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DOI: 10.1016/j.ijep.2016.12.001
Recurrence rate and risk factors for recurrence of seizures after withdrawal of antiepileptic drugs (AED) in Indian children treated for epilepsy
Corresponding author at
Publication History
Received: 01 July 2016
Accepted: 05 December 2016
Publication Date:
06 May 2018 (online)
- Introduction
- Methods
- Results: background data: see Table 1
- Discussion: comparison with other studies
- Conclusion
- Areas for further research
- Conflicts of interest
- References
Introduction
Epilepsy is a major public health problem affecting about 50 million people worldwide. Even though it is a chronic condition, it may not remain life-long. The causes are variable and hence the outcome is also heterogeneous.[1] There are considerable disadvantages of continuing AEDs indefinitely as they have potential adverse cognitive and behavioral side effects along with cost implications.[2]
The decision to discontinue AED therapy is weighed against the chances of recurrence by the physicians. Previous studies in children have shown a risk of recurrence ranging from less than 10–70%.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] A few Indian studies have looked at risk factors of seizure recurrence in adults,[16] [17] but there is none such study in Indian children.
In India, the epidemiology of epilepsy is different from western countries in view of high burden of symptomatic epilepsy due to prevalence of birth asphyxia, neonatal hypoglycemia, etc. resulting from poor antenatal and natal care services.[17] These children suffer from epilepsy of variable severity and the duration of treatment given is usually for 2–3 seizure free years after which the AED is/are withdrawn. We did this study to evaluate the rate of recurrence in children after AED withdrawal and the associated risk factors and reviewed the literature for similar such studies.
# 2
Methods
Patients were selected from the Pediatric Epilepsy Clinic in a referral Medical College between July 2005 and December 2013. Out of 2200 patients referred for seizures, 1108 children were diagnosed with epilepsy. Children (below the age of 18 years) with unequivocal epilepsy, who had been treated for a seizure free period of 2–3 years, after which their anti-epileptic drugs (AED) were slowly tapered over 2–3 months were selected, who were followed up for a minimum period of 6 months. 148 such children were identified in whom recurrence and presence of risk factors was noted ([Fig. 1]).
![](https://www.thieme-connect.de/media/10.1055-s-00037682/201701/thumbnails/10-1016-j-ijep-2016-12-001_gr1.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
Inclusion criteria
-
Age below 18 years
-
Children who had 2 or more unprovoked seizures
-
Treated with anti-epileptic drugs (AED)
-
Had been seizure free for 2–3 years
-
Follow-up of minimum 6 months was available after withdrawal.
# 2.2
Exclusion criteria
-
Children with single seizure but received AED
-
Those with acute symptomatic seizures but received prolonged AED therapy
-
Those on prolonged AED since neonatal period (after perinatal insult)
-
Those diagnosed with inborn errors of metabolism
-
Infants/Children with West syndrome.
The following factors were studied in these children: age of onset of seizures, sex, type of seizures, total duration of epilepsy, duration to control seizures after initiation of AED, number of AED used, number of seizures before starting AED, number of seizures after AED was started, total number of seizures, duration of AED therapy, age at withdrawal of AED, follow-up period after withdrawal, interval between AED withdrawal and seizure recurrence. To find the etiology, prior history of neonatal seizures, febrile seizures and family history of seizures was taken in detail. The motor and cognitive development and any morbidities were noted. Investigations included EEG at onset of AED, EEG before withdrawal, type of EEG abnormality and neuro-imaging findings (preferably MRI).
The data was entered on excel sheet. Those patients who did not follow up were called telephonically to check for seizure recurrence.
# 2.3
Statistical analysis
The information was collected and analyzed through SPSS (Statistical package for social sciences) version 17.0. For univariate analysis we have used Chi-square test, Fisher's exact test to find the association between recurrence and various risk factors. A multivariate analysis was carried out using Cox proportional Hazard model.
P value <0.05 was significant, <0.01 – highly significant
A detailed review of literature was performed by entering the key words – AED withdrawal, recurrence, relapse, risk factors. Databases searched were Pubmed, Embase, various articles in journals related to epilepsy and neurosciences and their cross references.
#
# 3
Results: background data: see [Table 1]
Rate and timing of recurrence
Recurrence was seen in 47 cases, with a recurrence rate was 32%. The time to recurrence varied from 1 month to 10 years (mean of 1.189 years) after withdrawal of AED. 68% of total relapses occurred within 1 year, while 89% of relapses were within 2 years of withdrawal of AED. Thus only 11% relapse happened after 2 years of withdrawal ([Fig. 2]).
![](https://www.thieme-connect.de/media/10.1055-s-00037682/201701/thumbnails/10-1016-j-ijep-2016-12-001_gr2.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
# 3.2
Risk factors for recurrence
3.2.1Univariate analysis ([Table 2])
The following factors were found to be significantly associated with higher risk of recurrence – duration of active epilepsy (if more than 2 years), symptomatic etiology, prior history of neonatal seizures, concomitant cerebral palsy, response time after starting AED of more than 1 year, more than 2 seizures after start of AED therapy, total duration of AED given was more than 3 years.
The risk factors not found significant were gender, type of epilepsy, total number of seizures, past history of febrile seizures, family history of epilepsy, prior developmental delay alone (without associated cerebral palsy), EEG at onset of AED therapy as well as before withdrawal, abnormal neuro-imaging, number of AED required to control seizures, number of seizures before the start of AED, type of AED used, duration of AED withdrawal and age of AED withdrawal.
# 3.2.2
Multivariate analysis: ([Table 3])
Cox proportional hazard model was used and three factors acquired significance for increased risk of seizures: duration of epilepsy more than 2 years, age of AED withdrawal if more than 10 years and total duration of AED more than 3 years.
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# 4
Discussion: comparison with other studies
The literature search included adult and pediatric studies that looked at recurrence on follow up after AED withdrawal including a meta-analysis (Berg and Shinnar[14]) and a literature review (Britton[15]).
Rate of recurrence : Most studies found a recurrence rate between 14% and 41%[3]–[5] [12]–[23] [25]–[27] Patients with JME reported a higher relapse rate, up to 80% while only 6.2% in CAE.[21] Ohta et al.,[12] reported a low recurrence rate of 9.2% in cryptogenic focal epilepsies with normal pre-withdrawal EEG. Hitiris et al.,[30] found 1 year seizure remission in upto 75% after treatment for 2–4 years. A prospective population based study (Cockerell et al.,[32]) found 3 and 5 years remission in 86% and 54% respectively, but they included single unprovoked seizures.
Timing of recurrence: In our study, 14% of relapses occurred during withdrawal, 68% within 1 year and 89% within 2 years of AED withdrawal. In other studies, 20–50% of relapses were noted during withdrawal itself.[5] [21] [25] The percentage of relapses happening within 1 year of withdrawal ranged from (30–40%)[5] [13] in some studies to (60–70%)[14] [16] [19] [21] [23] [27] up to more than 70%.[25] The percentage of relapses that happened within 2 years of AED withdrawal were (10–20%),[3] [17] (20–30%),[20] 30–40%,[4] (40–50%),[13] (70–80%),[3] and 95%.[21] Thus, maximum number of relapses is reported to occur within 2 years of withdrawal.
Risk factors for recurrence: [Table 4] shows an overview of different risk factors found significant/not significant in our study and their status in the literature. We did not consider specific AEDs or post withdrawal EEG to look for worsening. History of neonatal seizures and perinatal insult (HIE, hypoglycemia) was not studied in most of the other existing literature.
Risk factor for recurrence |
Our study result |
Studies that found the factor significant |
Studies that found the factor not significant |
Comments on the basis of existing literature |
---|---|---|---|---|
Age of onset of epilepsy |
Not significant (less or more than 1 year) |
Older age of onset – more than 10 years[8] [14] [15] [17] [21] [26] [31] More than 5 years[6] More than 6 years[12] |
Epilepsies with onset in adolescent age may have more recurrence. |
|
Sex |
Not significant |
Female sex may act as additional risk factor in IGE |
||
Duration of active epilepsy more than 2 years |
Significant |
Surrogate marker for difficult to control epilepsy |
||
Number of AED used more than one |
Not significant |
Surrogate marker for difficult to control epilepsy |
||
Type of epilepsy – focal or generalized |
Not significant |
Equivocal effect of type of seizures but multiple seizure types confer higher risk of recurrence |
||
Etiology – symptomatic versus idiopathic |
Significant |
Remote symptomatic[6] [8] [13]–[15] [18] [20] [24] [26] [31] [35]–[37] [40] |
Adolescent onset IGE may have equal risk as Symptomatic |
|
More than 2 seizures before starting AED |
Not significant |
Equivocal |
||
More than 2 seizures after starting AED |
Significant |
Surrogate marker for difficult to control epilepsy |
||
Time taken to control seizures was more than 1 year after start of AED |
Significant |
Surrogate marker for difficult to control epilepsy |
||
Total duration of AED if more than 3 years |
Significant |
Equivocal |
||
History of seizures in neonatal period |
Significant |
Not studied adequately |
||
Past history of febrile seizures |
Not significant |
Not studied adequately |
||
Family history of seizures |
Not significant |
Family history of seizures may not confer an additional risk for recurrence |
||
History of perinatal insult (asphyxia/hypoglycemia/seizures) |
Significant |
[17] |
[27] |
Not studied adequately |
History of prior developmental delay |
Not significant |
Associated developmental delay has higher risk of recurrence |
||
EEG at onset of AED (123 patients) |
Not significant |
Abnormal EEG at onset of AED may have a higher risk of recurrence |
||
EEG at withdrawal of AED (78) |
Not significant |
[3] |
Abnormal EEG at withdrawal of AED may have a higher risk of recurrence |
|
MRI findings (67 patients) |
Not significant |
Abnormal[17] |
Not adequately studied |
|
Concomitant cerebral palsy |
Significant |
Motor deficits[14] [15] [17] [18] [23] More risk in hemiplegia[45] |
[19] |
Associated Cerebral palsy has higher risk of recurrence |
Age of AED withdrawal more than 10 years |
Not significant |
Late onset epilepsies may have a higher risk of recurrence. |
||
Duration of AED withdrawal over 3 or more than 3 months |
Not significant |
May not be significant |
Britton[15] asserted that abnormal EEG prior to withdrawal has limited predictive value, as some medications like Valproate may have EEG normalizing effects. They pointed out that relapse rates were up to 83% in patients whose EEG worsened on dose reduction, compared to 54% in patients whose EEG remained unchanged, suggesting that post withdrawal EEGs may be useful. Berg[14] showed that slowing on EEG may be as important as presence of epileptiform abnormalities, as also photo-paroxysmal response which may be predict a higher risk of relapse.
4.1Multivariate analysis
We found only three factors achieved significance-duration of epilepsy of more than 2 years, age at AED withdrawal if more than 10 years and duration of AED therapy if more than 3 years conferred a higher risk of recurrence. Different studies found various combinations of risk factors to be significant for recurrence: e.g. female sex,[3] [22] higher age of onset of seizures,[12] [25] time to control seizures more than 5 years,[12] high initial seizure frequency,[13] seizures after start of AED,[25] remote symptomatic etiology,[13] abnormal EEG at onset or withdrawal,[22] [25] [27] abnormal neurological examination,[23] generalized seizures (primary or secondary),[25] polytherapy,[27] etc.
Elson[50] concluded that the most consistent factor is the ease of controlling seizures – how soon seizures are controlled on AED, frequency of seizures after AED initiation and the number of AED required to control seizures. Camfield and Camfield[51] found the following factors to predict remission in children (Class I evidence): normal neurologic/mental abilities, seizure onset below the age of 12 years and infrequent or easily controlled seizures. The remission rate was 80% if all three factors were present versus 20% if none were present.
# 4.2
Limitations of our study
There were several limitations in our study. 22% (45 out of 202) patients who completed 2 years of AED therapy did not follow up with us. Most patients were included retrospectively and the remaining patients were included over a period of 5 years from the onset of the study. Patients were treated for 2 or 3 years as per physician's discretion. It is possible that those patients who had difficult to control epilepsy and those who had florid abnormalities on pre withdrawal EEG were given prolonged therapy. We did not study type of EEG abnormalities, degree of mental retardation, etc. to stratify the risk of relapse. MRI was not available in many patients.
#
# 5
Conclusion
This is the first study to look at rate of recurrence and its risk factors amongst children treated for epilepsy in India. In general, older age of onset in a previously normal child points to Idiopathic generalized epilepsies (IGE) like JME which carry a greater risk of relapse even if easily controlled. Among the symptomatic group, mostly due to perinatal brain injury (asphyxia, hypoglycemia) – the presence of co-morbidities like motor deficits, difficult to control seizures along with an abnormal EEG at withdrawal is associated with a higher rate of recurrence. There is no consensus in the world literature regarding the combination of prognostic factors to predict recurrence.
# 6
Areas for further research
Larger prospective studies with longer follow up to generate survival curves and to find out the factors affecting the rate of recurrence are needed to address this important issue with impact on future physical, economic and social well being of these children.
#
Conflicts of interest
The authors have none to declare.
#
#
No conflict of interest has been declared by the author(s).
Acknowledgements
We thank Mr. Shrivallabh Sane, Statistician, Department of Community Medicine, Bharati Vidyapeeth Medical College, Pune for assistance in statistical analysis.
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References
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- 2 Specchio LM, Beghi E. Should antiepileptic drugs be withdrawn in seizure-free patients?. CNS Drugs 18 (04) 2004; 201-212
- 3 Olmez A, Arslan U, Turanli G. et al. Risk of recurrence after drug withdrawal in childhood epilepsy. Seizure 18 2009; 251-256
- 4 Verriotti A, D’Egidio C, Agostinelli S. et al. Antiepileptic drug withdrawal in childhood epilepsy: what are the risk factors associated with seizure relapse. Arch Dis Child 96 2011; 113-115
- 5 Magdy AA, Siam AG. Effect of the duration of withdrawal of antiepileptic drugs on the risk of seizure recurrence in childhood epilepsy. Egypt J Neurol Psychiat Neurosurg 47 (04) 2010; 593-598
- 6 Bouma PAD, Peters ACB, Brouwer OF. Long term course of childhood epilepsy following relapse after antiepileptic withdrawal. J Neurol Neurosurg Psychiatry 72 2002; 507-510
- 7 Altunbasak S, Artar O, Burgut R. et al. Relapse risk analysis after drug withdrawal in epileptic children with uncomplicated seizures. Seizure 8 1999; 384-389
- 8 Shinnar S, Berg AT, Moshe SL. Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol 35 1994; 534-545
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- 10 Andersson T, Braathen G, Persson A. et al. A comparison between one and three years of treatment in uncomplicated childhood epilepsy: a prospective study. II. The EEG as predictor of outcome after withdrawal of treatment. Epilepsia 38 (02) 1997; 225-232
- 11 Caviedes BE, Herranz JL. Seizure recurrence and risk factors after withdrawal of chronic antiepileptic therapy in children. Seizure 7 (02) 1998; 107-114
- 12 Ohta H, Ohtsuka Y, Tsuda T. et al. Prognosis after withdrawal of antiepileptic drugs in childhood-onset cryptogenic localisation related epilepsies. Brain Dev 26 (01) 2004; 19-25
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- 23 Lossius MI, Hessen E, Mowinckel P. et al. Consequences of antiepileptic drug withdrawal: a randomized Double Blind Study (Akhershus Study). Epilepsia 49 2008; 455-463
- 24 Hawash KY, Rosman NP. Do partial seizures predict an increased risk of seizure recurrence after antiepilepsy drugs are withdrawn?. J Child Neurol 18 (05) 2003; 331-337
- 25 Prognostic index for recurrence of seizures after remission of epilepsy. Medical Research Council Antiepileptic Drug Withdrawal Study Group. BMJ 306 1993; 1374-1378
- 26 Bonnett LJ, Shukralla A, Tudur-Smith C. Seizure recurrence after antiepileptic drug withdrawal and the implications for driving: further results from the MRC Antiepileptic Drug Withdrawal Study and a systematic review. J Neurol Neurosurg Psychiatry 82 2011; 1328-1333
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- 31 Peters AC, Brouwer OF, Geerts AT. et al. Randomized prospective study of early discontinuation of antiepileptic drugs in children with epilepsy. Neurology 50 1998; 724-730
- 32 Cockerell OC, Johnson AL, Sander JW. et al. Prognosis of epilepsy: a review and further analysis of the first nine years of British national General practice. Study of epilepsy: a prospective population based study. Epilepsia 38 1997; 31-46
- 33 Dooley J, Gordon K, Camfield P. et al. Discontinuation of anticonvulsant therapy in children free of seizures for 1 year: a prospective study. Neurology 46 1996; 969-974
- 34 Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 13 2006; 277-282
- 35 Tinuper P, Avoni P, Riva R. et al. The prognostic value of the electroencephalogram in antiepileptic drug withdrawal in partial epilepsies. Neurology 47 1996; 76-78
- 36 Avoni P, Riva R, Tinuper P. Prognosis of epilepsies in antiepileptic drugs discontinuation. Epilepsia 37 suppl (04) 1996; 58-59
- 37 Braathen G, Melander H. Early discontinuation of treatment in children with uncomplicated epilepsy: a prospective study with a model for prediction of outcome. Epilepsia 38 1997; 561-569
- 38 Sillanpaa M, Jalava M, Kaleva O. et al. Long term prognosis of seizures with onset in childhood. N Engl J Med 338 1998; 1715-1722
- 39 Berg AT, Shinnar S, Levy SR. et al. Two year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia 42 2001; 1253-1262
- 40 Hixson JD. Stopping antiepileptic drugs: when and why. Curr Treat Options Neurol 12 2010; 434-442
- 41 Tennison M, Greenwood R, Lewis D. et al. Discontinuing antiepileptic drugs in children with epilepsy: a comparison of a 6 week and a 9 month taper period. N Engl J Med 330 1994; 1407-1410
- 42 Sirven JL, Sperling M, Wingerchuk DM. Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. Cochrane Database Syst Rev. 3 2002
- 43 MacDonald BK, Johnson AL, Goodridge DM. et al. Factors predicting prognosis of epilepsy after presentation with seizures. Ann Neurol 48 2000; 833-841
- 44 Arts WF, Brouwer OF, Peters AC. et al. Course and prognosis of childhood epilepsy: 5 year follow-up of the Dutch study of epilepsy in childhood. Brain 127 2004; 1774-1784
- 45 Delgado MR, Riela AR, Mills J. et al. Discontinuation of antiepileptic drug treatment after two seizure free years in children with cerebral palsy. Pediatrics 97 1996; 192-197
- 46 Andersson T, Brathen G, Persson A. et al. A comparison between one and three years of treatment in uncomplicated childhood epilepsy: a prospective study, II: the EEG as predictor of outcome after withdrawal of treatment. Epilepsia 38 1997; 225-232
- 47 Serra J, Montenegro M, Guerreiro M. Antiepileptic drug withdrawal in childhood: does the duration of tapering off matter for seizure recurrence?. J Child Neurol 20 (07) 2005; 624-626
- 48 Guerra S, Augusta M, Guerreiro M. Antiepileptic drug withdrawal in childhood. Does the duration of tapering off matter for seizure recurrence?. J Child Neurol 20 (07) 2005; 624-626
- 49 Ranganathan LN, Ramaratnam S. Rapid versus slow withdrawal of antiepileptic drugs. Cochrane Database Syst Rev (02) 2006; CD005003
- 50 Elson L. Predictors of outcome in newly diagnosed epilepsy: clinical, EEG and MRI. Neurol Asia 16 (01) 2011; 27-29
- 51 Camfield PR, Camfield CS. Childhood epilepsy: what is the evidence for what we think and what we do. J Child Neurol 18 2003; 272-287
*
Corresponding author at
-
References
- 1 Kale R. Global campaign against epilepsy: the treatment gap. Epilepsia 43 (56) 2002; 31
- 2 Specchio LM, Beghi E. Should antiepileptic drugs be withdrawn in seizure-free patients?. CNS Drugs 18 (04) 2004; 201-212
- 3 Olmez A, Arslan U, Turanli G. et al. Risk of recurrence after drug withdrawal in childhood epilepsy. Seizure 18 2009; 251-256
- 4 Verriotti A, D’Egidio C, Agostinelli S. et al. Antiepileptic drug withdrawal in childhood epilepsy: what are the risk factors associated with seizure relapse. Arch Dis Child 96 2011; 113-115
- 5 Magdy AA, Siam AG. Effect of the duration of withdrawal of antiepileptic drugs on the risk of seizure recurrence in childhood epilepsy. Egypt J Neurol Psychiat Neurosurg 47 (04) 2010; 593-598
- 6 Bouma PAD, Peters ACB, Brouwer OF. Long term course of childhood epilepsy following relapse after antiepileptic withdrawal. J Neurol Neurosurg Psychiatry 72 2002; 507-510
- 7 Altunbasak S, Artar O, Burgut R. et al. Relapse risk analysis after drug withdrawal in epileptic children with uncomplicated seizures. Seizure 8 1999; 384-389
- 8 Shinnar S, Berg AT, Moshe SL. Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol 35 1994; 534-545
- 9 Pavlovic M, Jovic N, Pekmezovic T. Antiepileptic drugs withdrawal in patients with IGE. Seizure 20 September (7) 2011; 520-525
- 10 Andersson T, Braathen G, Persson A. et al. A comparison between one and three years of treatment in uncomplicated childhood epilepsy: a prospective study. II. The EEG as predictor of outcome after withdrawal of treatment. Epilepsia 38 (02) 1997; 225-232
- 11 Caviedes BE, Herranz JL. Seizure recurrence and risk factors after withdrawal of chronic antiepileptic therapy in children. Seizure 7 (02) 1998; 107-114
- 12 Ohta H, Ohtsuka Y, Tsuda T. et al. Prognosis after withdrawal of antiepileptic drugs in childhood-onset cryptogenic localisation related epilepsies. Brain Dev 26 (01) 2004; 19-25
- 13 Sillanpaa M, Schmidt D. Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure free patients: a long term population based study of childhood onset epilepsy. Epilepsy Behav 8 2006; 713-719
- 14 Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic drugs: a meta-analysis. Neurology 44 1994; 601-608
- 15 Britton J. Antiepileptic drug withdrawal: literature review. Mayo Clin Proc 77 2002; 1378-1388
- 16 Verma A, Mishra S. Risk of seizure recurrence after antiepileptic withdrawal, an Indian study. Neurol Asia 11 2006; 19-23
- 17 Lamdhade SJ, Taori GM. Study of factors responsible for recurrence of seizures in controlled epileptics for more than 1.5 years after withdrawal of antiepileptic drugs. Neurol India 50 2002; 295-300
- 18 Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 337 1991; 1175-1180
- 19 Boonluksiri P. Risk of seizure recurrence after antiepileptic drug withdrawal in Thai children with epilepsy. Neurol Asia 11 2006; 25-29
- 20 Ramos-Lizana J, Aguirre-Rodriguez J, Aguilera-Lopez P. et al. Recurrence risk after withdrawal of antiepileptic drugs in children with epilepsy: a prospective study. Eur J Pediatr Neurol 14 (02) 2010; 116-124
- 21 Pavlovic M, Jovic N, Pekmezovic T. Antiepileptic drugs withdrawal in patients with idiopathic generalized epilepsy. Seizure 20 (07) 2011; 520-525
- 22 Pavlovic M, Jovic N, Pekmezovic T. Withdrawal of antiepileptic drugs in young patients with cryptogenic focal epilepsies. Seizure 21 (06) 2012; 431-436
- 23 Lossius MI, Hessen E, Mowinckel P. et al. Consequences of antiepileptic drug withdrawal: a randomized Double Blind Study (Akhershus Study). Epilepsia 49 2008; 455-463
- 24 Hawash KY, Rosman NP. Do partial seizures predict an increased risk of seizure recurrence after antiepilepsy drugs are withdrawn?. J Child Neurol 18 (05) 2003; 331-337
- 25 Prognostic index for recurrence of seizures after remission of epilepsy. Medical Research Council Antiepileptic Drug Withdrawal Study Group. BMJ 306 1993; 1374-1378
- 26 Bonnett LJ, Shukralla A, Tudur-Smith C. Seizure recurrence after antiepileptic drug withdrawal and the implications for driving: further results from the MRC Antiepileptic Drug Withdrawal Study and a systematic review. J Neurol Neurosurg Psychiatry 82 2011; 1328-1333
- 27 Incecik F, Herguner OM, Altunbasak S. et al. Risk of recurrence after discontinuation of antiepileptic drug therapy in children with epilepsy. J Pediatr Neurosci 9 (02) 2014; 100-105
- 29 Speechio LM, Tramacere L, La Neve A. et al. Discontinuing antiepileptic drugs in patients who are seizure free on monotherapy. J Neurol Neurosurg Psychiatry 72 (01) 2002; 22-25
- 30 Hitiris N, Mohanraj R, Norrie J. et al. Predictors of pharmaco-resistant epilepsy. Epilepsy Res 75 2007; 192-196
- 31 Peters AC, Brouwer OF, Geerts AT. et al. Randomized prospective study of early discontinuation of antiepileptic drugs in children with epilepsy. Neurology 50 1998; 724-730
- 32 Cockerell OC, Johnson AL, Sander JW. et al. Prognosis of epilepsy: a review and further analysis of the first nine years of British national General practice. Study of epilepsy: a prospective population based study. Epilepsia 38 1997; 31-46
- 33 Dooley J, Gordon K, Camfield P. et al. Discontinuation of anticonvulsant therapy in children free of seizures for 1 year: a prospective study. Neurology 46 1996; 969-974
- 34 Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 13 2006; 277-282
- 35 Tinuper P, Avoni P, Riva R. et al. The prognostic value of the electroencephalogram in antiepileptic drug withdrawal in partial epilepsies. Neurology 47 1996; 76-78
- 36 Avoni P, Riva R, Tinuper P. Prognosis of epilepsies in antiepileptic drugs discontinuation. Epilepsia 37 suppl (04) 1996; 58-59
- 37 Braathen G, Melander H. Early discontinuation of treatment in children with uncomplicated epilepsy: a prospective study with a model for prediction of outcome. Epilepsia 38 1997; 561-569
- 38 Sillanpaa M, Jalava M, Kaleva O. et al. Long term prognosis of seizures with onset in childhood. N Engl J Med 338 1998; 1715-1722
- 39 Berg AT, Shinnar S, Levy SR. et al. Two year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia 42 2001; 1253-1262
- 40 Hixson JD. Stopping antiepileptic drugs: when and why. Curr Treat Options Neurol 12 2010; 434-442
- 41 Tennison M, Greenwood R, Lewis D. et al. Discontinuing antiepileptic drugs in children with epilepsy: a comparison of a 6 week and a 9 month taper period. N Engl J Med 330 1994; 1407-1410
- 42 Sirven JL, Sperling M, Wingerchuk DM. Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. Cochrane Database Syst Rev. 3 2002
- 43 MacDonald BK, Johnson AL, Goodridge DM. et al. Factors predicting prognosis of epilepsy after presentation with seizures. Ann Neurol 48 2000; 833-841
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