately stop
the AEDs without causing seizure recurrence”.
Schmidt D, et al. Drug treatment of epilepsy in adults. BMJ 2014;348:g254.

3. However,…
• We do not fully understand epileptogenesis.
• We do not fully understand the natural history of epilepsy.
• Therefore, predicting seizure control or relapse in an individual
patient is based more on probability than any accurate estimate.

4. 1. Why should we even consider
AED withdrawal?

5. Behavioural issues
Memory and Cognitive issues
Sedation and Insomnia
Learning issues
Cost of medications, hospital visits
Bone health
Other organ system adverse effects
Teratogenicity
Weight gain and cosmetic issues
Problems with comedications
Sense of being ‘unwell’, ‘still a patient’
Social stigma of being on AEDs
Fear of being on unnecessary treatment
Problems with continued use of AEDs

6. Pitfalls of stopping AEDs
• Sense of anxiety, fear, insecurity regarding relapse.
• Relapse of epilepsy, and the distress and dejection that follows.
• Effect of seizure relapse on employment, marriage, driving.
• Risk of injury, accidents, SUDEP.
• Medicolegal issues if the patient was not counselled adequately,
poor appreciation of the risks by the patient.
• Risk of refractoriness, or longer time for remission.

7. 2. When is the right time to
consider AED withdrawal?

8. Cochrane review 2015
• Five RCTs involving 924 children < 16 years of age.
• Early (< 2 years of seizure freedom) vs late (> 2 years) AED withdrawal.
• Median follow up of 5.6 years.
• The pooled risk ratio for seizure relapse after AED withdrawal was 1.34 (95% CI
1.13 to 1.59, P = 0.0007).
• Early discontinuation was associated with greater relapse rates in people with
partial seizures with a pooled risk ratio of 1.51 (95% CI 0.97 to 2.35, P = 0.07).

9. Variables associated with relapse
1. Abnormal EEG: (RR 1.44, 95% CI 1.13 to 1.83, P = 0.003),
especially epileptiform activity (RR 2.58, 95% CI 2.03 to 3.28, P <
0.0001).
2. Epilepsy onset before 2 years or after 10 years of age.
3. History of status epilepticus.
4. Intellectual disability (IQ < 70)
5. High seizure frequency before and during treatment.
• Gender and family history were not significant.

10. • Randomised to Group 1 (1 year of treatment) and group 2 (3 years of treatment).
• AEDs were stopped in 161 children who were seizure free in the previous 6 months.
• During the mean follow-up period of 5.8 years, 60 children (37%) relapsed.
• Predictors of recurrence were: age at seizure onset; generalized seizures, irregular
spike-wave activity on EEG after 1 year of treatment.

11. What is the likelihood of seizure
relapse after AED withdrawal, and the
factors that predict relapse?

12. Populations Recurrence rate Year
Adults and children.
25 studies, n= 5354
25% at 1 yr. (95%CI 21–30)
29% at 2 yrs. (95%CI 24–34)
range 12–67%
1994
Adults and children
9 studies, n= 1813
45%
range 23–66%
2004
Adults and children
13 studies, n= 2336
34% (95%CI 27–43)
range 12–66%
2005
Meta-analyses or systematic reviews on seizure relapse following AED
reduction in medically treated cohorts

13. • Meta-analysis of 25 studies to determine the risk of relapse at 1 and 2 years after
AED withdrawal.
• Relapse rate at 1 year: 25% (95% CI, 21-30) and at 2 years: 29% (95% CI, 24-34).
• The factors associated with higher risk of relapse were:
1. Adult-onset epilepsy: RR of 1.34 (95% CI, 1.00 to 1.81).
2. Remote symptomatic epilepsy: RR of 1.55 (95% CI, 1.21 to 1.98).
3. Abnormal EEG: RR of 1.45 (95% CI, 1.18 to 1.79).
Neurology 1994;44:601-608

14. Chadwick D et al. Lancet 1991; 337:1175-80.
• A prospective, multi-centre, randomized, unblinded study of slow AED
withdrawal (over 6 months) Vs AED continuation.
• 1013 patients seizure free for atleast 2 years and without any other progressive
medical illness.
• Adult patients were maintained on existing doses.
• Children (age 15 years or less) could withdraw treatment 1 year or more after
randomisation to continued treatment.

15. Results
• AED discontinuation doubles the risk of seizures for up to 2 years
after stopping AED compared to continued treatment.
• By 2 years, 22% of patients in whom AEDs were continued and
41% of those in whom it was withdrawn had relapsed.
• The difference in the recurrence risk between the two groups was
highest at 9 months but became equal after 2 years of follow-up.
• In the slow withdrawal group, 107 (48%) seizures occurred in
during AED reduction and 114 (52%) after drug withdrawal.

16. Major factors:
• 2 or more AEDs.
• Shorter prior seizure-free periods.
• Primary or secondary generalised
seizures.
Minor factors:
• Myoclonic seizures.
• History of neonatal seizures.
• Seizures while on AED therapy.
• Duration of AED therapy.
Factors predicting relapse of epilepsy

17. Chadwick D et al. BMJ 1993; 306: 1374-8
• Risk factors identified by the Cox proportional hazards model :
1. Age 16 or older at the time of withdrawal
2. 2 or more AEDs.
3. Seizures after starting AEDs
4. Primary or secondary generalised seizures.
5. Myoclonic seizures
6. Abnormal EEG.

18. • Prospective, randomized controlled, double-blind design.
• 150 patients were included in the intervention part of the study: 78 in the non-
withdrawal and 72 in the withdrawal group.
• Patients came for five visits over a 12-month period, or until seizure relapse.

19. Inclusion criteria Exclusion criteria
Epilepsy (2 or more unprovoked seizures) JME
Age 18-67 years Polytherapy
AED Monotherapy Pregnant or planning pregnancy
2 years seizure freedom or longer.
67% of pts were seizure free for 5 years.
Two prior withdrawal attempts
If prior withdrawal attempted and
unsuccessful, five years seizure freedom or
longer.
Paroxysmal epileptiform discharges in primary
generalised epilepsy
Mental retardation
Progressive neurological disease
Other serious disease which may influence the
health status of the patient in the study period
Comedication (except postmenopausal hormone
substitution, hormonal contraceptives, acetylic acid,
antihypertensives and thyroxin)

20. Results
• 15% of patients in the AED withdrawal and 7% in the continuation
group had a recurrence at 12 months (nonsignificant).
• Subsequent to the double blind period, 60 patients in the non-
withdrawal group, also stopped their AEDs.
• The risk of seizure recurrence was similar in this group compared
to the AED withdrawal group during the first year.
• Recurrence rate of the combined group was 27% after a median of
41 months off medication (open follow up).

21. Results
• Neither patient age, gender, age of epilepsy onset, partial versus
generalized epilepsy, MRI-findings, nor duration of seizure
freedom predicted seizure freedom after AED withdrawal.
• Treatment with CBZ and a normal neurological examination were
the only significant predictors (multivariate analysis) for seizure
freedom at 12 months.
• Well selected, low risk patients may have a 1 year recurrence rate of
only 15%.

24. Rapid vs Slow AED withdrawal?

25. • 133 children randomised to either 6 week or 9 month AED tapering.
• They were seizure free for 2-4 years, majority were on monotherapy.
• Seizures recurred in 53/133 patients (40%).
• Rapidity of taper and duration of seizure freedom before taper were not
significant for relapse.
• Trend toward higher recurrence was noted during the first 2 years in patients in
rapid withdrawal group.
• Mental subnormality and epileptiform discharges on EEG at the time of
tapering increased the risk of recurrence.
N Engl J Med 1994; 330: 1407-10.

26. Is EEG necessary prior to AED
withdrawal?

27. • Patients with a history of only tonic-clonic seizures, associated
with generalised spike wave abnormalities in EEG had higher
recurrence rates.
• Patients with a history of tonic-clonic seizures and focal (but not
generalised) abnormalities or non-specific abnormalities on EEG
were not at an increased risk of recurrence.
Chadwick D et al. Lancet 1991; 337:1175-80.

28. • A patient with abnormal EEG (with or without epileptiform activity,
specific EEG patterns) at the time of treatment discontinuation
should be informed of an increased risk of relapse.
• AEDs can be discontinued if this is the only negative predictor.

29. Can we consider AED withdrawal
in genetic generalised epilepsy?

30. • 21/31 patients (67.7%) became seizure free.
• 9/21 patients discontinued AEDs.
• 6/9 patients remained seizure free and off AEDs.
Factors predicting seizure recurrence:
1. GTCS preceded by bilateral myoclonic seizures (p = 0.03),
2. Long duration of epilepsy with unsuccessful treatment (p = 0.022),
3. Photoparoxysmal response (p=0.05)
4. AED polytherapy (p = 0.023)

31. • 59 patients with follow up after AED withdrawal of 2-10 years (median 3).
• 17 patients with JME, 21 with CAE, 11 with JAE, 10 with GTCS alone.
• 15/59 patients restarted AEDs due to worsening EEG.
• Relapse occurred in 23/44 patients (52.2%), including all JME patients.
• GTCS and GTCS + myoclonic/absence seizures (HR 2.12; 95%, CI 1.13–4.3) and,
worsening interictal EEG during or after AED withdrawal (HR 4.00; 95% CI 1.39–11.5)
were associated with increased risk of recurrence.

32. • 186 patients with JME with median age at treatment start of 16 years (range 13–44), and
median follow-up of 14 years (range 2–32).
• 171 patients (92%) achieved remission with AED treatment.
• After discontinuing treatment in 28 patients, only 11 remained seizure-free off AEDs.
• 15 patients (8%) continued to have seizures despite having tried up to 8 AED regimens.
• More male patients than female attained remission with their first or second AED.

33. • 66 patients with JME had a mean follow-up of 44.6 years (20–69 years).
• 39 (59.1%) patients were seizure free for at least 5 years before the last contact.
• 28/39 (71.8%) patients with 5 year seizure-freedom were still taking AEDs.
• 11/39 patients were seizure free and off AEDs for at least the last 5 years.
• Absence seizures at onset of JME was an independent predictor of an
unfavourable outcome (p<0.009).

34. Can we withdraw AEDs in focal
epilepsy of unknown cause?

35. • 89 children with cryptogenic partial epilepsy.
1. Group A, 45 children whose AEDs were
discontinued after 1 year from the last seizure.
2. Group B, 44 children whose AEDs were
stopped after 2 years from the last seizure.
• After 5 years of follow-up, the recurrence rate
was similar (Group A, 28.8%; Group B, 25%).

36. Can we consider AED withdrawal
in symptomatic epilepsies?

37. Symptomatic epilepsy
• ‘Symptomatic epilepsy’ is heterogenous, encompassing various
etiologies of differing epileptogenicity.
• Long term seizure freedom would be unlikely in patients with
lesions like MTS, FCD, major cortical malformations, TSC
complex etc.
• AED withdrawal would therefore be relevant to lesions where
prolonged seizure freedom with AED is feasible (eg NCC, post
stroke epilepsy, post traumatic epilepsy).

38. Expert Rev Neurother 2016; 16: 1079-85.
Risk factors for seizure recurrence:
1. History of status epilepticus
2. Poor seizure control during treatment; seizure free period of <2 years.
3. Neuroimaging evidence of perilesional gliosis
4. Hippocampal sclerosis
5. Calcified lesions.
6. Persistence of paroxysmal activity in the EEG.

39. • 71 adult patients, seizure free ≥ 1 year from the date of last antitumor treatment,
or ≥ 2 years if seizures occurred after the end of the last antitumor treatment.
• 46/71 patients (65%) decided to withdraw AEDs and 25 patients continued
AEDs.
• 12/46 (26%) who withdrew AED had seizure recurrence in 2.2 years follow up.
• 7 of these 12 patients had tumor recurrence.
• 2/25 (8%) patients who continued AEDs had seizure recurrence during follow up
of 1.7 years. One of them had tumor progression.

40. • Prospective study of patients with MTLE after ATL+AH.
• Slow AED withdrawal in 258 patients starting at 3 months following surgery in
those on duo therapy and at 1 year in those who were on monotherapy.
• Mean follow-up period of 8.0 ± 2.0 years.
• AED were stopped in 52% of patients.
• Seizures recurred in 64 patients (24.8%) during or after AED withdrawal.
• 90% became seizure free after reinstitution of AED.
• Predictors of recurrence: Longer duration of epilepsy, absence of HS on
pathology and abnormal EEG at 1st post-operative year.

41. If seizures recur after AED
withdrawal, are they difficult to
treat?

42. • 245 of the 510 patients randomized to slow discontinuation (48%) experienced
seizures during 5 year follow-up, as compared with 164 of 503 of those allocated to
continue treatment (33%).
• Total of 409 patients post randomization seizures were studied.

43. Results
• By 3 years after a seizure, 95% of patients experienced a further 1-year
remission.
• By 5 years 90% of patients have experienced a further 2-year remission.
• The most important factors contributing to the risk of further seizures after a
first seizure after randomization were:
1. Previous seizure-free interval,
2. Having partial seizures at recurrence,
3. Having previously experienced seizures while on AEDs.

44. • Study of 148 children with incident epilepsy.
• Average follow-up after AED withdrawal of 32 ± 8.7 years.
• 33/90 (37%) patients who stopped AEDs relapsed.
• Relapse occurred within the first year in 36%, within the first 2 years in 46%, and
within the first 3 years in 67%.
• Treatment duration prior to withdrawal was shorter in patients who relapsed than
in those who did not (P=0.0284).
Epilepsy & Behavior 2006; 8: 713–719

45. 24 of 25 patients who received no AEDs after relapse with one or several seizures
regained 5-year terminal remission (5YTR), but after an average of 8.2 years.

46. Does AED withdrawal result in
good psychosocial outcomes and
quality of life?

47. • A normal result to all 15 neuropsychological tests increased from 11% to 28% post-
withdrawal compared to a decrease in the proportion of normal results from 11%
to 9%, in the non-withdrawal group.
• Withdrawal did however not affect general health measured as quality of life (?due
to placebo).

48. Conclusion
• AED withdrawal should be attempted only after achieving seizure
freedom of atleast 2 years, or even more, in adults.
• 30% of patients will relapse on attempted AED withdrawal.
• In well selected patients, risk of relapse can be as low as 15%.
• AED withdrawal results in a transient two-fold risk of seizures for
the first 2 years after stopping AEDs.
• Majority who relapse will eventually become seizure-free again.
• Decision to withdraw AEDs should be individualised as part of
shared decision making.

49. Risk factors for seizure recurrence after AED withdrawal
Longer duration of epilepsy.
Epileptiform discharges in the EEG at the time of withdrawal.
Worsening EEG after discontinuation.
Onset of epilepsy at age < 2 years of > 10 years.
IQ < 70.
High seizure frequency (>5/year) before or during treatment.
Polytherapy.
Focal epilepsy.
Primary or secondary generalised seizures.
History of myoclonus.
Remote symptomatic etiology.
Abnormal neurological examination.
Shorter seizure free period prior to withdrawal.
History of neonatal seizures.

50. THANK YOU