Anti epileptic drug withdrawal in adult onset symptomatic epilepsy

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1. “Is it advisable to taper medication in well- controlled patients with symptomatic adult- onset focal epilepsy” ? Dr Pramod Krishnan, M.D, D.M Consultant…
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  • 1. “Is it advisable to taper medication in well- controlled patients with symptomatic adult- onset focal epilepsy” ? Dr Pramod Krishnan, M.D, D.M 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. 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
  • 5. 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.
  • 6. Approach to AED discontinuation • AEDs are often withdrawn in a patients entering prolonged remission, especially in India. • Surprisingly, class I evidence on the consequences of doing so on seizure outcome and general health are rather limited. Braun KP, et al. Curr Opin Neurol 2014; 27(2):219–26. • The decision to continue or to stop AED treatment is a difficult one and requires a full assessment of the risk- benefit balance of AED discontinuation for the individual patient. Rathore C, Paterson R. Neurology India 2014. Vol 62.
  • 7. 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
  • 8. Would this approach be different in symptomatic epilepsy? • The general impression would be that patients with symptomatic epilepsy would fare worse than others. • However, ‘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.
  • 9. Caveats to remember…. • Most large studies focused on epilepsy patients in general (adults and children), not only the symptomatic epilepsy group. • The very nature of the inclusion criteria in many studies, essentially ruled out patients with severe brain disease or highly epileptogenic lesions. • Therefore, the evidence presented would probably be relevant only to patients with symptomatic epilepsy of a milder degree, due to lesions with low epileptogenicity.
  • 10. A prospective, multi-centre, randomized, unblinded study of slow AED withdrawal Vs AED continuation in 1013 patients with seizure freedom of atleast 2 years and without any other progressive medical illness.
  • 11. Results • AED discontinuation doubles the risk of seizures for up to 2 years after stopping AED compared to continued treatment. • By 2 years after randomization, 78% of patients in whom treatment was continued and 59% of those in whom it was withdrawn remained seizure free. • Thereafter the differences between the two groups diminished. • This suggests that the long-term seizure outcome is not affected by drug discontinuation.
  • 12. Factors predicting relapse of epilepsy • Polytherapy (2 or more AEDs). • Shorter prior seizure-free periods • Primary or secondary generalised seizures. • Myoclonic seizures • History of neonatal seizures. • Seizures while on AED therapy. • Duration of AED therapy. ‘Symptomatic epilepsy was not identified as a predictive factor’
  • 13. BMJ 1993; 306: 1374-8 • The following factors are were used to calculate seizure recurrence: 1. AED withdrawal or not. 2. Seizure free period. 3. AED polytherapy (2 or more AEDs). 4. Seizures after starting AEDs 5. Age 16 or older at the time of withdrawal 6. Myoclonic seizures 7. Primary or secondary generalised seizures. 8. Abnormal EEG. ‘Symptomatic epilepsy was not identified as a predictive factor’
  • 14. Prospective, randomized controlled, double-blind design. Patients came for five visits over a 12-month period, or until seizure relapse
  • 15. 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 patients 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) 150 patients were included in the intervention part of the study: 78 in the non-withdrawal and 72 in the withdrawal group.
  • 16. Results • 15% of patients randomized to treatment withdrawal and 7% of those randomized to remain on treatment had a recurrence at 12 months (nonsignificant). • Recurrence rates were 27% after a median of 41 months off medication (open follow up). • Those who stopped AEDs improved significantly in their neuropsychological performance. • Withdrawal did however not affect general health measured as quality of life and the EEG findings.
  • 17. 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. • At a median of 41 months, patients on CBZ had a 3-fold chance of remaining seizure-free after withdrawal, compared to other AEDS. • A normal neurological examination was also a significant predictor (multivariate analysis) for seizure freedom at 12 months. • Well selected, low risk patients may have a 1 year recurrence rate of only 15%.
  • 18. Risk factors for seizure recurrence 1. History of status epilepticus 2. Poor seizure control during treatment 3. Neuroimaging evidence of perilesional gliosis 4. Hippocampal sclerosis 5. Calcified lesions. 6. Persistence of paroxysmal activity in the EEG. Bustos JA, et al. Expert Rev Neurother 2016; 16: 1079-85.
  • 19. • 71 patients: 46 patients (65%) decided to withdraw AEDs and 25 patients (35%) continued AEDs. • 12/46 (26%) who withdrew AED had seizure recurrence in 2.2 years follow up. • 7 of these patients had tumor recurrence.
  • 20. Inclusion criteria • The inclusion criteria were as follows; • Adults > 18 years of age • Histologically confirmed WHO grade II–III glioma • Clinically and radiologically stable disease for at least 12 months. • Seizure freedom for at least 12 months from the date of last surgery, irradiation or chemotherapy cycle, or • Seizure freedom for at least 24 months from the last seizure when a seizure occurred after the last antitumor treatment. 2/25 (8%) patients who continued AEDs had seizure recurrence during follow up of 1.7 years. One of them had tumor progression.
  • 21. Should we consider withholding treatment in patients with an abnormal EEG at time of discontinuation? • 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. • Need not continue AEDs if this is the only negative prognostic predictor. • The decision to stop treatment should be considered in the light of social and personal complications of a seizure relapse [Strength of recommendation: B].
  • 22. Should we consider withholding treatment in patients with a documented etiology of epilepsy (including mental retardation and perinatal insults)? • Such patients should be informed of an increased risk of relapse but need not continue treatment if this is the only negative prognostic predictor. • This also applies to the presence of mental retardation and/or abnormal neurologic or imaging findings. • The decision to stop treatment should be considered in the light of the social and personal complications of a seizure relapse. • However, a patient with an abnormal EEG and a documented etiology should be advised not to discontinue AEDs. (strength of recommendation B)
  • 23. Should we consider withholding treatment in patients with partial seizures? • The presence of partial seizures should not be considered per se a reason for continuing treatment in a patient who is seizure free and does not have other relevant predictors of relapse. Should we consider treatment withdrawal only in patients with lower seizure frequency before entering remission and/ or shorter duration of active epilepsy and/or less difficult seizure control? • Prolonged duration of active disease before and during treatment and high seizure frequency should not be a contraindication to treatment discontinuation [Strength of recommendation: C].
  • 24. Prognosis of seizures after recurrence Likelihood of remission Risk of refractoriness
  • 25. • 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.
  • 26. 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.
  • 27. Study of 148 children with incident epilepsy followed up for upto 37 years.
  • 28. 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.
  • 29. Results • 33/90 (37%) patients who stopped AEDs relapsed. • Average follow-up after AED withdrawal was 32 ± 8.7 years. • 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 (5.1 ± 6.2, vs 9.2 ± 9.0, P=0.0284).
  • 30. Conclusion • AED withdrawal exposes patients who were seizure-free to a transient two-fold risk of seizures for the first 2 years after stopping AEDs. • Seizures do not recur in most (70%) of individuals on stopping AEDs. • Majority who relapse have no complications and will eventually become seizure-free again. • Symptomatic epilepsy patients with low risk have similar relapse and subsequent remission rates as compared to other epilepsy patients. • Cautious AED withdrawal can be offered to patients with symptomatic epilepsy with low risk of relapse (no mental retardation, or abnormal EEG).
  • 31. THANK YOU
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