Long Term Outcome after Temporal Lobe Epilepsy Surgery in Children

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Long term outcome after temporal lobe epilepsy surgery in children

Dennis J. Dlugos, MD

Abstract

The outcome of temporal lobe epilepsy surgery in children is influenced by the underlying pathology. In general, children with low grade neoplasms have the most favorable outcome, followed by hippocampal sclerosis and cortical dysplasia. More study is needed regarding the impact of temporal lobectomy on cognition and quality of life in children. The optimal timing of temporal lobe epilepsy surgery in children is also unclear, but hopefully this question will be addressed by an upcoming randomized controlled trial.

Introduction

Temporal lobectomy (TL) is a valuable treatment option for adults and children with drug-resistant temporal lobe epilepsy (TLE). A recent randomized controlled trial provided long-awaited evidence of the efficacy of TL in adults with drug-resistant TLE (1). No such randomized trial has been conducted in children, but numerous case series speak to the efficacy of the procedure in children with drug-resistant TLE (2-6).

Critical differences exist between TLE in adults and children. The etiology is more varied in children, with isolated hippocampal sclerosis (HS) reported as the underlying pathology in relatively few childhood cases. Low-grade neoplasms (LGN) and cortical dysplasia (CD) are common causes of TLE in children. Most series have shown that seizure-frequency outcome after TL in childhood is dependent on the underlying pathology - children with LGN have the best outcome, while children with CD are less likely to be seizure-free following TL. Post-surgical outcome in children with HS is more difficult to assess, since HS is often not an isolated finding in children, but rather co-exists with CD (7, 8).

Many other important issues regarding TL in children have not been well-studied, including long-term outcome beyond 2-3 years, impact on neuropsychological function and quality of life (QOL), and the optimal timing of surgery. This review will focus on what is known and unknown regarding outcome of and patient selection for TL in children.


Pathology and seizure-frequency outcome

Recent case series of TL in children and adolescents (Table 1) suggest that patients with LGN have the most favorable seizure-frequency outcome, with seizure-free (SF) rates of 66-100% following TL (2, 4-6). In contrast, patients with CD have SF rates of 0-65% and patients with HS have SF rates of 44-75%. The largest series is from the Cleveland Clinic, with 72 patients less than 12 years of age at the time of TL (2). Overall, 78% of the patients were SF, with mean follow-up of 3.6 years, but SF rates reflected the underlying pathology - LGN 86% SF, HS 75%, and CD 56%. At Children’s Hospital of Philadelphia (CHOP), our series of 49 patients found similar results - LGN 90% SF, HS 67%, and CD 65%, with mean follow-up of 2.6 years. The CHOP series includes both children and adolescents and has a shorter duration of follow-up than the Cleveland series.

Table 1 also shows rather striking differences in patient mix between centers, some of which is likely explained by different age ranges. For example, the Miami series (5) included no patients with HS and a majority of patients with CD, while the Indiana series (4) included no patients with CD and a majority of patients with HS.

The Boston series (6) makes the important point that long-term follow-up is important, since four of 15 patients were initially SF but had recurrence of seizures between 11 and 28 months after TL. Adult TL data has suggested that 2-year outcome is predictive of longer-term outcome (9), but that point has not been demonstrated in children. Of particular concern is long-term outcome of children with CD, who may have areas of microscopic cortical dysplasia extending beyond the margin of surgical resection. Children with TLE due to CD had a somewhat more favorable surgical outcome in a recent series from Bethel, Germany, which was limited to patients with focal CD in the temporal or extra-temporal lobes (10). Of 68 children in this study, only 8 patients (12%) had CD limited to the temporal lobe, but 75% of these children were seizure-free following surgery. In this largely extra-temporal series, complete resection of the dysplastic lesion correlated with favorable post-surgical outcome.


Pre-operative MRI and seizure-frequency outcome

Several adult case series have shown that patients with unilateral hippocampal atrophy on MRI, along with other concordant data, have the best outcome following TL, with up to a 90% chance of seizure-freedom following TL (11, 12). In contrast, adults with drug-resistant TLE and no MRI lesion had only a 48% chance of seizure-freedom following TL (13).

While it seems intuitive that a localized lesion on MRI would also forebode a favorable outcome in children with TLE, the issue in children appears more complicated. An earlier series from CHOP found a dramatic improvement in SF rates if a temporal lobe lesion was present on MRI (89% SF) compared with children with a normal MRI (20% SF) (14). However, a larger series from Miami found that completeness of resection was the only significant predictor of outcome for temporal resections and extra-temporal resections confined to a single lobe (3). A complete resection was defined as removal of the entire structural lesion (if present) and removal of the ictal onset zone and prominent inter-ictal abnormalities on intra-cranial EEG (IEEG). In this series, IEEG was recorded either through extra-operative monitoring using subdural grids/strips or through intra-operative corticography. Inter-ictal abnormalities which merited resection included prominent spikes with consistent focal or rhythmic features, trains of focal fast activity, or spikes associated with focal attenuation of background. Of 29 TL patients, 20 had lesions on imaging and 14/20 (70%) were SF; nine patients were non-lesional and 5/9 (56%) were SF. This difference did not reach statistical significance.

Extra-operative IEEG is being used less frequently in many centers, since multiple imaging techniques including MR spectroscopy, MR volumetric analysis, SPECT scans, and PET scans may provide sufficient concordance to obviate the need for IEEG. However, experience with newer imaging techniques is more limited in children, and brain stimulation using IEEG may still be needed to assess the language function of the temporal lobe cortex slated to be removed. In older patients, functional MRI (fMRI) may soon replace functional cortical mapping using IEEG, but older brain stimulation techniques may still be needed in children too young to cooperate with fMRI.


Cognitive outcome following temporal lobectomy in childhood

The benefits of seizure-freedom must be weighed against the risk of verbal memory loss, a well-known morbidity in patients who undergo dominant hemisphere (usually left) temporal lobe resection (15). Risk factors for postoperative verbal memory loss in adults include a high level of preoperative memory function (16), absence of hippocampal sclerosis (17) and older age of epilepsy onset (18). Studies in children are limited and conflicting; one series reported no changes or improvements in verbal memory function (19), while others report postoperative declines (20-22).

Helmstaedter and Elger (18) found that verbal learning scores were unchanged or improved in 12 patients less than 15 years of age who underwent left TL. Adams et al (20) noted that verbal memory scores declined significantly in 16 children after left TL, but did not change in 12 children after right TL. They found a tendency for those with better pre-operative memory to show greater loss and those with hippocampal sclerosis to be less affected. Szabo et al (21) reported 14 children (7 left, 7 right) and found both immediate and delayed verbal memory performance declined following TL. Immediate verbal memory performance especially decreased in left TL patients with above average pre-operative scores. Williams et al (22), in a study of nine children, reported declines in delayed verbal memory regardless of side of resection, but found no other changes. The functional significance of verbal memory declines following TL in children has not been emphasized in these studies.

A CHOP series (23) examined pre- and post-operative neuropsychological evaluations in eight school-aged patients who underwent TL (5 left, 3 right). All five left temporal lobectomy patients demonstrated significant language-related cognitive declines on post-operative testing, including deficits in verbal IQ (1 patient), verbal learning (4 patients), naming (1 patient), and reading comprehension (1 patient). These deficits were clinically evident in four of the five left temporal lobectomy patients, leading to declines in educational performance. No significant declines were found following surgery in three right temporal lobectomy patients. Average or high pre-operative functioning may have predisposed to post-operative deficits in this series, while MRI or pathological abnormalities did not protect against post-operative deficits. This series cannot be used to estimate the incidence of cognitive declines following TL, since patients with clinically evident deficits were much more likely to have formal post-operative testing. However, it is now clear that outcome studies of TL in childhood should utilize neuropsychological testing to identify cognitive deficits.


Quality of life (QOL) following temporal lobectomy

Post-operative improvements in QOL following TL have been documented in adults (24), but are not well-studied in children (25). Several outcome studies in adults measuring psychological well-being (26, 27), QOL (28) or employment (9, 29) have found benefits only in patients who are completely seizure-free following surgery and not in patients with reduced numbers of seizures. In one study of 97 adults, the most powerful predictors of a favorable postoperative psychosocial outcome were the adequacy of preoperative psychosocial adjustment and a totally seizure-free outcome (30). QOL in children with TLE has not been specifically assessed in a medical or surgical series, but this is a critical area for future research.


Patient selection and optimal timing of surgery

A randomized controlled trial comparing TL plus intensive medical therapy with intensive medical therapy alone should begin patient enrollment in the United States in early 2003 (31). Patients 12 years and older with intractable mesial TLE of less than 2 years duration will be eligible. Until this study is completed, it is difficult to make definitive statements about the role of early surgery in childhood TLE. Population-based data on the natural history of childhood TLE, whether lesional or non-lesional, are simply not available. Based on the experience of epilepsy referral centers, it appears that drug-resistant TLE can be identified early (32, 33), but these results may be not be generalizable to broader patient populations. Until better data are available, the following guidelines may be helpful:

1) Children with drug-resistant TLE, normal intelligence and normal MRI scans could harbor an area of microscopic CD or potentially could have a variant of benign focal epilepsy of childhood (BFEC). Children with BFEC presumably have normal brain anatomy, but display age-related alterations in gene expression, leading to neuronal hyperexcitability and clinical epilepsy. Most children with BFEC respond very well to medication, but there are occasional patients who are drug-resistant. The natural history of such patients is particularly uncertain, and remission may be possible over time. Surgical options should be pursued cautiously in such children.

2) Children with drug-resistant TLE and a temporal lobe lesion on MRI do not have BFEC, but medication must be given a chance. In general, most centers prefer at least 2 maximally-tolerated medication trials before considering surgical options. Ultimately, the timing of surgery depends on the certainty of the diagnosis of TLE and the extent to which seizures or medications are disabling to the child.

3) Children with drug-resistant TLE and associated developmental delay or mental retardation may have diffuse CD in addition to focal CD in the temporal lobe. Such CD may be present even if MRI scans are normal or show isolated HS. Such patients have a less favorable outcome following TL and should be counseled appropriately. Surgery may still be indicated since the chance of a SF outcome following TL (even if only 50%) is likely higher than a SF outcome with additional medication.

For now, it appears that TL is an effective treatment for carefully selected patients with drug-resistant TLE, but unanswered questions remain regarding long-term outcome, patient selection and optimal timing of surgery. At least the key questions are now clear, and hopefully the next few years will bring substantially better answers to the many uncertainties about treatment of childhood TLE.


References

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