When does surgical treatment have to be performed?

Epilepsy represents one of the most common neurological disorders in childhood. Epilepsy surgery is a particularly effective treatment option for children and adolescents with pharmacoresistant focal epilepsy. Why a decision for surgical treatment as early as possible makes sense, this article elaborates.

Epilepsy represents one of the most common neurological disorders in childhood. The incidence of epilepsy is highest in the first year of life. Thereafter, it remains high in childhood and drops sharply again from the age of ten. Anticonvulsant drug therapy is usually the primary treatment. But not every epilepsy can be treated so successfully. One in three children with an epilepsy manifestation before the age of three develops pharmacoresistance. This is defined as failure of two appropriate treatment attempts with well-tolerated as well as appropriately selected anticonvulsants in monotherapy or combination therapy. In particular, structural brain changes as a cause of epilepsy have been shown to be a strong predictor of pharmacoresistance. Refractory epilepsy is often associated with relevant comorbidities. This includes deficits in cognitive development, behavioral disorders, psychiatric disorders including depression and anxiety disorder, and increased SUDEP (Sudden Unexpected Death in Epilepsy) risk. Not least because of severe limitations in the quality of life and the burden on the social environment (family, school), rapid seizure control is absolutely desirable.

Due to major advances in neurosurgery, neuroanesthesia, and intensive care medicine, epilepsy surgery can now be performed at specialized centers with relatively low risks. However, the smaller blood volume compared to adults, especially in infants, the immature physiology of the developing brain, and the often large extent of structural changes and thus resulting interventions continue to present challenges. However, careful presurgical assessment and planning of the procedures within a specialized interdisciplinary team of epileptologists, neuropsychologists, neuroradiologists, neurosurgeons, and anesthesiologists, can ensure a favorable risk-benefit ratio.

Early decisions

Pharmacoresistance can usually be detected relatively early in the course of epilepsy. For this reason, in children with structural brain lesions or with other evidence of focal epilepsy, the possibility of epilepsy surgery should be discussed at the latest when pharmacoresistance has been demonstrated, and the appropriate presurgical diagnostic workup should be initiated. Epilepsy surgery intervention should be considered as early as possible after testing for pharmacoresistance, including in the first years of life, and the child should be referred to an epilepsy center with pediatric expertise for more detailed evaluation.

Despite significant advances in neurophysiological and imaging diagnostics and the increasing acceptance of epilepsy surgery in recent years, the latency between the establishment of pharmacoresistance in children and their referral to an epilepsy center for presurgical evaluation with pediatric expertise has unfortunately remained high. For example, an international survey of epilepsy centers with a pediatric focus found that surgical treatment was performed within two years of the initial manifestation of epilepsy in only one-third of the children operated on, although epilepsy manifested itself in the first two years of life in two-thirds of these children [1]. In a US cohort study, the incidence of early childhood pharmacorefractory focal epilepsies was reported to be 11.3/100,000 of the population per year, whereas the incidence of epilepsy surgery in the same cohort was 1.3/100,000 per year [2]. Only 45% of children with pharmacorefractory epilepsy were referred to specialized epilepsy centers for further evaluation, representing a significant gap in care.

Etiology and assignment

As mentioned above, structural brain changes are the main cause of pharmacoresistant epilepsies. According to a 2004 ILAE (International League Against Epilepsy) survey of 20 different epilepsy surgery centers, focal cortical dysplasia (FCD) at 42% and glioneuronal tumors (ganglioglioma, DNET: dysembryoplastic neuroepithelial tumor) at 19% were the most common etiologies in pediatric patients [3]. In contrast, vascular lesions, Rasmussen encephalitis, or Sturge-Weber syndrome were less common. A major feature of childhood epilepsies is the broad spectrum of childhood epilepsy syndromes and their etiology, as well as the wide variability of clinical and electroencephalographic seizure patterns across age groups.

Pre-surgical work-up and indication for epilepsy surgery

The goal of epilepsy surgery is to achieve complete resection or disconnection of the epileptogenic zone and to spare eloquent brain areas and their function. This represents the prerequisite for achieving seizure freedom, which should be maintained even after gradual reduction and discontinuation of anticonvulsant medication. The epileptogenic zone is defined as the cortex area causative for the development of epileptic seizures. This may correspond to the extent of the structural lesion-if the epilepsy is associated with a structural lesion-but it may extend beyond the lesion. Despite the great advances in pediatric presurgical epilepsy diagnosis, the identification of the epileptogenic zone as well as the eloquent cortex areas is often a particular challenge, especially in the first years of life.

EEG abnormalities in young children are often extended, multifocal, or bilateral in focal epilepsies and thus less informative regarding the localization of seizure origin. In addition, seizure semiology in focal seizures in the first years of life is less often lateralizing or barely localizing; consciousness is often difficult to assess. Focal epileptogenic lesions in the first year of life may manifest as epileptic spasms in the setting of West syndrome. The interpretation of MRI imaging is particularly challenging due to the immature myelination of the medullary canal during the first two years of life, especially with regard to the diagnosis of focal cortical dysplasia. In this age group, repeated MRI examinations are necessary to identify possible cortical malformations during postnatal brain development. The identification of eloquent brain areas is also challenging, especially since noninvasive functional imaging as well as invasive procedures such as WADA testing require good cooperation from the child. In addition, the child’s brain has a pronounced plasticity, so that functional areas, especially the language area, can shift to the contralateral side due to the epilepsy and establish themselves there.

Epilepsy surgery is generally indicated when seizure semiology, EEG findings, and imaging allow a clear definition of the epileptogenic area and resection of this area is possible without unacceptable neurological and neuropsychological limitations.

Risk consideration for early treatment

Epilepsy surgery is now an established treatment modality for selected pediatric candidates of all ages with structural and pharmacorefractory epilepsy. However, diagnosis in the first years of life is associated with difficulties in EEG assessment as well as limitations regarding MR tomographic delineation of the epileptogenic lesion. Nevertheless, in infants and young children, epilepsy surgery should be considered as early as possible, based on the high incidence of epilepsy in the first year of life, with evidence of pharmacoresistance in one-third of affected children, and the severity of epilepsy syndromes in this age group. Similarly, impaired cognition and behavior with early epilepsy onset, longer seizure duration, higher seizure frequency, continuous epilepsy-type potentials on EEG, and polypharmacotherapy argue for rapid consideration of epilepsy surgery options. Epilepsy surgery in the first years of life benefits from the plasticity of the infant brain. It is supported by studies that have shown the superiority of epilepsy surgery treatment over pharmacotherapy and the possibility of improving seizure burden and developmental deficit with successful early intervention [2,4–6].

Outcome

Surgical epilepsy treatment in children is aimed at seizure freedom and reduction or, in the longer term, possible discontinuation of anticonvulsant medication. Given the detrimental effect of seizures and anticonvulsants on the developing brain, successful surgery can be expected to have a positive effect on the developmental course. Two-thirds of children and adolescents with pharmacorefractory focal epilepsies become seizure-free in the long-term after epilepsy surgery. Most children are unimpaired or even improved in their developmental course postoperatively. Parents often report dramatic improvement in quality of life with relief from social adjustment disorder with seizure control. However, the outcome with respect to seizures depends on several factors and especially on the etiology of the epilepsy. Mortality and morbidity in epilepsy surgery are related to the extent of resection or disconnection, but tend to be low compared with other neurosurgical procedures. Across all surgeries, the risk of acquiring a severe neurologic deficit is less than 5% and mortality is well below 1% [7]. Minor complications such as problems with wound healing or cerebrospinal fluid pads may occur. Especially in children, new neurological impairments can often improve significantly over the course of surgery.

Conclusion

In children and adolescents with pharmacoresistant structural epilepsy, epilepsy surgery is a very effective treatment option. The vast majority of patients can benefit from the procedure. Young age, severe developmental delay, and psychiatric comorbidities are not contraindications. Pre-surgical diagnosis should also be initiated in pharmacorefractory epilepsy with focal seizures and nonpathing MRI. Younger children often require greater resection, but can usually compensate well for potential neurologic deficits due to functional plasticity. It is essential to shorten the interval between determination of pharmacoresistance, presurgical workup, and epilepsy surgery. Thus, better postoperative results regarding cognitive development can be achieved. To better identify predictors of seizure freedom and of positive cognitive development in children, multicenter studies with longer observation intervals would be needed. This could further optimize candidate selection and counseling for children and their families.

Take-Home Messages

Epilepsy surgery is a particularly effective treatment option for children and adolescents with pharmacoresistant focal epilepsy.
The younger the patient, the greater the resection or disconnection: young children often require more extensive procedures than older children and adolescents.
Focal cortical dysplasias, glioneuronal brain tumors, and porencephaly due to perinatal hemorrhagic ischemic insults represent the most common etiologies in this age group.
Two-thirds of children remain seizure-free in the long-term after epilepsy surgery. Postoperative cognitive development remains stable overall.
Epilepsy surgery in children and adolescents is no longer considered a last resort, but must be viewed as “disease modifying,” especially in the first years of life.

Literature:

Berg AT, et al: Frequency, prognosis and surgical treatment of structural abnormalities seen with magnetic resonance imaging in childhood epilepsy. Brain 2009; 132(Pt10): 2785-2797.
Loddenkemper T, et al: Developmental outcome after epilepsy surgery in infancy. Pediatrics. 2007; 119(5): 930-935.
Harvey AS, et al: ILAE Pediatric Epilepsy Surgery Survey Taskforce. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia 2008; 49(1): 146-155.
Jonas R, et al: Surgery for symptomatic infant-onset epileptic encephalopathy with and without infantile spasms. Neurology 2005; 64(4): 746-750.
Ramantani G, et al: Seizure and cognitive outcomes of epilepsy surgery in infancy and early childhood. Eur J Paediatr Neurol 2013; 17(5): 498-506.
Ramantani G, et al: Cognitive Development in Pediatric Epilepsy Surgery. Neuropediatrics 2018; 49(2): 93-103.
Walter J, et al. Complications of epilepsy surgery-A systematic review of focal resections and invasive EEG monitoring. Epilepsia 2013; 54(5): 840-847.