Risk factors for recurrence after drug withdrawal in childhood epilepsy

Commentary

Dr Jyotindra Narayan Goswami

DM (Paed Neurology), Associate Prof, Department of Pediatrics

Army Hospital (Research and Referral), Delhi, India

The optimal duration of antiepileptic drug (AED) therapy in children with epilepsy is an area of active clinical and research interest. Decisions about AED discontinuation require consideration of both the risks of seizure recurrence and those of adverse effects of therapy. Chronic AED exposure poses multiple health risks, including frequent cognitive and behavioral effects as well as risks of more serious adverse reactions. AED withdrawal can be associated with seizures, with possible associated injuries, and SUDEP [1].

In 2008 Camfield et al suggested that seizure freedom of one to two years is a valid ground for AED discontinuation [2]. In 2015 a Cochrane review analyzing five trials encompassing 924 children up to sixteen years of age with epilepsy concluded that AED discontinuation before two years of seizure freedom is associated with higher seizure recurrence rates [3]. An abnormal EEG, onset of epilepsy prior to 2 years or later than 10 years of age, occurrence of status epilepticus and underlying intellectual disability (Intelligence Quotient < 70) were found to be additional high-risk factors [3]. In 2019, Yao et al performed a metanalysis in over 700 patients and found that patients with abnormal EEGs during withdrawal had a higher recurrence rate than patients with normal EEGs [4].

The current study is a retrospective hospital-based analysis examining risk factors associated with seizure recurrence after AED withdrawal in 284 children with epilepsy. Inclusion criteria included 1) children with epilepsy with seizure-onset between one month to sixteen years of age, 2) discontinuation of AEDs after a minimum two-year seizure freedom, 3) at least three-year follow-up post AED discontinuation. AEDs were withdrawn over 6-12 months. Mean duration of follow-up was 8 years. Fifty-one children (18%) had seizure recurrence after AED withdrawal. Of these, 21 (41%) had recurrence within the initial six months following AED discontinuation and 33 (65%) within the initial twelve months. Only 1 patient (2%) had seizure recurrence more than five years after AED discontinuation. These findings are consistent with published literature, suggesting seizure recurrence rates after AED discontinuation in 20-31% of children with epilepsy [5,6].

In the current study, univariable analysis found no relationship between age at onset (> 6 years), cognitive impairment, or pre-withdrawal EEG and risk of recurrence. Multivariate regression analysis suggested that a seizure-free period of <3 years="" before="" aed="" withdrawal="" and="" genetic="" structural-metabolic="" unknown="" etiology="" were="" the="" main="" risk="" factors="" for="" recurrence="" after="" with="" hazard="" ratios="" of="" 2="" 62="" p="0.009)" 15="" respectively="" span="">

The strengths of the study include its sample size, long follow-up period, simplistic model and consideration of multiple factors with potential prognostic implications. One limitation is its inclusion of children from heterogeneous etiological groups spanning a wide age range. As the approach to discontinuation of AEDs is not necessarily uniform across epilepsy syndromes, the inclusion of such a broad subject population could impede application of the study. Another potential limitation is the slow rate at which AEDs were withdrawn, ranging from 6 months to a year, a practice not shared by all institutions or practitioners, as the optimal rate of AED withdrawal remains under study [7].  The inclusion of rate of withdrawal in the multivariate analysis could have provided additional information.  It is also unclear how the authors picked the time point of 3 years (as opposed to the widely used 2-year cut-off).

Overall, this is a useful study addressing a relevant topic with immense practical implications. Further studies in this line are warranted to derive to a universal consensus on this topic.

Abstract

Background

Several studies have been conducted to determine the risk of recurrence after withdrawal of antiepileptic drugs (AEDs) in recent years. There is no consensus concerning the circumstances affecting discontinuation of AEDs. This study was designed to determine the recurrence rate of epilepsy after withdrawal of AEDs and the risk factors related with recurrence.

Methods

Children with epilepsy onset between 1 month and 16 years of age who were followed up at least 3 years after AED treatment withdrawal were enrolled. Patients were classified into groups according to defined risk factors for recurrence.

Results

A total of 284 patients, 137 (48.2%) girls and 147 (51.8%) boys were included, and seizures recurred after withdrawal in 51 patients (18%). Thirty-three (64.7%) patients had recurrence in the first year after withdrawal. The recurrence risk was calculated based on the electro-clinical syndromes classification; the recurrence risk was the highest in the juvenile myoclonic/absence group and lowest in the benign infantile seizure group. No recurrence was observed in the infantile spasm group. Data evaluated by multivariable analysis showed that having the structural-metabolic and unknown epilepsy and <3 years="" seizure="" free="" period="" before="" withdrawal="" of="" aeds="" were="" the="" main="" risk="" factors="" for="" recurrence="" after="" aed="" in="" our="" study="" span="">

Conclusion

We suggest a seizure-free period of at least 3 years under AED medication and we must be cautious in patients with structural-metabolic and unknown epilepsy before AED withdrawal.

References:

1.            Camfield PR, Camfield CS. (2003). Childhood epilepsy: what is the evidence for what we think and what we do? Journal of Child Neurol , 18,272–287.      

2.            Camfield P, Camfield C. (2008). When is it safe to discontinue AED treatment? Epilepsia , 49(S 9),25–28.

3.            Strozzi I, Nolan SJ, Sperling MR, Wingerchuk DM, Sirven J. (2015). Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD001902. DOI: 10.1002/14651858.CD001902.pub2.

4.            Yao J, Wang H1, Xiao Z. (2019) Correlation between EEG during AED withdrawal and epilepsy recurrence: a meta-analysis. Neurol Sci. 2019 Aug;40(8):1637-1644. doi: 10.1007/s10072-019-03855-x. Epub 2019 Apr 22.

5.            American Academy of Neurology: Practice parameter: a guideline for discontinuing antiepileptic drugs in seizure-free patients—summary statement. Neurology (1996). 47,600–602.

6.            Hixson JD. (2010). Stopping antiepileptic drugs: when and why? Current treatment options in neurology,12(5),434-442.

7.            Ayuga Loro F, Gisbert Tijeras E, Brigo F. Rapid versus slow withdrawal of antiepileptic drugs. (2020). Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD005003. DOI: 10.1002/14651858.CD005003.pub3.