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Cognitive Outcome After Epilepsy Surgery in Children
Author’s Accepted Manuscript Cognitive Outcome after Epilepsy Surgery in Children Ahsan N.V. Moosa, Elaine Wyllie
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S1071-9091(17)30134-1 http://dx.doi.org/10.1016/j.spen.2017.10.010 YSPEN691
To appear in: Seminars in Pediatric Neurology Cite this article as: Ahsan N.V. Moosa and Elaine Wyllie, Cognitive Outcome after Epilepsy Surgery in Children, Seminars in Pediatric Neurology, http://dx.doi.org/10.1016/j.spen.2017.10.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cognitive Outcome after Epilepsy Surgery in Children. Ahsan NV Moosa & Elaine Wyllie Epilepsy Center, Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
Ahsan NV Moosa, MD Epilepsy Center, Cleveland Clinic 9500 Euclid Avenue, Desk S-51 Cleveland, OH 44195, USA Phone: 216 4456746 Fax: 216 445 6813 E mail: [email protected]
Elaine Wyllie, MD Epilepsy Center, Cleveland Clinic 9500 Euclid Avenue, Desk S-51 Cleveland, OH 44195, USA Phone: 216 444 2095 Fax: 216 445 6813 Email: [email protected]
Cognitive Outcome after Epilepsy Surgery in Children. Ahsan NV Moosa & Elaine Wyllie
ABSTRACT Cognitive dysfunction in children with epilepsy is primarily contributed by etiology, seizures, frequency of inter-ictal epileptiform discharges, and adverse effects of antiepileptic drugs. The direct impact of epilepsy surgery on cognitive outcome depends on 2 key factors: the function that is present in the epileptogenic zone to be removed, and the dysfunction outside the epileptogenic zone caused by epilepsy. Studies on cognitive outcome in children after various types of epilepsy surgery estimate ‘no significant change’ in about 70% of children, improvement in cognition in 10-15%, and decline in 10-15%. In young children with epileptic encephalopathy, the reversible dysfunction outside the epileptogenic zone is larger and hence carry better chances of improved outcome after successful surgery. If the epileptogenic zone harbors significant cognitive function (memory, language or other function), then a decline in function may occur with its resection. Understanding the pathophysiological basis for the cognitive changes after epilepsy surgery assists in counseling patients and families prior to surgery.
INTRODUCTION Cognitive dysfunction in children with refractory epilepsy is common. 1-3 Factors that contribute to cognitive dysfunction include – the primary etiology of epilepsy, seizures per se, interictal epileptiform discharges, and adverse effects of anti-epileptic medications.
2,4
In patients with surgically remediable epilepsies, a successful surgery
has the potential to influence all these factors and positively influence the cognitive outcome. 5-8
The predominant factor causing cognitive dysfunction may vary in each child.
For
example, in a 2 year-old child with perinatal stroke-related left hemiparesis, developmental delay, 2 brief focal seizures at age 6 months, and infrequent interictal epileptiform abnormalities on EEG, most clinicians would agree that the primary vascular injury to the brain is the cause for the delay. Even in such scenario, the effect of the two seizures on the long term cognitive outcome is debatable as there is some evidence to suggest that seizures in infancy are linked to adverse cognitive outcome.9 In the same child, if the seizures were epileptic spasms and EEG showed hypsarrhythmia, then the developmental delay could be contributed additionally by epileptic encephalopathy. Not infrequently these children are on multiple anti-epileptic drugs which may adversely affect the cognition.10 In a cross-sectional evaluation, it may be difficult to clarify the contribution of each of these factors for developmental delay. Careful review of the temporal course of the cognitive changes may suggest the potential causes. Any regression of skills from the earlier state is likely attributed to the epileptic encephalopathy or medications.
From a practical standpoint, identifying modifiable factors provides opportunity for the neurologist to impact the outcome. In patients with medically refractory surgicallyremediable epilepsies, successful epilepsy surgery offers the opportunity to stop the seizures, reverse the epileptic encephalopathy (when present), and reduce the antiseizure medications, thereby improving not only the seizure outcome but also the cognitive outcome.
The primary goal for epilepsy surgery in children with focal epilepsy without major cognitive problems is to stop seizures. In children with epileptic encephalopathy, typically due to early brain lesions, the goal of surgery is both to stop seizures and reverse the epileptic encephalopathy. In rare instances such as epilepsy surgery specifically for the syndrome of electrical status epilepticus in sleep (ESES), the main goal for surgery would be to improve the cognitive and behavioral outcome. In this paper, we will review the cognitive and developmental outcome after some common epilepsy surgical procedures in children and discuss the pathophysiological reasons for variability in outcome.
CHALLENGES AND LIMITATIONS OF COGNTIIVE OUTCOME STUDIES IN CHILDREN Effects of epilepsy surgery on cognitive measures such as memory are most studied in adults. There are several challenges in conducting these studies in children. Some of them are discussed below.
1. Many young children with severe intractable epilepsy from early infancy cannot be tested reliably by standardized intelligence scales.11 More than 70% of children who undergo hemispherectomy, a relatively common procedure in the pediatric epilepsy surgery series, are mentally challenged.
12, 13
In the absence of
baseline testing, interpretation of the postoperative cognitive function results and the impact of surgery are difficult to interpret. Additionally, children with severe delays in early life thus may be excluded from many studies. Such children may benefit the most from epilepsy surgery as resolution of epileptic encephalopathy in early-onset epilepsy offers the best chances for improved developmental outcome. 2. A cognitive test that is applicable at a younger age may be invalid at on older age. This poses challenges for interpreting longitudinal data. 3. Unlike in adults, there is a wide age range within the pediatric group and hence there exists a wide range of normalcy. Acquisition of new abilities as expected with ‘normal development’ with advancing age may make the postoperative ‘improvement’ difficult to interpret. 4. Each child with surgically remediable epilepsy has unique characteristics that have potential to affect the outcome. It is difficult to form a homogenous group in sufficient numbers to gather a generalizable knowledge on the outcome. Categorizing them into surgery type is the most convenient way to make the group appear homogeneous but is very imperfect as the same surgery type could be targeting different electro-clinical phenotypes.
8, 12, 13
A hypothetical scenario
would be temporal lobectomy for focal epilepsy of mesial temporal origin that had
onset at age 5 years. The same surgery type, temporal lobectomy, may be offered for an infant with epileptic spasms due to anterior temporal lobe dysplasia. Seizure types, seizure frequency, and frequency of inter-ictal spiking vary widely among these patients within the same surgical group. Lumping such cases together does not capture the unique differences among patients. Studying the predictors of outcome helps to distinguish the impact some of these differences. 5. Temporal lobe epilepsy, a common phenotype on which the majority of cognitive outcome studies have been performed in adults, is a relatively homogenous group in adults, with mesial temporal sclerosis as a common substrate. In children, dual pathology and low grade tumors are frequent.
8, 14
Because of
variability in pathology, no two temporal lobe epilepsy series in children are similar as surgical procedures are not uniform with variable sparing of the hippocampal structures. Thus it is exceedingly difficult to compare between the studies due to marked variability in lesion, extent of lesion, and the type of surgery. 6, 8, 15-20 6. Episodic memory, a key cognitive function of mesial temporal structures, is established relatively later in childhood and thus episodic memory dysfunction may not be detected until age 5 or 6 years of age. 21,22 7. Translation of the cognitive scores to meaningful daily living skills is often not straight forward. Formal IQ tests have limitations in capturing real life improvement. It is common in clinical practice not to see any significant
improvement in scores on IQ tests despite families reporting drastic changes in behavior, attention and social skills. 8. Positive changes in IQ changes are often delayed (as late as 6 years) and only long term follow up several years after surgery may detect positive changes in outcome.
6,23,24
Studies with cognitive outcome at 6 months and 1 year after
surgery may underestimate the effect of surgery. 9. The effect of surgery is well studied if the outcome is compared with a control group with similar epilepsy phenotype. Normal age-matched children or children with epilepsy who are not candidates for epilepsy surgery serve as poor control groups. Very few studies have appropriate control groups.
COGNITIVE OUTOME AFTER EPILEPSY SURGERY TYPES For the purposes of this review, we focus on the cognitive outcome after hemispherectomy and temporal lobectomy - two common procedures performed in children with intractable epilepsy.
HEMISPHERECTOMY Hemispherectomy is among the most effective type of epilepsy surgery to achieve seizure freedom in appropriate candidates with large hemispheric lesions. 12, 13, 25-28 As it implies removal or disconnection of the whole hemisphere, patients and families are frequently concerned about its effects on cognition in addition to motor deficits and visual deficits. Almost all patients who undergo hemispherectomy have pre-existing
hemiplegia and many have visual field defects as well. In most patients, because of the extensive nature of the structural abnormalities in the affected hemisphere, the actual amount of ‘normal’ brain tissue removed or disconnected during the surgery is minimal. Epilepsy surgery is expected to stop the seizures and abolish the epileptic encephalopathy (if present), thereby restoring the function of the opposite hemisphere. However, in individual cases, the extent of brain lesion is variable and the effect of the surgery on cognition may vary. Thus the ultimate outcome is influenced by the extent of the lesion in the hemisphere, presence of residual function in the affected hemisphere, the effect of epilepsy on the opposite hemisphere, and the seizure control after surgery. Of note, for children with an early left hemisphere brain lesion, cognitive (specifically language) outcome after hemispherectomy benefits from plasticity, with language development reliably in the healthy right hemisphere. 25-29
Several studies reported neuropsychological outcome using standardized cognitive tests measuring intelligence quotient, developmental quotient, and tests for various cognitive domains. Such formal testing may be possible in about two-thirds of children at an average of about 5 years after hemispherectomy.
11
Only a handful of studies on
cognitive outcome after hemispherectomy had more than 30 patients.
11, 13, 26, 30
In a
series of 53 patients, at a mean follow up of 5.4 years after surgery, 68% had no change in cognitive scores, 13% had improvement (defined as increase of 15 IQ points) and 19% had deterioration.30 In another series of 43 patients, of 34 children had pre and postoperative cognitive assessment, 19 were severely delayed, 11 were moderately delayed (MDI/DQ 55-75), 3 mildly delayed and one patient performed in
normal range before surgery.
13
After surgery, 22 (65%) remained stable, 9 had
improvement (in DQ/IQ scores by 10 points) and 3 had decline.
13
In a pooled analysis
of cognitive outcome after hemispherectomy from 11 studies of children who had formal pre- and post-operative cognitive testing, 90% had either improvement (29%) or were unchanged (61%) after surgery.
11-13, 26,30-34
decline in IQ/DQ scores after surgery.
31
About 10% of children reportedly had
These results reflect the Cleveland Clinic
experience in clinical practice.
It remains difficult to translate these cognitive scores into a clear picture of patients’ skills in the real world. To address this issue, functional status was assessed in a series of 115 children using a semi-structured questionnaire to evaluate the developmental skills of these children as perceived by the parents.
24
Formal cognitive testing and IQ
scores were not part of this study. Caregivers estimated satisfactory age-appropriate spoken language skills in one-third of children; about 36% had mild to moderate difficulties and the remaining had profound speech difficulties. Among 105 children aged 6 years or older at evaluation, only 18% had age-appropriate reading abilities. These results reflect the status of these children after surgery, which may not equal the ‘outcome’ as a result of surgery.
25
More than two-thirds of children undergoing
hemispherectomy are significantly cognitively challenged prior to surgery.
12,26,30
It is
difficult to know what the outcome would have been without surgery as the epilepsy in these cases remain refractory, negatively affecting the developmental trajectory.
The predictors of cognitive outcome after surgery have been analyzed in several studies. In a study of 43 children, lower pre-operative scores, shorter duration of epilepsy, and lower age at surgery were associated with poor postoperative scores. 13 All these 3 factors are interlinked as children requiring surgery early in life typically have poor baseline scores and shorter duration of epilepsy prior to surgery. Children who require hemispherectomy at a younger age are also those with severe epilepsy, most frequently secondary to brain malformations.
26,30
Mean IQ is frequently very low (in the
30s) for hemispherectomy candidates with malformations compared to generally higher scores (in 70s) for patients with Rasmussen encephalitis but children with malformations, although worse in cognition compared to other pathologies requiring hemispherectomy, have the most to gain after surgery. 26, 30, 34 Larger gains in cognitive function were also observed in children requiring early surgery in Sturge-Weber syndrome. 35
The side of disease was not predictive of functional outcome after hemispherectomy for children with vascular lesions and dysplasias, but the language outcome was poor in left hemispheric Rasmussen encephalitis.
25, 26, 30
This could be explained by the usual age
of onset of disease in Rasmussen encephalitis at around 5-6 years of age, with reduced plasticity potential of the opposite hemisphere at that age. On the contrary, large hemispheric lesions of other etiologies requiring hemispherectomy often have an earlier age of brain injury, typically prenatal or in infancy. Left hemispheric injury sustained before 5 years of age often leads to reorganization of the language network with good
recovery of language functions. Such plasticity potential of the opposite hemisphere declines significantly with age thereafter. 25, 36-38
Presence of contralateral brain abnormalities was significantly associated with poor postoperative cognitive outcome. In a series of 43 children, none with bilateral abnormalities had improved DQ/IQ scores whereas 38% of children without contralateral abnormalities had improved scores after surgery.
13
In another series of
115 patients, patients with contralateral abnormalities on brain MRI had poor outcome in spoken language and reading.
25
Bilateral abnormalities on MRI in hemispherectomy
candidates range from 25 to 74%. outcome in many studies.
13, 25, 26
13, 25, 39
Finally, seizure freedom is linked to better
Seizure recurrence after hemispherectomy could also
be viewed as a surrogate marker of dysfunction on the opposite hemisphere.
TEMPORAL LOBECTOMY Temporal lobe epilepsy surgery cohorts are probably the most well-studied groups with regard to impact on memory after surgery, due to the key role of the temporal lobes in verbal and visual memory.
The dominant temporal lobe (ipsilateral to language
dominance, e.g. left temporal lobe in individuals with language in the left hemisphere) is critical for verbal memory, while the non-dominant temporal lobe plays a key role in nonverbal / visual memory function. Removal of both mesial temporal structures leads to an amnestic syndrome, well-described in patient “HM”. The impact of the episodic memory
on overall IQ is not necessarily linear as evident from the overall above-average IQ of “HM” despite profound episodic memory dysfunction. 38 Several studies in adults on cognitive outcome after temporal lobectomy have suggested some specific patterns. Patients who have high pre-operative verbal memory scores are at risk for decline in memory after surgery that involves removal of their dominant temporal lobe.
40-42
The same is applicable for non-dominant temporal
resection impacting the visual memory scores.
43
The impact of this decline in the
quality of life of a given subject depends on the pre-operative functional and occupational status of the affected individual. Severity of the epilepsy and the degree of hippocampal atrophy may influence the memory decline.
44, 45
Patients with marked
hippocampal atrophy and high seizure burden often have low pre-operative memory scores and are at low risk for decline in memory scores. Studies in children with standardized pre- and postoperative testing are often limited for reasons cited above. Epileptogenic substrates leading to temporal lobe surgery in children are different from adults with higher frequency of dual pathology – anterior temporal dysplasia with ipsilateral hippocampal sclerosis and long term epilepsyassociated tumors.
8, 14
Lack of control groups, heterogeneity of patient population, and
short follow up periods pose challenges in interpreting many pediatric series. Findings from two studies with comparison groups are noteworthy as they highlight some key features. 6, 46
In a series of 53 children with temporal lobe epilepsy (mesial temporal sclerosis or dysembryoplastic neuroepithelial tumor, excluding dual pathology), memory functions were analyzed between surgically treated (n-42) and medically treated (n-11) children. 6 Variable degree of sparing of the temporal pole and hippocampal structures provided ways to analyze the differential impact of these structures. Careful analysis of various memory scores were correlated with pre and postoperative temporal lobe structure volumes. The key findings from this study were: (i) memory had no significant decline on long term follow up after left- or right-sided surgery; (ii) visual memory improved after left temporal surgery; (iii) verbal memory improved after right temporal surgery; (iv) postoperative episodic memory functions were better with higher residual hippocampal volumes; (v) semantic memory functions were better with preserved temporal poles. Transient decline in memory on short term follow-up with recovery at 1-2 years after surgery has been noted in this as well as other studies.
16
The improvement of memory
function mediated by the un-operated temporal lobe is counterintuitive but could be explained by improved function of the healthier temporal lobe, ‘released’ after surgery from the irritation from the ongoing pre-operative seizures from the diseased side. Similar findings have been documented by others.
6, 47
44, 48
In another study that used a control group, 31 children who had epilepsy surgery (majority had unilateral temporal resections) were compared with 14 children with refractory surgically-remediable epilepsy who did not have surgery due to refusal or other reasons.
46
The electro-clinical characteristics between the two groups may have
been different as the ‘control’ group selection was not matched, but the frequency of
left-sided surgeries and dysplasias was similar between the 2 groups. All children had cognitive testing at the time of evaluation for surgery, and 1 year and 2 years later. Although the overall DQ/IQ was not significantly different between the groups, the developmental trajectory showed a positive trend in patients who had surgery. Better recall abilities and forward digit span abilities were noted in surgical group. Of note, 80% of children in surgical group had Engel 1 outcome at 2 years after surgery whereas none were seizure free in the control group. 46 When examining studies that had 20 or more children with pre- and post-operative cognitive testing, no significant decline in IQ was noted for patients as a whole group. In particular, about 2/3rd of patients had no change in verbal IQ or memory. Improvement in cognitive scores has been reported in 9-14% of children and decline in 10-14%. (Table- 1).
6, 8, 17, 20, 46
Therefore, individual patients may improve or decline in their
cognitive abilities, but the majority will experience no change.
Upon analysis of the predictors impacting cognitive outcome, unilobar epileptogenic focus and mesial temporal sclerosis were predictive of better outcome. other than mesial temporal sclerosis carried a higher risk for decline.
8, 47
49
Pathology
Whereas one
study reported a higher risk of decline with older age at surgery, others reported better outcome with older age at surgery.
8, 49, 20
Postoperative seizure freedom has been
associated with better cognitive outcome in many pediatric surgical series.
5, 20
Earlier
surgery thereby reducing the duration of epilepsy has been reported to improve outcome, 5 but this is not a consistent observation in other studies. 20, 50
OTHER SPECIAL SETTINGS Three epilepsy phenotypes that are unique in children may have special implication in studying cognitive outcome after surgery. These include electrical status epilepticus in sleep (ESES), Landau-Kleffner syndrome (LKS), and hypothalamic hamartomas.
Electrical status epilepticus in slow wave sleep (ESES): ESES is an electroclinical syndrome with major cognitive decline and behavioral problems linked to abundant epileptiform discharges in slow wave sleep. When ESES causes regression of language as the predominant deficit, it is referred to as Landau-Kleffner syndrome. Structural lesions contribute to about 50% of patients with ESES. 51 For medically refractory ESES secondary to well defined brain lesions, epilepsy surgery may be an option. Unlike many other indications for epilepsy surgery, in children with ESES, the surgery may be aimed to improve cognitive function and resolve behavioral problems as clinical seizures may be under good control in many children. Type and extent of surgery is often guided by the extent of the lesion on brain MRI, and other preoperative neurological deficits, and may range from small focal resections to hemispherectomy. In a series of 8 patients with ESES secondary to multilobar or hemispheric lesions, 6 underwent hemispherectomy and 2 had focal resection. ESES resolved in all and 6 of 8 were seizure free post operatively.
52
Small focal lesions such as focal cortical dysplasia
in temporal region can also result in ESES. Focal resection can be effective in such cases, as shown in an illustrative case in figure 1.
In a pooled analysis of 575 cases with ESES, epilepsy surgery was done in 62 patients and 90% reported improvement in EEG or cognition.
51
Surgeries in these 62 patients
were varied and comprised of multiple sub-pial transections in 31, hemispherectomy in 13, corpus callosotomy in 9, and lobar or multilobar resection in 7. Improvement after surgery was better than other frontline medical therapy such as steroids (81% of 166 patients) and benzodiazepines (68% of 171). Improvement after surgery was also more likely to be sustained compared to other forms of therapy. The role of MST in nonlesional cases with ESES remains controversial, as discussed below. Multiple subpial transection in Landau-Kleffner Syndrome: Multiple subpial transection (MST), a unique procedure was targeted to disrupt the epileptogenic irritative ‘lesion’ without causing loss of function.
53
This evolved from the experimental
evidence that suggested that the physiological function of the cortex is primarily mediated by vertically oriented columns (and the afferent and efferent pathways in the vertical column), whereas the hyper-synchronous epileptiform activity depend more on the horizontal side to side connections between neurons. Multiple sub-pial transection targeted the later circuitry and was proposed to stop or reduce seizures with preservation of function, and this was particularly an attractive option when epileptogenic cortex and functional cortex overlap. Early MST procedures were performed over the primary sensory motor cortex with promising results. 53
In 1995, Morrell and colleagues reported their experience of MST over the posterior superior temporal gyrus and the perisylvian cortex in patients with Landau-Kleffner syndrome, a form of epileptic encephalopathy with acquired epileptic aphasia.
53
In a
carefully selected group of 14 children with Landau-Kleffner syndrome, MST was reported to result in marked improvement in 11, including normal age appropriate skills in seven. A follow up study that included 10 patients from the previous study, reaffirmed these findings.
54
Similar findings were reported in another series of 5 patients that
reported marked improvement in EEG, seizure frequency, behavior and language.
55
A
major limitation of these studies was the lack of control group for a condition like LKS that is known to fluctuate over time and remit electrophysiologically with advancing age. To address this, a recent study compared the surgical group (14 patients) to a nonsurgical comparison group (21 patients) that comprised of LKS and ESES related regression. This study found no difference in the outcomes between the 2 groups on long term follow up. The electroclinical phenotype between these various studies may not be necessarily similar.
The inclusion criteria in original study by Morrell were very
stringent with use of methohexital test and intra-carotid amobarbital to clarify the unilateral origin of the apparent diffuse epileptiform discharges. Use of such modalities in this clinical setting is not widely practiced and the role of MST in the treatment of LKS is still unclear. Hypothalamic hamartomas: Hypothalmaic hamartomas (HH) are a unique group of surgically remediable epilepsy syndromes that poses special challenges. Gelastic seizures are classically associated with HH; other seizure types have also been described, including an epileptic encephalopathy phenotype with tonic seizures and falls
consistent with Lennox-Gastaut syndrome.
57
Cognitive comorbidities are frequently
present in un-operated children with HH. Surgery of the lesion carries additional risk of injury to adjacent structures, including the mammillary bodies and fornix that form the circuitry for episodic memory. Surgical approaches vary between centers ranging from radiosurgery to disconnection. In a series of 48 patients with HH who underwent epilepsy surgery (radiosurgery in 22 and disconnection in 26), post-operative intellectual functions for entire cohort had a positive trend. As noted in several other studies, individual outcomes in patients vary, with major improvement in some and decline in others. Among the predictors for cognitive outcome, children with higher level of preoperative function were at risk for decline. 58
PATHOPHYSIOLOGY OF COGNTIVE OUTCOME AFTER SURGERY Counseling families about the benefits and risk of epilepsy surgery requires good understanding about the factors impacting outcome unique to each patient. Results from published studies are often not directly applicable in many situations due to heterogeneous patient populations and a multitude of factors unique to each patient. On the surface, the results from various studies on the predictors of outcome may appear conflicting. This is particularly true for factors such as age at seizure onset and age at surgery. How should one make sense of this apparent conflicting data, to assess the benefits and risks of epilepsy surgery on cognition and function?
In the context of surgically remediable epilepsies, the concepts of various cortical zones of dysfunction/ function have been proposed to improve the understanding and localization of epileptogenic zone. 59 These include the symptomatogenic zone, irritiative zone, seizure onset zone, functional deficit zone, epileptogenic lesion and eloquent cortex. Careful analysis of the various tests that provide information about these zones guides the epileptologist to determine the region of the brain to be removed, referred to us the ‘epileptogenic zone’. Epileptogenic zone is a hypothetical zone that refers to ‘the area of cortex indispensable for the generation of epileptic seizures’, removal of which leads to seizure freedom. 59 The functional deficit zone refers to the dysfunction caused by the epilepsy and this typically involves regions in and around the epileptogenic zone. Findings from several tests may contribute to the understanding of the functional deficit zone. These include neurological exam, neuropsychological testing, slowing on EEG, extent of irritative zone determined by EEG, and hypometabolism on PET scan, to name a few. Dysfunction of the networks/ regions connected to the epileptogenic zone, remote from the epileptogenic zone, is well recognized. This is especially true in children with epileptic encephalopathy where a focal epileptogenic zone in one hemisphere may cause more diffuse dysfunction in the same or both hemispheres.
The effect of epilepsy surgery on cognitive outcome could be viewed as a result of an interplay of 2 factors: function inside the epileptogenic zone versus the dysfunction outside the epileptogenic zone caused by epilepsy. Let us examine these 3 scenarios of cognitive outcome (unchanged, improved, or worsened) after a successful epilepsy
surgery that leads to seizure freedom using the concept of epileptogenic zone and functional deficit zone (figure 2).
In scenario A, “unchanged” cognition after surgery, if the epileptogenic zone and the functional deficit zone are fairly congruent, and if the epileptogenic zone did not harbor critical cognitive function, then surgical removal of the epileptogenic zone does not lead to significant decline in function. A classical clinical example is lack of significant postoperative dysfunction after right temporal lobectomy in a patient with non-dominant right temporal epilepsy due to mesial temporal sclerosis. Such benign post-operative outcomes are not uncommon even in ‘dominant’ (left) temporal lobectomy in the presence of significant atrophy of the hippocampus. Such severely diseased hippocampi may not harbor residual major cognitive function and the cognitive deficits may
not
decline
after
surgery.
Other
examples
of
this
scenario
include
hemispherectomy in a child with extensive hemispheric encephalomalacia, and resection of small focal dysplasia in a non-eloquent region. The relationship between a lesion and function are complex but large destructive lesions often cause loss of function in the regions for resection. ‘No significant change’ in cognition is the most frequently observed outcome in epilepsy surgery series. 6, 8, 11, 13, 34
In scenario B, “improved” cognition after surgery, the functional deficit zone is larger than the epileptogenic zone. If the dysfunction outside the epileptogenic zone is caused by repeated excessive spiking may affect contiguous regions surrounding the epileptogenic zone or remote from it – a network dysfunction. If this more extensive functional deficit zone is caused by the epileptiform discharges emanating from the epileptogenic zone, then removal of the epileptogenic zone may lead to recovery of the functional deficit zone. If the core epileptogenic zone harbored no significant cognitive function, then the net benefit of removal of epileptogenic zone may lead to improvement of the function. A typical scenario is a child with infantile spasms and hypsarrhythmia due to a focal cortical lesion such as anterior temporal dysplasia. In such children, removal of the epileptogenic zone (frequently surgery driven by lesion on MRI) and resolution of the diffuse epileptic encephalopathy leads to major improvement in development soon after surgery. Another example of this scenario includes ESES due to a focal lesion. Improvement in ‘verbal’ memory after non-dominant right temporal resections observed in pediatric series also implies release of excitotoxic injury by ongoing seizures from the opposite temporal region.
6, 44, 48
In our experience, some
degree of epileptic encephalopathy that does not meet the criteria for the commonlydescribed epileptic encephalopathies is frequent in many children with refractory epilepsy and abundant diffuse spikes.
60
As surgically remediable epileptic
encephalopathies inherently occur in children, opportunities to improve cognition after epilepsy surgery are also more frequent in children. 60, 61
In scenario C, cognitive ‘decline’ after surgery, the core epileptogenic zone harbors significant cognitive function and the dysfunction outside the EZ is minimal. In this situation, epilepsy surgery, though it may lead to seizure freedom, it may also result in cognitive or neurological dysfunction. Classical examples include non-lesional left mesial temporal epilepsy in left hemisphere dominant subject, and focal dysplasia in or near the Broca’s area. In many such cases, the post-operative worsening in cognition is expected and may stop patients from having epilepsy surgery. This is particularly true in the case of risk for major language decline after surgery. In young children, particularly before the age of 6 years, the potential plasticity of the brain to adapt to brain injury enables recovery of the function. This is particularly true for language function. This factor may need to be taken into account when considering the timing of surgery, particularly surgery that involves regions that potentially harbor language function.
When faced with a child considered for epilepsy surgery, the above scenarios can be applied to understand the potential effect on surgery on cognitive outcome. In some cases with scenario C with risk for decline, the poor quality of life due to high seizure burden may force the clinician and families to proceed with a surgery that carries definite risk of decline in neurological function. Such scenarios are uncommon even in large epilepsy surgery centers. As highlighted earlier, when counseling the risks of negative cognitive outcome after surgery, one should weigh the potential risk of continuing decline in patients with ongoing seizures.
ANTI-EPILEPTIC DRUGS AFTER SURGERY The negative impact of the anti-epileptic drugs (AED) on a child’s cognition should be carefully evaluated. The risks vs benefits should be assessed in individual patients. The cognitive effect of anti-epileptic drugs on cognition and behavior would depend on the specific drug(s) and the dose of the drug(s). The risks for cognitive and behavioral side effects are higher with polytherapy. 10 Patient factors predisposing to specific cognitive behavioral side effects are poorly understood. Successful epilepsy surgery provides opportunity to minimize anti-epileptic drugs and in many cases completely discontinued.
Results from multicenter trials in post-surgical populations (TimeToStop cognitive outcome study group) confirmed that AED withdrawal, reduction in number of AED, and complete cessation of AED influence the postoperative scores positively with resultant gain in IQ.
62, 63
Weaning anti-epileptic drugs after successful surgery in patients on
monotherapy is typically performed after 1 year of seizure freedom. In patients on polytherapy, particularly in those with side effects to medications, reduction of AEDs may be done earlier. Complete weaning will be determined based on the risks of recurrence based on clinical, electrophysiological and neuroimaging factors.
CONCLUSION Refractory epilepsy in children is frequently associated with cognitive deficits of variable degree. Successful epilepsy surgery leads to seizure freedom and stabilization of cognitive functions in two-third of patients. Comparison studies with patients not undergoing surgery has shown a positive trend for better development in surgically treated patients. Children with epileptic encephalopathies due to early focal brain lesions carry the best chances to improve cognition after successful epilepsy surgery. A minority of patients may experience decline in cognitive abilities. Understanding the reasons for variability in cognitive outcome assist in counseling patients and families prior to surgery.
Disclosure of interests: The authors have no commercial, proprietary, or financial interest in any products or companies described in this article.
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14. Mohamed A, Wyllie E, Ruggieri P, et al.: Temporal lobe epilepsy due to hippocampal sclerosis in pediatric candidates for epilepsy surgery. Neurology 56:16431649, 2001.
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22. Perner J, Ruffman T: Episodic memory and autonoetic consciousness: developmental evidence and a theory of childhood amnesia. J Exp Child Psychol 59:516-548, 1995.
23. Puka K, Smith ML: Academic skills in the long term after epilepsy surgery in childhood. Epilepsy Behav 62:97-103, 2016.
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25. Moosa AN, Jehi L, Marashly A, et al.: Long-term functional outcomes and their predictors after hemispherectomy in 115 children. Epilepsia 54:1771-1779, 2013.
26. Jonas R, Nguyen S, Hu B, et al.: Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology 62:1712-1721, 2004.
27. Delalande O, Bulteau C, Dellatolas G, et al.: Vertical parasagittal hemispherotomy: surgical procedures and clinical long-term outcomes in a population of 83 children. Neurosurgery 60:ONS19-32; discussion ONS32, 2007.
28. Cook SW, Nguyen ST, Hu B, et al.: Cerebral hemispherectomy in pediatric patients with epilepsy: comparison of three techniques by pathological substrate in 115 patients. J Neurosurg 100:125-141, 2004.
29. Moosa AN, Gupta A, Jehi L, Marashly A, et al.: Longitudinal seizure outcome and prognostic predictors after hemispherectomy in 170 children. Neurology 80:253-260, 2013.
30. Pulsifer MB, Brandt J, Salorio CF, et al.: The cognitive outcome of hemispherectomy in 71 children. Epilepsia 45:243-254, 2004.
31. D'Argenzio L, Colonnelli MC, Harrison S, et al.: Cognitive outcome after extratemporal epilepsy surgery in childhood. Epilepsia 52:1966-1972, 2011.
32. Loddenkemper T, Holland KD, Stanford LD, et al.: Developmental outcome after epilepsy surgery in infancy. Pediatrics 119:930-935, 2007.
33. Lettori D, Battaglia D, Sacco A, et al.: Early hemispherectomy in catastrophic epilepsy: a neuro-cognitive and epileptic long-term follow-up. Seizure 17:49-63, 2008.
34. Van Schooneveld MM, Braun KP: Cognitive outcome after epilepsy surgery in children. Brain Dev 35:721-729, 2013.
35. Bourgeois M, Crimmins DW, de Oliveira RS, et al.: Surgical treatment of epilepsy in Sturge-Weber syndrome in children. J Neurosurg 106:20-28, 2007.
36. Boatman D, Freeman J, Vining E, et al.: Language recovery after left hemispherectomy in children with late-onset seizures. Ann Neurol 46:579-586, 1999.
37. Curtiss S, de Bode S, Mathern GW: Spoken language outcomes after hemispherectomy: factoring in etiology. Brain Lang 79:379-396, 2001.
38. Chilosi AM, Pecini C, Cipriani P, et al.: Atypical language lateralization and early linguistic development in children with focal brain lesions. Dev Med Child Neurol 47:725-730, 2005.
39. Dossani RH, Missios S, Nanda A: The Legacy of Henry Molaison (1926-2008) and the Impact of His Bilateral Mesial Temporal Lobe Surgery on the Study of Human Memory. World Neurosurg 84:1127-1135, 2015.
40. Sherman EM, Wiebe S, Fay-McClymont TB, et al.: Neuropsychological outcomes after epilepsy surgery: systematic review and pooled estimates. Epilepsia 52:857-869, 2011.
41. Hermann BP, Wyler AR, Somes G, et al.: Declarative memory following anterior temporal lobectomy in humans. Behav Neurosci 108:3-10, 1994.
42. Lambon Ralph MA, Ehsan S, Baker GA, Rogers TT: Semantic memory is impaired in patients with unilateral anterior temporal lobe resection for temporal lobe epilepsy. Brain 135:242-258, 2012.
43. Vaz SA: Nonverbal memory functioning following right anterior temporal lobectomy: a meta-analytic review. Seizure 13:446-452, 2004.
44. Baxendale SA, Thompson PJ, Kitchen ND: Postoperative hippocampal remnant shrinkage and memory decline: a dynamic process. Neurology 55:243-249, 2000.
45. Trenerry MR, Jack CR,Jr, Ivnik RJ, et al.: MRI hippocampal volumes and memory function before and after temporal lobectomy. Neurology 43:1800-1805, 1993.
46. Sibilia V, Barba C, Metitieri T, et al.: Cognitive outcome after epilepsy surgery in children: A controlled longitudinal study. Epilepsy Behav 73:23-30, 2017.
47. Berg AT: Paediatric epilepsy surgery: making the best of a tough situation. Brain 138:4-5, 2015.
48. Kuehn SM, Keene DL, Richards PM, Ventureyra EC: Are there changes in intelligence and memory functioning following surgery for the treatment of refractory epilepsy in childhood?. Childs Nerv Syst 18:306-310, 2002.
49. Puka K, Smith ML: Predictors of language skills in the long term after pediatric epilepsy surgery. Epilepsy Behav 63:1-8, 2016.
50. Skirrow C, Cross JH, Cormack F, et al.: Long-term intellectual outcome after temporal lobe surgery in childhood. Neurology 76:1330-1337, 2011.
51. van den Munckhof B, van Dee V, Sagi L, et al.: Treatment of electrical status epilepticus in sleep: A pooled analysis of 575 cases. Epilepsia 56:1738-1746, 2015.
52. Loddenkemper T, Cosmo G, Kotagal P, et al.: Epilepsy surgery in children with electrical status epilepticus in sleep. Neurosurgery 64:328-37; discussion 337, 2009.
53. Morrell F, Whisler WW, Smith MC, et al.: Landau-Kleffner syndrome. Treatment with subpial intracortical transection. Brain 118 ( Pt 6):1529-1546, 1995.
54. Grote CL, Van Slyke P, Hoeppner JA: Language outcome following multiple subpial transection for Landau-Kleffner syndrome. Brain 122 ( Pt 3):561-566, 1999.
55. Irwin K, Birch V, Lees J, et al.: Multiple subpial transection in Landau-Kleffner syndrome. Dev Med Child Neurol 43:248-252, 2001.
56. Downes M, Greenaway R, Clark M, et al.: Outcome following multiple subpial transection in Landau-Kleffner syndrome and related regression. Epilepsia 56:17601766, 2015.
57. Pati S, Deep A, Troester MM, Kossoff EH, Ng YT: Lennox-Gastaut syndrome symptomatic to hypothalamic hamartoma: evolution and long-term outcome following surgery. Pediatr Neurol 49:25-30, 2013.
58. Wagner K, Wethe JV, Schulze-Bonhage A, et al.: Cognition in epilepsy patients with hypothalamic hamartomas. Epilepsia 58 Suppl 2:85-93, 2017.
59. Rosenow F, Luders H: Presurgical evaluation of epilepsy. Brain 124:1683-1700, 2001.
60. Wyllie E, Lachhwani DK, Gupta A, et al.: Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology 69:389-397, 2007.
61. Holthausen H, Pieper T, Kudernatsch M: Towards early diagnosis and treatment to save children from catastrophic epilepsy -- focus on epilepsy surgery. Brain Dev 35:730741, 2013.
62. Boshuisen K, Arzimanoglou A, Cross JH, et al.: Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study. Lancet Neurol 11:784-791, 2012.
63. Boshuisen K, van Schooneveld MM, Uiterwaal CS, et al.: Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery. Ann Neurol 78:104-114, 2015.
LEGENDS FOR TABLE AND FIGURES Table 1. Cognitive outcome after temporal lobe surgery in children
Figure 1. Illustrative case of a 9-year old girl with ESES secondary to left temporal dysplasia. Her seizures started at age 5 years and was under good control. ESES evolved between 7 and 9 years age. ESES and behavioral problems resolved after left temporal resection at age 9 years.
Figure 2. A schematic illustration of the reasons for variations in functional outcome after surgery. In scenario A, the epileptogenic zone and the functional deficits zone are congruent with resultant ‘no change’ after surgery. In scenario B, the dysfunction due to epilepsy extends outside the epileptogenic zone as in epileptic encephalopathy due to focal lesions; resection of the epileptogenic zone leads to ‘release’ of the regions disturbed by the epilepsy, leading to ‘improvement’. In scenario C, the epileptogenic zone harbors eloquent function; resection of epileptogenic zone carries risk for decline in function.
Table 1. Cognitive outcome after temporal lobe resection from selected studies in children Study
Mean age
Side of
at surgery
surgery
Cognitive outcome
Comments
(S) & Follow up (F) & seizure freedom Westerveld
S: 14.4
43- left
No significant decline in IQ in the
50% non-
et al, 2000
years
39- right
whole group; 10% had decline and
lesional; Extent
(n-82). 8
F: 1.2 years
9% improvement in verbal
of resection not
Multicenter
Seizure
functioning; left temporal surgery
studied; FSIQ
study
free rates-
associated with improved non-
<70 excluded.
not given
verbal cognition. Older age at surgery and nonmesial temporal sclerosis lesion – higher risk for decline.
Skirrow et
S- 13.8
25- left
No significant decline in memory in Variability in
al, 2015 (n-
years
17- right
with left or right sided surgery;
extent of
53);
F- 9 years
Another 11
visual memory improved after left
resection and
2011 (n-42)
86%
medically
temporal surgery; verbal memory
sparing of
6, 50
seizure free
treated
improved after right temporal
mesial
in surgical
surgery. Postoperative memory
structures
group
functions were dependent on residual temporal lobe structures.
Increase in IQ noted only in surgical group. Jambaque
S- 12.2
12- left
Post operatively, improved
Fairly
et al, 2007
years
8 - right
memory efficiency. Attention/
homogenous
(n-20). 17
F- > 6
working memory, naming and
group; All 20
months
some episode verbal memory
with
All seizure
scores improved.
hippocampal
free
resection; 17
(inclusion
had temporal
criteria)
pole resection
Miranda &
S- 13.3
25- left
Verbal IQ: No change in 72%;
10 had dual
Smith, 2001
years
25- right
improved in 14% and declined in
pathology; 13
(n-50) 20
F- 15
14%. Performance IQ: No change
had gliosis/
months
in 67%; improved in 24% and
sclerosis; 15
68%
declined in 8%.
had tumor
seizure free Sibilia et al,
S- 8.7
17- left
Overall DQ/IQ was not significantly At 2 years, 80%
2017 (n-31)
years
14- right
different between the groups.
of in surgical
46
F- 1 and 2
Developmental trajectory showed
group had
31 surgical
years after
a positive trend in patients who
Engel 1
14 ‘control’
surgery
had surgery. Better recall abilities
outcome
and forward digit span abilities
whereas none
were noted in surgical group.
were seizure free in the controls.
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(17)30134-1 http://dx.doi.org/10.1016/j.spen.2017.10.010 YSPEN691
To appear in: Seminars in Pediatric Neurology Cite this article as: Ahsan N.V. Moosa and Elaine Wyllie, Cognitive Outcome after Epilepsy Surgery in Children, Seminars in Pediatric Neurology, http://dx.doi.org/10.1016/j.spen.2017.10.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cognitive Outcome after Epilepsy Surgery in Children. Ahsan NV Moosa & Elaine Wyllie Epilepsy Center, Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
Ahsan NV Moosa, MD Epilepsy Center, Cleveland Clinic 9500 Euclid Avenue, Desk S-51 Cleveland, OH 44195, USA Phone: 216 4456746 Fax: 216 445 6813 E mail: [email protected]
Elaine Wyllie, MD Epilepsy Center, Cleveland Clinic 9500 Euclid Avenue, Desk S-51 Cleveland, OH 44195, USA Phone: 216 444 2095 Fax: 216 445 6813 Email: [email protected]
Cognitive Outcome after Epilepsy Surgery in Children. Ahsan NV Moosa & Elaine Wyllie
ABSTRACT Cognitive dysfunction in children with epilepsy is primarily contributed by etiology, seizures, frequency of inter-ictal epileptiform discharges, and adverse effects of antiepileptic drugs. The direct impact of epilepsy surgery on cognitive outcome depends on 2 key factors: the function that is present in the epileptogenic zone to be removed, and the dysfunction outside the epileptogenic zone caused by epilepsy. Studies on cognitive outcome in children after various types of epilepsy surgery estimate ‘no significant change’ in about 70% of children, improvement in cognition in 10-15%, and decline in 10-15%. In young children with epileptic encephalopathy, the reversible dysfunction outside the epileptogenic zone is larger and hence carry better chances of improved outcome after successful surgery. If the epileptogenic zone harbors significant cognitive function (memory, language or other function), then a decline in function may occur with its resection. Understanding the pathophysiological basis for the cognitive changes after epilepsy surgery assists in counseling patients and families prior to surgery.
INTRODUCTION Cognitive dysfunction in children with refractory epilepsy is common. 1-3 Factors that contribute to cognitive dysfunction include – the primary etiology of epilepsy, seizures per se, interictal epileptiform discharges, and adverse effects of anti-epileptic medications.
2,4
In patients with surgically remediable epilepsies, a successful surgery
has the potential to influence all these factors and positively influence the cognitive outcome. 5-8
The predominant factor causing cognitive dysfunction may vary in each child.
For
example, in a 2 year-old child with perinatal stroke-related left hemiparesis, developmental delay, 2 brief focal seizures at age 6 months, and infrequent interictal epileptiform abnormalities on EEG, most clinicians would agree that the primary vascular injury to the brain is the cause for the delay. Even in such scenario, the effect of the two seizures on the long term cognitive outcome is debatable as there is some evidence to suggest that seizures in infancy are linked to adverse cognitive outcome.9 In the same child, if the seizures were epileptic spasms and EEG showed hypsarrhythmia, then the developmental delay could be contributed additionally by epileptic encephalopathy. Not infrequently these children are on multiple anti-epileptic drugs which may adversely affect the cognition.10 In a cross-sectional evaluation, it may be difficult to clarify the contribution of each of these factors for developmental delay. Careful review of the temporal course of the cognitive changes may suggest the potential causes. Any regression of skills from the earlier state is likely attributed to the epileptic encephalopathy or medications.
From a practical standpoint, identifying modifiable factors provides opportunity for the neurologist to impact the outcome. In patients with medically refractory surgicallyremediable epilepsies, successful epilepsy surgery offers the opportunity to stop the seizures, reverse the epileptic encephalopathy (when present), and reduce the antiseizure medications, thereby improving not only the seizure outcome but also the cognitive outcome.
The primary goal for epilepsy surgery in children with focal epilepsy without major cognitive problems is to stop seizures. In children with epileptic encephalopathy, typically due to early brain lesions, the goal of surgery is both to stop seizures and reverse the epileptic encephalopathy. In rare instances such as epilepsy surgery specifically for the syndrome of electrical status epilepticus in sleep (ESES), the main goal for surgery would be to improve the cognitive and behavioral outcome. In this paper, we will review the cognitive and developmental outcome after some common epilepsy surgical procedures in children and discuss the pathophysiological reasons for variability in outcome.
CHALLENGES AND LIMITATIONS OF COGNTIIVE OUTCOME STUDIES IN CHILDREN Effects of epilepsy surgery on cognitive measures such as memory are most studied in adults. There are several challenges in conducting these studies in children. Some of them are discussed below.
1. Many young children with severe intractable epilepsy from early infancy cannot be tested reliably by standardized intelligence scales.11 More than 70% of children who undergo hemispherectomy, a relatively common procedure in the pediatric epilepsy surgery series, are mentally challenged.
12, 13
In the absence of
baseline testing, interpretation of the postoperative cognitive function results and the impact of surgery are difficult to interpret. Additionally, children with severe delays in early life thus may be excluded from many studies. Such children may benefit the most from epilepsy surgery as resolution of epileptic encephalopathy in early-onset epilepsy offers the best chances for improved developmental outcome. 2. A cognitive test that is applicable at a younger age may be invalid at on older age. This poses challenges for interpreting longitudinal data. 3. Unlike in adults, there is a wide age range within the pediatric group and hence there exists a wide range of normalcy. Acquisition of new abilities as expected with ‘normal development’ with advancing age may make the postoperative ‘improvement’ difficult to interpret. 4. Each child with surgically remediable epilepsy has unique characteristics that have potential to affect the outcome. It is difficult to form a homogenous group in sufficient numbers to gather a generalizable knowledge on the outcome. Categorizing them into surgery type is the most convenient way to make the group appear homogeneous but is very imperfect as the same surgery type could be targeting different electro-clinical phenotypes.
8, 12, 13
A hypothetical scenario
would be temporal lobectomy for focal epilepsy of mesial temporal origin that had
onset at age 5 years. The same surgery type, temporal lobectomy, may be offered for an infant with epileptic spasms due to anterior temporal lobe dysplasia. Seizure types, seizure frequency, and frequency of inter-ictal spiking vary widely among these patients within the same surgical group. Lumping such cases together does not capture the unique differences among patients. Studying the predictors of outcome helps to distinguish the impact some of these differences. 5. Temporal lobe epilepsy, a common phenotype on which the majority of cognitive outcome studies have been performed in adults, is a relatively homogenous group in adults, with mesial temporal sclerosis as a common substrate. In children, dual pathology and low grade tumors are frequent.
8, 14
Because of
variability in pathology, no two temporal lobe epilepsy series in children are similar as surgical procedures are not uniform with variable sparing of the hippocampal structures. Thus it is exceedingly difficult to compare between the studies due to marked variability in lesion, extent of lesion, and the type of surgery. 6, 8, 15-20 6. Episodic memory, a key cognitive function of mesial temporal structures, is established relatively later in childhood and thus episodic memory dysfunction may not be detected until age 5 or 6 years of age. 21,22 7. Translation of the cognitive scores to meaningful daily living skills is often not straight forward. Formal IQ tests have limitations in capturing real life improvement. It is common in clinical practice not to see any significant
improvement in scores on IQ tests despite families reporting drastic changes in behavior, attention and social skills. 8. Positive changes in IQ changes are often delayed (as late as 6 years) and only long term follow up several years after surgery may detect positive changes in outcome.
6,23,24
Studies with cognitive outcome at 6 months and 1 year after
surgery may underestimate the effect of surgery. 9. The effect of surgery is well studied if the outcome is compared with a control group with similar epilepsy phenotype. Normal age-matched children or children with epilepsy who are not candidates for epilepsy surgery serve as poor control groups. Very few studies have appropriate control groups.
COGNITIVE OUTOME AFTER EPILEPSY SURGERY TYPES For the purposes of this review, we focus on the cognitive outcome after hemispherectomy and temporal lobectomy - two common procedures performed in children with intractable epilepsy.
HEMISPHERECTOMY Hemispherectomy is among the most effective type of epilepsy surgery to achieve seizure freedom in appropriate candidates with large hemispheric lesions. 12, 13, 25-28 As it implies removal or disconnection of the whole hemisphere, patients and families are frequently concerned about its effects on cognition in addition to motor deficits and visual deficits. Almost all patients who undergo hemispherectomy have pre-existing
hemiplegia and many have visual field defects as well. In most patients, because of the extensive nature of the structural abnormalities in the affected hemisphere, the actual amount of ‘normal’ brain tissue removed or disconnected during the surgery is minimal. Epilepsy surgery is expected to stop the seizures and abolish the epileptic encephalopathy (if present), thereby restoring the function of the opposite hemisphere. However, in individual cases, the extent of brain lesion is variable and the effect of the surgery on cognition may vary. Thus the ultimate outcome is influenced by the extent of the lesion in the hemisphere, presence of residual function in the affected hemisphere, the effect of epilepsy on the opposite hemisphere, and the seizure control after surgery. Of note, for children with an early left hemisphere brain lesion, cognitive (specifically language) outcome after hemispherectomy benefits from plasticity, with language development reliably in the healthy right hemisphere. 25-29
Several studies reported neuropsychological outcome using standardized cognitive tests measuring intelligence quotient, developmental quotient, and tests for various cognitive domains. Such formal testing may be possible in about two-thirds of children at an average of about 5 years after hemispherectomy.
11
Only a handful of studies on
cognitive outcome after hemispherectomy had more than 30 patients.
11, 13, 26, 30
In a
series of 53 patients, at a mean follow up of 5.4 years after surgery, 68% had no change in cognitive scores, 13% had improvement (defined as increase of 15 IQ points) and 19% had deterioration.30 In another series of 43 patients, of 34 children had pre and postoperative cognitive assessment, 19 were severely delayed, 11 were moderately delayed (MDI/DQ 55-75), 3 mildly delayed and one patient performed in
normal range before surgery.
13
After surgery, 22 (65%) remained stable, 9 had
improvement (in DQ/IQ scores by 10 points) and 3 had decline.
13
In a pooled analysis
of cognitive outcome after hemispherectomy from 11 studies of children who had formal pre- and post-operative cognitive testing, 90% had either improvement (29%) or were unchanged (61%) after surgery.
11-13, 26,30-34
decline in IQ/DQ scores after surgery.
31
About 10% of children reportedly had
These results reflect the Cleveland Clinic
experience in clinical practice.
It remains difficult to translate these cognitive scores into a clear picture of patients’ skills in the real world. To address this issue, functional status was assessed in a series of 115 children using a semi-structured questionnaire to evaluate the developmental skills of these children as perceived by the parents.
24
Formal cognitive testing and IQ
scores were not part of this study. Caregivers estimated satisfactory age-appropriate spoken language skills in one-third of children; about 36% had mild to moderate difficulties and the remaining had profound speech difficulties. Among 105 children aged 6 years or older at evaluation, only 18% had age-appropriate reading abilities. These results reflect the status of these children after surgery, which may not equal the ‘outcome’ as a result of surgery.
25
More than two-thirds of children undergoing
hemispherectomy are significantly cognitively challenged prior to surgery.
12,26,30
It is
difficult to know what the outcome would have been without surgery as the epilepsy in these cases remain refractory, negatively affecting the developmental trajectory.
The predictors of cognitive outcome after surgery have been analyzed in several studies. In a study of 43 children, lower pre-operative scores, shorter duration of epilepsy, and lower age at surgery were associated with poor postoperative scores. 13 All these 3 factors are interlinked as children requiring surgery early in life typically have poor baseline scores and shorter duration of epilepsy prior to surgery. Children who require hemispherectomy at a younger age are also those with severe epilepsy, most frequently secondary to brain malformations.
26,30
Mean IQ is frequently very low (in the
30s) for hemispherectomy candidates with malformations compared to generally higher scores (in 70s) for patients with Rasmussen encephalitis but children with malformations, although worse in cognition compared to other pathologies requiring hemispherectomy, have the most to gain after surgery. 26, 30, 34 Larger gains in cognitive function were also observed in children requiring early surgery in Sturge-Weber syndrome. 35
The side of disease was not predictive of functional outcome after hemispherectomy for children with vascular lesions and dysplasias, but the language outcome was poor in left hemispheric Rasmussen encephalitis.
25, 26, 30
This could be explained by the usual age
of onset of disease in Rasmussen encephalitis at around 5-6 years of age, with reduced plasticity potential of the opposite hemisphere at that age. On the contrary, large hemispheric lesions of other etiologies requiring hemispherectomy often have an earlier age of brain injury, typically prenatal or in infancy. Left hemispheric injury sustained before 5 years of age often leads to reorganization of the language network with good
recovery of language functions. Such plasticity potential of the opposite hemisphere declines significantly with age thereafter. 25, 36-38
Presence of contralateral brain abnormalities was significantly associated with poor postoperative cognitive outcome. In a series of 43 children, none with bilateral abnormalities had improved DQ/IQ scores whereas 38% of children without contralateral abnormalities had improved scores after surgery.
13
In another series of
115 patients, patients with contralateral abnormalities on brain MRI had poor outcome in spoken language and reading.
25
Bilateral abnormalities on MRI in hemispherectomy
candidates range from 25 to 74%. outcome in many studies.
13, 25, 26
13, 25, 39
Finally, seizure freedom is linked to better
Seizure recurrence after hemispherectomy could also
be viewed as a surrogate marker of dysfunction on the opposite hemisphere.
TEMPORAL LOBECTOMY Temporal lobe epilepsy surgery cohorts are probably the most well-studied groups with regard to impact on memory after surgery, due to the key role of the temporal lobes in verbal and visual memory.
The dominant temporal lobe (ipsilateral to language
dominance, e.g. left temporal lobe in individuals with language in the left hemisphere) is critical for verbal memory, while the non-dominant temporal lobe plays a key role in nonverbal / visual memory function. Removal of both mesial temporal structures leads to an amnestic syndrome, well-described in patient “HM”. The impact of the episodic memory
on overall IQ is not necessarily linear as evident from the overall above-average IQ of “HM” despite profound episodic memory dysfunction. 38 Several studies in adults on cognitive outcome after temporal lobectomy have suggested some specific patterns. Patients who have high pre-operative verbal memory scores are at risk for decline in memory after surgery that involves removal of their dominant temporal lobe.
40-42
The same is applicable for non-dominant temporal
resection impacting the visual memory scores.
43
The impact of this decline in the
quality of life of a given subject depends on the pre-operative functional and occupational status of the affected individual. Severity of the epilepsy and the degree of hippocampal atrophy may influence the memory decline.
44, 45
Patients with marked
hippocampal atrophy and high seizure burden often have low pre-operative memory scores and are at low risk for decline in memory scores. Studies in children with standardized pre- and postoperative testing are often limited for reasons cited above. Epileptogenic substrates leading to temporal lobe surgery in children are different from adults with higher frequency of dual pathology – anterior temporal dysplasia with ipsilateral hippocampal sclerosis and long term epilepsyassociated tumors.
8, 14
Lack of control groups, heterogeneity of patient population, and
short follow up periods pose challenges in interpreting many pediatric series. Findings from two studies with comparison groups are noteworthy as they highlight some key features. 6, 46
In a series of 53 children with temporal lobe epilepsy (mesial temporal sclerosis or dysembryoplastic neuroepithelial tumor, excluding dual pathology), memory functions were analyzed between surgically treated (n-42) and medically treated (n-11) children. 6 Variable degree of sparing of the temporal pole and hippocampal structures provided ways to analyze the differential impact of these structures. Careful analysis of various memory scores were correlated with pre and postoperative temporal lobe structure volumes. The key findings from this study were: (i) memory had no significant decline on long term follow up after left- or right-sided surgery; (ii) visual memory improved after left temporal surgery; (iii) verbal memory improved after right temporal surgery; (iv) postoperative episodic memory functions were better with higher residual hippocampal volumes; (v) semantic memory functions were better with preserved temporal poles. Transient decline in memory on short term follow-up with recovery at 1-2 years after surgery has been noted in this as well as other studies.
16
The improvement of memory
function mediated by the un-operated temporal lobe is counterintuitive but could be explained by improved function of the healthier temporal lobe, ‘released’ after surgery from the irritation from the ongoing pre-operative seizures from the diseased side. Similar findings have been documented by others.
6, 47
44, 48
In another study that used a control group, 31 children who had epilepsy surgery (majority had unilateral temporal resections) were compared with 14 children with refractory surgically-remediable epilepsy who did not have surgery due to refusal or other reasons.
46
The electro-clinical characteristics between the two groups may have
been different as the ‘control’ group selection was not matched, but the frequency of
left-sided surgeries and dysplasias was similar between the 2 groups. All children had cognitive testing at the time of evaluation for surgery, and 1 year and 2 years later. Although the overall DQ/IQ was not significantly different between the groups, the developmental trajectory showed a positive trend in patients who had surgery. Better recall abilities and forward digit span abilities were noted in surgical group. Of note, 80% of children in surgical group had Engel 1 outcome at 2 years after surgery whereas none were seizure free in the control group. 46 When examining studies that had 20 or more children with pre- and post-operative cognitive testing, no significant decline in IQ was noted for patients as a whole group. In particular, about 2/3rd of patients had no change in verbal IQ or memory. Improvement in cognitive scores has been reported in 9-14% of children and decline in 10-14%. (Table- 1).
6, 8, 17, 20, 46
Therefore, individual patients may improve or decline in their
cognitive abilities, but the majority will experience no change.
Upon analysis of the predictors impacting cognitive outcome, unilobar epileptogenic focus and mesial temporal sclerosis were predictive of better outcome. other than mesial temporal sclerosis carried a higher risk for decline.
8, 47
49
Pathology
Whereas one
study reported a higher risk of decline with older age at surgery, others reported better outcome with older age at surgery.
8, 49, 20
Postoperative seizure freedom has been
associated with better cognitive outcome in many pediatric surgical series.
5, 20
Earlier
surgery thereby reducing the duration of epilepsy has been reported to improve outcome, 5 but this is not a consistent observation in other studies. 20, 50
OTHER SPECIAL SETTINGS Three epilepsy phenotypes that are unique in children may have special implication in studying cognitive outcome after surgery. These include electrical status epilepticus in sleep (ESES), Landau-Kleffner syndrome (LKS), and hypothalamic hamartomas.
Electrical status epilepticus in slow wave sleep (ESES): ESES is an electroclinical syndrome with major cognitive decline and behavioral problems linked to abundant epileptiform discharges in slow wave sleep. When ESES causes regression of language as the predominant deficit, it is referred to as Landau-Kleffner syndrome. Structural lesions contribute to about 50% of patients with ESES. 51 For medically refractory ESES secondary to well defined brain lesions, epilepsy surgery may be an option. Unlike many other indications for epilepsy surgery, in children with ESES, the surgery may be aimed to improve cognitive function and resolve behavioral problems as clinical seizures may be under good control in many children. Type and extent of surgery is often guided by the extent of the lesion on brain MRI, and other preoperative neurological deficits, and may range from small focal resections to hemispherectomy. In a series of 8 patients with ESES secondary to multilobar or hemispheric lesions, 6 underwent hemispherectomy and 2 had focal resection. ESES resolved in all and 6 of 8 were seizure free post operatively.
52
Small focal lesions such as focal cortical dysplasia
in temporal region can also result in ESES. Focal resection can be effective in such cases, as shown in an illustrative case in figure 1.
In a pooled analysis of 575 cases with ESES, epilepsy surgery was done in 62 patients and 90% reported improvement in EEG or cognition.
51
Surgeries in these 62 patients
were varied and comprised of multiple sub-pial transections in 31, hemispherectomy in 13, corpus callosotomy in 9, and lobar or multilobar resection in 7. Improvement after surgery was better than other frontline medical therapy such as steroids (81% of 166 patients) and benzodiazepines (68% of 171). Improvement after surgery was also more likely to be sustained compared to other forms of therapy. The role of MST in nonlesional cases with ESES remains controversial, as discussed below. Multiple subpial transection in Landau-Kleffner Syndrome: Multiple subpial transection (MST), a unique procedure was targeted to disrupt the epileptogenic irritative ‘lesion’ without causing loss of function.
53
This evolved from the experimental
evidence that suggested that the physiological function of the cortex is primarily mediated by vertically oriented columns (and the afferent and efferent pathways in the vertical column), whereas the hyper-synchronous epileptiform activity depend more on the horizontal side to side connections between neurons. Multiple sub-pial transection targeted the later circuitry and was proposed to stop or reduce seizures with preservation of function, and this was particularly an attractive option when epileptogenic cortex and functional cortex overlap. Early MST procedures were performed over the primary sensory motor cortex with promising results. 53
In 1995, Morrell and colleagues reported their experience of MST over the posterior superior temporal gyrus and the perisylvian cortex in patients with Landau-Kleffner syndrome, a form of epileptic encephalopathy with acquired epileptic aphasia.
53
In a
carefully selected group of 14 children with Landau-Kleffner syndrome, MST was reported to result in marked improvement in 11, including normal age appropriate skills in seven. A follow up study that included 10 patients from the previous study, reaffirmed these findings.
54
Similar findings were reported in another series of 5 patients that
reported marked improvement in EEG, seizure frequency, behavior and language.
55
A
major limitation of these studies was the lack of control group for a condition like LKS that is known to fluctuate over time and remit electrophysiologically with advancing age. To address this, a recent study compared the surgical group (14 patients) to a nonsurgical comparison group (21 patients) that comprised of LKS and ESES related regression. This study found no difference in the outcomes between the 2 groups on long term follow up. The electroclinical phenotype between these various studies may not be necessarily similar.
The inclusion criteria in original study by Morrell were very
stringent with use of methohexital test and intra-carotid amobarbital to clarify the unilateral origin of the apparent diffuse epileptiform discharges. Use of such modalities in this clinical setting is not widely practiced and the role of MST in the treatment of LKS is still unclear. Hypothalamic hamartomas: Hypothalmaic hamartomas (HH) are a unique group of surgically remediable epilepsy syndromes that poses special challenges. Gelastic seizures are classically associated with HH; other seizure types have also been described, including an epileptic encephalopathy phenotype with tonic seizures and falls
consistent with Lennox-Gastaut syndrome.
57
Cognitive comorbidities are frequently
present in un-operated children with HH. Surgery of the lesion carries additional risk of injury to adjacent structures, including the mammillary bodies and fornix that form the circuitry for episodic memory. Surgical approaches vary between centers ranging from radiosurgery to disconnection. In a series of 48 patients with HH who underwent epilepsy surgery (radiosurgery in 22 and disconnection in 26), post-operative intellectual functions for entire cohort had a positive trend. As noted in several other studies, individual outcomes in patients vary, with major improvement in some and decline in others. Among the predictors for cognitive outcome, children with higher level of preoperative function were at risk for decline. 58
PATHOPHYSIOLOGY OF COGNTIVE OUTCOME AFTER SURGERY Counseling families about the benefits and risk of epilepsy surgery requires good understanding about the factors impacting outcome unique to each patient. Results from published studies are often not directly applicable in many situations due to heterogeneous patient populations and a multitude of factors unique to each patient. On the surface, the results from various studies on the predictors of outcome may appear conflicting. This is particularly true for factors such as age at seizure onset and age at surgery. How should one make sense of this apparent conflicting data, to assess the benefits and risks of epilepsy surgery on cognition and function?
In the context of surgically remediable epilepsies, the concepts of various cortical zones of dysfunction/ function have been proposed to improve the understanding and localization of epileptogenic zone. 59 These include the symptomatogenic zone, irritiative zone, seizure onset zone, functional deficit zone, epileptogenic lesion and eloquent cortex. Careful analysis of the various tests that provide information about these zones guides the epileptologist to determine the region of the brain to be removed, referred to us the ‘epileptogenic zone’. Epileptogenic zone is a hypothetical zone that refers to ‘the area of cortex indispensable for the generation of epileptic seizures’, removal of which leads to seizure freedom. 59 The functional deficit zone refers to the dysfunction caused by the epilepsy and this typically involves regions in and around the epileptogenic zone. Findings from several tests may contribute to the understanding of the functional deficit zone. These include neurological exam, neuropsychological testing, slowing on EEG, extent of irritative zone determined by EEG, and hypometabolism on PET scan, to name a few. Dysfunction of the networks/ regions connected to the epileptogenic zone, remote from the epileptogenic zone, is well recognized. This is especially true in children with epileptic encephalopathy where a focal epileptogenic zone in one hemisphere may cause more diffuse dysfunction in the same or both hemispheres.
The effect of epilepsy surgery on cognitive outcome could be viewed as a result of an interplay of 2 factors: function inside the epileptogenic zone versus the dysfunction outside the epileptogenic zone caused by epilepsy. Let us examine these 3 scenarios of cognitive outcome (unchanged, improved, or worsened) after a successful epilepsy
surgery that leads to seizure freedom using the concept of epileptogenic zone and functional deficit zone (figure 2).
In scenario A, “unchanged” cognition after surgery, if the epileptogenic zone and the functional deficit zone are fairly congruent, and if the epileptogenic zone did not harbor critical cognitive function, then surgical removal of the epileptogenic zone does not lead to significant decline in function. A classical clinical example is lack of significant postoperative dysfunction after right temporal lobectomy in a patient with non-dominant right temporal epilepsy due to mesial temporal sclerosis. Such benign post-operative outcomes are not uncommon even in ‘dominant’ (left) temporal lobectomy in the presence of significant atrophy of the hippocampus. Such severely diseased hippocampi may not harbor residual major cognitive function and the cognitive deficits may
not
decline
after
surgery.
Other
examples
of
this
scenario
include
hemispherectomy in a child with extensive hemispheric encephalomalacia, and resection of small focal dysplasia in a non-eloquent region. The relationship between a lesion and function are complex but large destructive lesions often cause loss of function in the regions for resection. ‘No significant change’ in cognition is the most frequently observed outcome in epilepsy surgery series. 6, 8, 11, 13, 34
In scenario B, “improved” cognition after surgery, the functional deficit zone is larger than the epileptogenic zone. If the dysfunction outside the epileptogenic zone is caused by repeated excessive spiking may affect contiguous regions surrounding the epileptogenic zone or remote from it – a network dysfunction. If this more extensive functional deficit zone is caused by the epileptiform discharges emanating from the epileptogenic zone, then removal of the epileptogenic zone may lead to recovery of the functional deficit zone. If the core epileptogenic zone harbored no significant cognitive function, then the net benefit of removal of epileptogenic zone may lead to improvement of the function. A typical scenario is a child with infantile spasms and hypsarrhythmia due to a focal cortical lesion such as anterior temporal dysplasia. In such children, removal of the epileptogenic zone (frequently surgery driven by lesion on MRI) and resolution of the diffuse epileptic encephalopathy leads to major improvement in development soon after surgery. Another example of this scenario includes ESES due to a focal lesion. Improvement in ‘verbal’ memory after non-dominant right temporal resections observed in pediatric series also implies release of excitotoxic injury by ongoing seizures from the opposite temporal region.
6, 44, 48
In our experience, some
degree of epileptic encephalopathy that does not meet the criteria for the commonlydescribed epileptic encephalopathies is frequent in many children with refractory epilepsy and abundant diffuse spikes.
60
As surgically remediable epileptic
encephalopathies inherently occur in children, opportunities to improve cognition after epilepsy surgery are also more frequent in children. 60, 61
In scenario C, cognitive ‘decline’ after surgery, the core epileptogenic zone harbors significant cognitive function and the dysfunction outside the EZ is minimal. In this situation, epilepsy surgery, though it may lead to seizure freedom, it may also result in cognitive or neurological dysfunction. Classical examples include non-lesional left mesial temporal epilepsy in left hemisphere dominant subject, and focal dysplasia in or near the Broca’s area. In many such cases, the post-operative worsening in cognition is expected and may stop patients from having epilepsy surgery. This is particularly true in the case of risk for major language decline after surgery. In young children, particularly before the age of 6 years, the potential plasticity of the brain to adapt to brain injury enables recovery of the function. This is particularly true for language function. This factor may need to be taken into account when considering the timing of surgery, particularly surgery that involves regions that potentially harbor language function.
When faced with a child considered for epilepsy surgery, the above scenarios can be applied to understand the potential effect on surgery on cognitive outcome. In some cases with scenario C with risk for decline, the poor quality of life due to high seizure burden may force the clinician and families to proceed with a surgery that carries definite risk of decline in neurological function. Such scenarios are uncommon even in large epilepsy surgery centers. As highlighted earlier, when counseling the risks of negative cognitive outcome after surgery, one should weigh the potential risk of continuing decline in patients with ongoing seizures.
ANTI-EPILEPTIC DRUGS AFTER SURGERY The negative impact of the anti-epileptic drugs (AED) on a child’s cognition should be carefully evaluated. The risks vs benefits should be assessed in individual patients. The cognitive effect of anti-epileptic drugs on cognition and behavior would depend on the specific drug(s) and the dose of the drug(s). The risks for cognitive and behavioral side effects are higher with polytherapy. 10 Patient factors predisposing to specific cognitive behavioral side effects are poorly understood. Successful epilepsy surgery provides opportunity to minimize anti-epileptic drugs and in many cases completely discontinued.
Results from multicenter trials in post-surgical populations (TimeToStop cognitive outcome study group) confirmed that AED withdrawal, reduction in number of AED, and complete cessation of AED influence the postoperative scores positively with resultant gain in IQ.
62, 63
Weaning anti-epileptic drugs after successful surgery in patients on
monotherapy is typically performed after 1 year of seizure freedom. In patients on polytherapy, particularly in those with side effects to medications, reduction of AEDs may be done earlier. Complete weaning will be determined based on the risks of recurrence based on clinical, electrophysiological and neuroimaging factors.
CONCLUSION Refractory epilepsy in children is frequently associated with cognitive deficits of variable degree. Successful epilepsy surgery leads to seizure freedom and stabilization of cognitive functions in two-third of patients. Comparison studies with patients not undergoing surgery has shown a positive trend for better development in surgically treated patients. Children with epileptic encephalopathies due to early focal brain lesions carry the best chances to improve cognition after successful epilepsy surgery. A minority of patients may experience decline in cognitive abilities. Understanding the reasons for variability in cognitive outcome assist in counseling patients and families prior to surgery.
Disclosure of interests: The authors have no commercial, proprietary, or financial interest in any products or companies described in this article.
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LEGENDS FOR TABLE AND FIGURES Table 1. Cognitive outcome after temporal lobe surgery in children
Figure 1. Illustrative case of a 9-year old girl with ESES secondary to left temporal dysplasia. Her seizures started at age 5 years and was under good control. ESES evolved between 7 and 9 years age. ESES and behavioral problems resolved after left temporal resection at age 9 years.
Figure 2. A schematic illustration of the reasons for variations in functional outcome after surgery. In scenario A, the epileptogenic zone and the functional deficits zone are congruent with resultant ‘no change’ after surgery. In scenario B, the dysfunction due to epilepsy extends outside the epileptogenic zone as in epileptic encephalopathy due to focal lesions; resection of the epileptogenic zone leads to ‘release’ of the regions disturbed by the epilepsy, leading to ‘improvement’. In scenario C, the epileptogenic zone harbors eloquent function; resection of epileptogenic zone carries risk for decline in function.
Table 1. Cognitive outcome after temporal lobe resection from selected studies in children Study
Mean age
Side of
at surgery
surgery
Cognitive outcome
Comments
(S) & Follow up (F) & seizure freedom Westerveld
S: 14.4
43- left
No significant decline in IQ in the
50% non-
et al, 2000
years
39- right
whole group; 10% had decline and
lesional; Extent
(n-82). 8
F: 1.2 years
9% improvement in verbal
of resection not
Multicenter
Seizure
functioning; left temporal surgery
studied; FSIQ
study
free rates-
associated with improved non-
<70 excluded.
not given
verbal cognition. Older age at surgery and nonmesial temporal sclerosis lesion – higher risk for decline.
Skirrow et
S- 13.8
25- left
No significant decline in memory in Variability in
al, 2015 (n-
years
17- right
with left or right sided surgery;
extent of
53);
F- 9 years
Another 11
visual memory improved after left
resection and
2011 (n-42)
86%
medically
temporal surgery; verbal memory
sparing of
6, 50
seizure free
treated
improved after right temporal
mesial
in surgical
surgery. Postoperative memory
structures
group
functions were dependent on residual temporal lobe structures.
Increase in IQ noted only in surgical group. Jambaque
S- 12.2
12- left
Post operatively, improved
Fairly
et al, 2007
years
8 - right
memory efficiency. Attention/
homogenous
(n-20). 17
F- > 6
working memory, naming and
group; All 20
months
some episode verbal memory
with
All seizure
scores improved.
hippocampal
free
resection; 17
(inclusion
had temporal
criteria)
pole resection
Miranda &
S- 13.3
25- left
Verbal IQ: No change in 72%;
10 had dual
Smith, 2001
years
25- right
improved in 14% and declined in
pathology; 13
(n-50) 20
F- 15
14%. Performance IQ: No change
had gliosis/
months
in 67%; improved in 24% and
sclerosis; 15
68%
declined in 8%.
had tumor
seizure free Sibilia et al,
S- 8.7
17- left
Overall DQ/IQ was not significantly At 2 years, 80%
2017 (n-31)
years
14- right
different between the groups.
of in surgical
46
F- 1 and 2
Developmental trajectory showed
group had
31 surgical
years after
a positive trend in patients who
Engel 1
14 ‘control’
surgery
had surgery. Better recall abilities
outcome
and forward digit span abilities
whereas none
were noted in surgical group.
were seizure free in the controls.