Postoperative Epileptic Seizures in Children: Is the Brain Incision a Risk Factor?

Postoperative Epileptic Seizures in Children: Is the Brain Incision a Risk Factor? Abstract BACKGROUND Postoperative seizures (PSs) after neurosurgical operations are common but little is known about the role of surgical brain incision on their genesis. This topic has not been addressed so far. OBJECTIVE To verify if the corticotomy affects the risk of PSs and postoperative epilepsy (PE) in children. METHODS One hundred forty-three consecutive pediatric cases operated on for supratentorial lesions at the same institution in the last 15 yr have been retrospectively reviewed by dividing them into group A, 68 children who required brain corticotomy mainly for hemispheric tumors, and group B, 75 children treated through extracortical approaches mainly for suprasellar and optic tumors. Patients with possible “epileptic” biases, like preoperative seizures, were excluded. RESULTS No significant differences have been found between group A and B as far as incidence of PSs (11.7% vs 14.5%) and PE (4.5% vs 6.5%), timing, and type of seizures are concerned after a mean 6.8 yr follow-up. The size of corticotomy in group A (<3 cm2 vs >3 cm2) had no impact on epileptogenesis as well as the other variables considered in both groups (age, sex, extent of lesion resection). CONCLUSION This study shows that the surgical cortical “trauma” would not represent a risk factor for PSs and PE. According to the present analysis and the literature, other causes seem to be involved (namely, electrolytic imbalance and brain gliosis). This information is important for preoperative surgical planning and postoperative management. A validation by both adult series and prospective studies is needed. Epilepsy, Postoperative seizures, Cortical incision, Neurosurgery, Brain tumors ABBREVIATIONS ABBREVIATIONS AED antiepileptic drug GTR gross total removal MRI magnetic resonance imaging PE postoperative epilepsy PS postoperative seizure Epileptic seizures account for one of the most common postoperative complications in neurosurgery, concerning about 10% to 15% of patients.1-7 The risk factors of postoperative seizures (PSs) include histotype (in particular, low-grade gliomas and meningiomas), tumor location, some nontumoral lesions (namely, abscess, aneurysm, and chronic subdural hemorrhage), preoperative cognitive impairment (in adults), age less than 2 yr and postoperative electrolytic imbalance (in children).8-13 The surgical cortical damage is thought to possibly contribute to PSs,11 but no specific investigation on its clinical role has been carried out so far. The goal of the present paper is to assess the effects of cortical incision on the risk of PSs in children. METHODS Participants, Setting, Study Design All consecutive pediatric patients operated on for supratentorial lesions in the last 15 yr (January 1998-January 2013; patients with a follow-up less than 2 yr were not included) were retrospectively reviewed and divided into 2 cohorts: group A (cases), including children who underwent a corticotomy for a hemispheric or deep lesion (eg, transcortical route for low-grade glioma), and group B (controls), including children treated by a noncorticotomic approach for “extracerebral” lesions (eg, subfrontal route for craniopharyngioma). The following exclusion criteria were used to reduce as much as possible the biases related to the occurrence of PSs: preoperative seizures, perioperative antiepileptic drug (AED) prophylaxis (even patients receiving prophylactic AEDs for a short cycle were excluded), head-injury-related and infectious lesions, repeated surgery, transcallosal approach, preoperative electrolytic imbalance, lost follow-up. Preoperative seizures were excluded according to the patient's clinical history (clearly pointing out the occurrence of epileptic seizures) and the routine use of preoperative electroencephalography (children with epileptic activities were not included). Moreover, patients operated by noncraniotomic approaches or shunting procedures were excluded. The study was carried out following the local Ethical Committee guidelines (no patient consent required). Data Measurement The occurrence of immediate (within 24 h from surgery), early (within 1 wk), and late seizures (after 1 wk) was recorded for each patient together with the electroencephalogram that was analyzed to confirm the epileptic activity. Seizures were classified according to ILAE 2010 classification.14 Preoperative magnetic resonance imaging (MRI) of all patients were reviewed seeking for the location of the brain lesion and its size, while the extent of the lesion resection was looked for on postoperative MRI. Early neuroimaging data on the extent of corticotomy were matched with that resulting from the surgical report. Histological specimens of all cases were reviewed. Statistical Methods The statistical analysis was used to compare the patients’ data and the results of the 2 groups other than to verify the role of each variable in each group. The variables were age (≤ vs >3 yr), sex, size of the lesion (≤ vs >3 cm), extent of the corticotomy (≤ 3 vs >3 cm2, group A only), extent of the tumor/lesion resection (gross total, which is not residual lesion detectable on postoperative imaging, vs subtotal/partial removal). For these purposes, χ2 test and 2-tailed t-test were employed by using SAS version 9.2 (SAS Institute Inc, Cary, North Carolina) and Excel 2010 (Microsoft Corp, Redmond, Washington). Statistical significance was assumed for P values ≤ .05. RESULTS Participants and Descriptive Data Overall, 143 pediatric patients were eligible for the study out of 813 children who received a craniotomy for supratentorial lesion in the considered period (they account only for less than 20% due to the adopted exclusion criteria). Their main characteristics are summarized in Table 1. TABLE 1. Main Characteristics of the 2 Groups   Group A (cases)  Group B (controls)  P value  No. of patients  68  75  .9  M/F ratio  1.12 (36/32)  1.27 (42/33)  .71  Mean age at surgery (years)  10.4 (range: 1 mo-18 yr)  11.3 (range: 3 mo-18 yr)  .48  Infants (≤3 yr)  15 (22%)  26 (34.5%)  .09  Type of lesion          Astrocytoma: 23 (34%)  Craniopharyngioma: 31 (41.5%)      Ganglioglioma/DNET: 5 (7%)  Pituitary adenoma: 8 (10.5%)      Choroid plexus tumors: 13 (19%)  Optic glioma: 14 (19%)      Ependymoma: 11 (16%)  Pineal tumors: 10 (13.5%)      Cavernous angioma: 10 (15%)  Arachnoid cyst: 8 (10.5%)      Other: 6 (9%)  Other: 4 (5%)    Location          Ventricles: 25 (37%)  Sellar/suprasellar: 53 (71%)      Frontal lobe: 15 (22%)  Pineal region: 10 (13.5%)      Parieto-occipital lobe: 10 (15%)  Middle cranial fossa: 7 (9%)      Temporal lobe: 6 (9%)  Dural/intracranial: 3 (4%)      Thalamus: 12 (17%)  Interhemispheric fissure: 2 (2.5%)    Tumor diameter         ≤3 cm  32 (47%)  24 (32%)  .22   >3 cm  36 (53%)  51 (68%)  .36  Extent of tumor removal         Gross total  52 (76%)  43 (64%)a  .18   Subtotal  10 (15%)  15 (22.5%)a  .40   Partial/biopsy  6 (9%)  9 (13.5%)a  .55  Mean corticotomic surface         ≤3 cm2  30 (44%)  /     >3 cm2  38 (66%)  /      Group A (cases)  Group B (controls)  P value  No. of patients  68  75  .9  M/F ratio  1.12 (36/32)  1.27 (42/33)  .71  Mean age at surgery (years)  10.4 (range: 1 mo-18 yr)  11.3 (range: 3 mo-18 yr)  .48  Infants (≤3 yr)  15 (22%)  26 (34.5%)  .09  Type of lesion          Astrocytoma: 23 (34%)  Craniopharyngioma: 31 (41.5%)      Ganglioglioma/DNET: 5 (7%)  Pituitary adenoma: 8 (10.5%)      Choroid plexus tumors: 13 (19%)  Optic glioma: 14 (19%)      Ependymoma: 11 (16%)  Pineal tumors: 10 (13.5%)      Cavernous angioma: 10 (15%)  Arachnoid cyst: 8 (10.5%)      Other: 6 (9%)  Other: 4 (5%)    Location          Ventricles: 25 (37%)  Sellar/suprasellar: 53 (71%)      Frontal lobe: 15 (22%)  Pineal region: 10 (13.5%)      Parieto-occipital lobe: 10 (15%)  Middle cranial fossa: 7 (9%)      Temporal lobe: 6 (9%)  Dural/intracranial: 3 (4%)      Thalamus: 12 (17%)  Interhemispheric fissure: 2 (2.5%)    Tumor diameter         ≤3 cm  32 (47%)  24 (32%)  .22   >3 cm  36 (53%)  51 (68%)  .36  Extent of tumor removal         Gross total  52 (76%)  43 (64%)a  .18   Subtotal  10 (15%)  15 (22.5%)a  .40   Partial/biopsy  6 (9%)  9 (13.5%)a  .55  Mean corticotomic surface         ≤3 cm2  30 (44%)  /     >3 cm2  38 (66%)  /    aArachnoid cyst excluded / = none View Large Group A consists of 68 children (mean age at surgery: 10.4 yr) prevalently affected by lesions located within the cerebral hemispheres (46%) or the supratentorial ventricles (37%). A gross total removal (GTR) of the lesion was achieved in 76% of cases. The corticotomy area at the end of the operation ranged from 1 × 1 cm to 4.5 × 3 cm, meanly 2 × 1.5 (3 cm2; Figures 1 and 2). FIGURE 1. View largeDownload slide A and B, T2-weighted A and T1-weighted B after gadolinium administration brain MRI showing a solid-cystic, left parietal pilocytic astrocytoma in an 8-yr-old boy. C, Approach through a 1.5 × 0.5 cm corticotomy. FIGURE 1. View largeDownload slide A and B, T2-weighted A and T1-weighted B after gadolinium administration brain MRI showing a solid-cystic, left parietal pilocytic astrocytoma in an 8-yr-old boy. C, Approach through a 1.5 × 0.5 cm corticotomy. FIGURE 2. View largeDownload slide A and B, T1-weighted sagittal A and axial B brain MRI after gadolinium of a 12-yr-old girl showing a huge, solid, left temporo-parieto-occipital pilocytic astrocytoma. C, The corticotomy at the end of the operation is 4 × 2 cm. FIGURE 2. View largeDownload slide A and B, T1-weighted sagittal A and axial B brain MRI after gadolinium of a 12-yr-old girl showing a huge, solid, left temporo-parieto-occipital pilocytic astrocytoma. C, The corticotomy at the end of the operation is 4 × 2 cm. Group B is composed of 75 children (mean age at surgery: 11.2 yr) with lesions of the sellar/suprasellar region (71%), the pineal region, and the middle cranial fossa. GTR in this group was as high as 64% (arachnoid cysts are excluded from this count because they were treated by microsurgical fenestration alone). No patient received corticotomy. No statistical differences were found between the 2 groups as far as patients’ age and sex, size of the lesion, and extent of lesion resection were concerned. Outcome Data and Main Results PSs occurred in 8 children (11.7%) in group A and 11 children (14.5%) in group B (see also Table 2). No statistical differences between the 2 groups were recorded as far as PSs and late epilepsy are concerned. Both groups showed a homogeneous distribution of immediate, early, and late seizures. TABLE 2. Postoperative Seizures and Late Epilepsy   Group A (cases)  Group B (controls)  Total  P value  No. of patients  68  75  143              Immediate seizures  3 (4.5%)  3 (4%)  6 (4.2%)  .90  Early seizures  3 (4.5%)  5 (6.5%)  8 (5.6%)  .55  Late seizures  2 (3%)  3 (4%)  5 (3.5%)  .73  Type of seizure           Focal  5/8  7/11  12/19 (63%)  .25   Generalized  3/8  4/11  7/19 (37%)  .25    Tonic-clonic  /  1/4  1/7      Tonic  1/3  /  1/7      Absence  2/3  3/4  5/7              Epilepsy  3 (4.5%)  5 (6.5%)  8 (5.6%)  .55  Mean time from surgery  90 d  67 d  78.5 d  .57  Type of epilepsy           Focal  2/3  3/5  5/8 (62.5%)  .92   Generalized  1/3  2/5  3/8 (37.5%)  .92    Tonic-clonic  /  1/2  1/3      Tonic  1/3  /  1/3      Absence  /  1/2  1/3      Group A (cases)  Group B (controls)  Total  P value  No. of patients  68  75  143              Immediate seizures  3 (4.5%)  3 (4%)  6 (4.2%)  .90  Early seizures  3 (4.5%)  5 (6.5%)  8 (5.6%)  .55  Late seizures  2 (3%)  3 (4%)  5 (3.5%)  .73  Type of seizure           Focal  5/8  7/11  12/19 (63%)  .25   Generalized  3/8  4/11  7/19 (37%)  .25    Tonic-clonic  /  1/4  1/7      Tonic  1/3  /  1/7      Absence  2/3  3/4  5/7              Epilepsy  3 (4.5%)  5 (6.5%)  8 (5.6%)  .55  Mean time from surgery  90 d  67 d  78.5 d  .57  Type of epilepsy           Focal  2/3  3/5  5/8 (62.5%)  .92   Generalized  1/3  2/5  3/8 (37.5%)  .92    Tonic-clonic  /  1/2  1/3      Tonic  1/3  /  1/3      Absence  /  1/2  1/3    / = none View Large Five of 8 children in group A experienced isolated seizures while the remaining 3 had multiple seizures. Transient AED treatment was required in 2 cases. Three children (4.5%) finally developed epilepsy requiring continued medical treatment. On average, epilepsy started 3 mo after surgery (ranging from 20 d to 6 mo). After a 6.8-yr mean follow-up, 2 of these children still require AEDs while the remaining 1 is seizure-free and drug-free. Five of 11 children in group B developed isolated seizures while 6 had multiple focal or absence seizures (requiring transient AEDs in 5 cases). Five children (6.5%) developed epilepsy about 2 mo after surgery (range: 8 d-3.6 mo). At late follow-up (6.8 yr), all of them still receive AEDs. In both groups, no statistical correlation was found between the occurrence of PSs/postoperative epilepsy (PE) and all the variables considered (sex, age less or more than 3 yr, tumor less or more than 3 cm, GTR vs subtotal/partial resection). No correlation was found between PSs/PE and extent of corticotomy (≤3 cm2 vs >3 cm2). DISCUSSION Seizures occur immediately (within 24 h), early (within 1 wk), or late (more than 1 wk) after head injuries or neurosurgical operations.15 Immediate and early seizures are the most commonly experienced by neurosurgical patients.1,16 However, only late seizures are considered as “true” epilepsy because of the risk of epileptic focus formation.11 The incidence of PSs ranges from 10% to 20% in adults and from 5% to 15% in children, the estimated frequency of PE being about 5% to 7%.1,2,4,9,17-19 The underreporting of very early and isolated seizures, the presence of preoperative seizures or preoperative electrolytic imbalance, and the use of AED prophylaxis makes it hard to assess the real frequency of PSs. The present study provides a confirmation of the rates of PSs (PSs: 13.2%; PE: 5.6%) without the bias of the aforementioned limitations. As observed by other authors,2,11 epilepsy meanly started 78.5 d after surgery (in no cases after 1 yr) and was mainly characterized by focal or “absence” generalized seizures Key Results and Interpretation The goal of the present paper was to investigate the role of the surgical cortical “damage” as possible etiological factor for seizures. PSs can result from a multifactorial process including brain lesion, patient comorbidities (namely, hyponatremia or fever), and surgical damage. Both clinical and experimental observations suggest that seizures may arise from acute cortical damage: more than 20% of subjects with head injury-related cortical damage present seizures within 2 yr from the trauma20 as a possible result of oxidative stress and free radical formation (extravascular leakage of blood components) and membrane ion imbalance (hypoxic-ischemic injury).11,21-23 Similarly, the microhemorrhages due to the cortical incision and the local ischemic damage resulting from coagulation and/or brain retraction (edema) can induce those alterations in neurosurgical patients. To the best of our knowledge, this is the first time that this problem is specifically addressed and the first time that only children without preoperative seizures are considered. Our results show that the cortical incision and the extent of the corticotomy are not adjunctive risk factors for PSs. Actually, children of group A (corticotomy) showed even a reduced rate of PSs and late epilepsy compared with those of group B (noncorticotomic way, as sylvian or interhemispheric or suboccipital transtentorial route), being 11.7% and 4.5% vs 14.5% and 6.5%, respectively. Moreover, the risk of seizures in group A was equally distributed between the patients with ≤3 cm2 and those with >3 cm2 corticotomy. These results can be considered conclusive because of the length of the mean follow-up (6.8 yr) and the absence of other influencing factors (sex, age, type and location of tumor, extent of tumor resection). Such a “missing” epileptogenesis could result, at least in part, also from the progress in neurosurgical technique and technology and from the attention paid by the neurosurgeon to neuroprotection during the operation. Indeed, nonepileptic complications (cerebrospinal fluid leakage, infection, fever, bleeding, electrolytic imbalance, neurological deficits) are more frequent than PSs.24,25 Generalizability The main explanation for these results could be the predominant role of other risk factors. Low-grade glioma, meningioma, vascular (arteriovenous malformation and aneurysm) and infectious lesions (brain abscess) are considered important risk factors for PSs in adults.5,7 Abscess and vascular lesions in particular are associated with up to 90% and 50% risk for PE, respectively. Moreover, the comorbidities of adult patients significantly contribute to PSs7,11 because even patients undergoing evacuation of subdural chronic collection with burr holes present important rates of PSs (15%-18%).8,26 In children, on the other hand, no significant correlation between type of lesion and PSs can be found. Indeed, the only study available on this topic was provided by Hardesty et al9 (223 children; PE: 7.4%), who pointed out supratentorial location, age < 2 yr, and hyponatremia as independent factors associated with perioperative seizures, while histotype, affected lobe, length of surgery, and blood loss were not.9 Our experience reinforces these observations (no correlation between PSs and tumor type, size and location, and extent of tumor resection) except for age that was not significant in ours as well as in other series.13,19 Even children operated on for posterior fossa tumors show a high incidence of PSs (1.8%-6% in spite of AEDs prophylaxis) as a result of metabolic problems (acidosis, hyponatremia) or air embolism due to the sitting position.19,27 Hyponatremia seems to be the most important risk factors in the pediatric age because it occurs in about 12% of children undergoing a neurosurgical operation for brain tumors, causing seizures and mental status alteration in 21% and 41% of cases, respectively.28 In our series, hyponatremia was associated with PE in half of all cases (overall, 4 out of 8 patients). Four of 5 children in group B who developed epilepsy (2 with optic-hypothalamic astrocytoma and 2 with craniopharyngioma), indeed, presented postoperative hyponatremia due to SIADH (syndrome of inappropriate antidiuretic hormone secretion; 1 child with craniopharyngioma also had postoperative hemorrhagic infarction and 1 child with optic glioma had a right sylvian ischemia). The remaining patient (pineal tumor) developed postoperative occipital subcortical glio-malacic degeneration. This latter complication occurred also in 1 of the 3 children of group A who experienced PSs (Figure 3). The surgical brain retraction, which should be avoided to reduce the risk of postoperative edema, infarction, and cortical thinning,29 but which is sometimes required in children where the arachnoid cisterns are small and the brain is trophic and swollen, may explain the PSs in both groups because of the glio-malacic brain damage. Indeed, the brain manipulation is associated with an increased risk of PSs,30 while this risk drops up to 1% when brain manipulation or retraction can be avoided (eg, endoscopic transphenoidal approaches).31 FIGURE 3. View largeDownload slide A-C, T2-weighted axial A, B and sagittal C postoperative brain MRI of an 18-yr-old girl operated for an occipital pilocytic astrocytoma. The glio-malacic area 6 mo after the operation is about 3.5 × 5 cm. FIGURE 3. View largeDownload slide A-C, T2-weighted axial A, B and sagittal C postoperative brain MRI of an 18-yr-old girl operated for an occipital pilocytic astrocytoma. The glio-malacic area 6 mo after the operation is about 3.5 × 5 cm. Limitations We realized a single-institution, retrospective, observational study. Therefore, despite the number of patients, homogeneous population, and same surgical and neurological team over time, a selection bias was inherent to the type of study and the long period encompassed. Moreover, the strict exclusion criteria, adopted to “purify” as much as possible the cohorts from the biases resulting from preoperative seizures and/or perioperative AED administration, could have “flattened” them, thus explaining the absence of a statistical relevance. A further limitation (which is also the newest aspect of the study) is the absence of corresponding data from the literature to be compared with our results. Although our data suggest that a surgical corticotomy is not burdened by an increased risk of PSs/PE, a certain risk of false negative should be considered due to a missing statistically reliable null hypothesis. This results also from the use of 2 very different cohorts of patients that, however, were needed to have a reliable comparison between children where a cortical disruption was carried out and those where the cortical surface was definitely left intact. CONCLUSION The present study confirms the 5% to 6% rate of de novo onset epilepsy following pediatric neurosurgical operations in a context of a 13% rate of PSs. These rates are lower than in adults or head injury where comorbidities and severe brain damage play a predominant role, respectively. The surgical brain incision and the corticotomy do not increase the risk for PSs and PE in children where hyponatremia and, probably, brain retraction are the most important risk factors. The latter point is raised by the literature more than by our study alone. Due to the retrospective analysis and the selection of 2 distinct cohorts, our results cannot be considered as absolute. These data, indeed, should be validated either by series including adults or by prospective studies. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. 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Little AS, Liu S, Beeman S et al.   Brain retraction and thickness of cerebral neocortex: an automated technique for detecting retraction-induced anatomic changes using magnetic resonance imaging. Neurosurgery . 2010; 67( 3 Suppl Operative): 277- 282. 30. Conte V, Carrabba G, Magni L et al.   Risk of perioperative seizures in patients undergoing craniotomy with intraoperative brain mapping. Minerva Anestesiol . 2015; 81: 379- 388. Google Scholar PubMed  31. Lai L, Morgan MK, Trooboff S, Harvey RJ. A systematic review of published evidence on expanded endoscopic endonasal skull base surgery and the risk of postoperative seizure. J Clin Neurosci . 2013; 20: 197- 203. Google Scholar CrossRef Search ADS PubMed  COMMENTS In this retrospective study, the authors attempt to determine whether cortical incision during brain surgery is a risk factor for postoperative seizures or epilepsy. A highly-selected cohort of pediatric patients undergoing craniotomy were divided into 2 groups based on whether there was disruption of the cortex in order to approach a subcortical lesion (Group A, 68 patients) or no disruption to approach an extra-cortical lesion (Group B, 75 patients). They found that there were similar rates of postoperative seizures and epilepsy in both groups and conclude that cortical disruption does not lead to significantly higher risk of postoperative seizure activity. New seizures sometimes occur after craniotomy and the contribution of approach-related cortical disruption is unclear. This study represents a good effort to address this issue, although the pathology and operative site differ so substantially between the 2 groups that their comparability is questionable, and the lack of statistically significant differences precludes any firm conclusions. Nevertheless, the frequency of postoperative seizures in cases without any cortical involvement is strikingly high in this study, and this observation supports the concept that seizures and epilepsy after craniotomy can occur in the absence of focal cortical disruption. More research is necessary to identify the etiology of epileptic activity in these patients in order to design better prophylaxis and treatment. Jonathan P. Miller Cleveland, Ohio The authors analyzed a single-center experience with supratentorial lesions in pediatric patients - they found that incidence of postoperative seizures and subsequent development of epilepsy were not influenced by whether or not the surgery included corticotomy; both groups with and without brain incision had small but noticeable proportion of patients who developed postoperative seizures and epilepsy. The findings are interesting but not surprising - one would expect seeing epileptic activity with all kinds of brain manipulation. As a matter of fact, one may make an argument (and this data supports it) that the effect of brain retraction as observed in cases without corticotomy is more epileptogenic than the same retraction delivered through a brain incision. Similarly, one may hypothesize that cortical disruption in corticotomy has some antiepileptic effect, akin to subpial transections used in treatment of epilepsy. The concern of possible functional impairment has always prompted us to limit cortical disruption as much as possible - but this paper indicates that even in absence of cortical incision, brain retraction alone may result in development of detrimental postoperative seizures and epilepsy. Obviously, the importance of prompt correction (and prevention) of metabolic issues (hyponatremia, acidosis, etc) cannot be overestimated - but emphasizing avoidance or minimization of brain retraction may be just as important, particularly if one wants to reduce the incidence of epileptic complications. Konstantin Slavin Chicago, Illinois Copyright © 2017 by the Congress of Neurological Surgeons http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Postoperative Epileptic Seizures in Children: Is the Brain Incision a Risk Factor?

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Copyright © 2017 by the Congress of Neurological Surgeons
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0148-396X
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10.1093/neuros/nyx221
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Abstract

Abstract BACKGROUND Postoperative seizures (PSs) after neurosurgical operations are common but little is known about the role of surgical brain incision on their genesis. This topic has not been addressed so far. OBJECTIVE To verify if the corticotomy affects the risk of PSs and postoperative epilepsy (PE) in children. METHODS One hundred forty-three consecutive pediatric cases operated on for supratentorial lesions at the same institution in the last 15 yr have been retrospectively reviewed by dividing them into group A, 68 children who required brain corticotomy mainly for hemispheric tumors, and group B, 75 children treated through extracortical approaches mainly for suprasellar and optic tumors. Patients with possible “epileptic” biases, like preoperative seizures, were excluded. RESULTS No significant differences have been found between group A and B as far as incidence of PSs (11.7% vs 14.5%) and PE (4.5% vs 6.5%), timing, and type of seizures are concerned after a mean 6.8 yr follow-up. The size of corticotomy in group A (<3 cm2 vs >3 cm2) had no impact on epileptogenesis as well as the other variables considered in both groups (age, sex, extent of lesion resection). CONCLUSION This study shows that the surgical cortical “trauma” would not represent a risk factor for PSs and PE. According to the present analysis and the literature, other causes seem to be involved (namely, electrolytic imbalance and brain gliosis). This information is important for preoperative surgical planning and postoperative management. A validation by both adult series and prospective studies is needed. Epilepsy, Postoperative seizures, Cortical incision, Neurosurgery, Brain tumors ABBREVIATIONS ABBREVIATIONS AED antiepileptic drug GTR gross total removal MRI magnetic resonance imaging PE postoperative epilepsy PS postoperative seizure Epileptic seizures account for one of the most common postoperative complications in neurosurgery, concerning about 10% to 15% of patients.1-7 The risk factors of postoperative seizures (PSs) include histotype (in particular, low-grade gliomas and meningiomas), tumor location, some nontumoral lesions (namely, abscess, aneurysm, and chronic subdural hemorrhage), preoperative cognitive impairment (in adults), age less than 2 yr and postoperative electrolytic imbalance (in children).8-13 The surgical cortical damage is thought to possibly contribute to PSs,11 but no specific investigation on its clinical role has been carried out so far. The goal of the present paper is to assess the effects of cortical incision on the risk of PSs in children. METHODS Participants, Setting, Study Design All consecutive pediatric patients operated on for supratentorial lesions in the last 15 yr (January 1998-January 2013; patients with a follow-up less than 2 yr were not included) were retrospectively reviewed and divided into 2 cohorts: group A (cases), including children who underwent a corticotomy for a hemispheric or deep lesion (eg, transcortical route for low-grade glioma), and group B (controls), including children treated by a noncorticotomic approach for “extracerebral” lesions (eg, subfrontal route for craniopharyngioma). The following exclusion criteria were used to reduce as much as possible the biases related to the occurrence of PSs: preoperative seizures, perioperative antiepileptic drug (AED) prophylaxis (even patients receiving prophylactic AEDs for a short cycle were excluded), head-injury-related and infectious lesions, repeated surgery, transcallosal approach, preoperative electrolytic imbalance, lost follow-up. Preoperative seizures were excluded according to the patient's clinical history (clearly pointing out the occurrence of epileptic seizures) and the routine use of preoperative electroencephalography (children with epileptic activities were not included). Moreover, patients operated by noncraniotomic approaches or shunting procedures were excluded. The study was carried out following the local Ethical Committee guidelines (no patient consent required). Data Measurement The occurrence of immediate (within 24 h from surgery), early (within 1 wk), and late seizures (after 1 wk) was recorded for each patient together with the electroencephalogram that was analyzed to confirm the epileptic activity. Seizures were classified according to ILAE 2010 classification.14 Preoperative magnetic resonance imaging (MRI) of all patients were reviewed seeking for the location of the brain lesion and its size, while the extent of the lesion resection was looked for on postoperative MRI. Early neuroimaging data on the extent of corticotomy were matched with that resulting from the surgical report. Histological specimens of all cases were reviewed. Statistical Methods The statistical analysis was used to compare the patients’ data and the results of the 2 groups other than to verify the role of each variable in each group. The variables were age (≤ vs >3 yr), sex, size of the lesion (≤ vs >3 cm), extent of the corticotomy (≤ 3 vs >3 cm2, group A only), extent of the tumor/lesion resection (gross total, which is not residual lesion detectable on postoperative imaging, vs subtotal/partial removal). For these purposes, χ2 test and 2-tailed t-test were employed by using SAS version 9.2 (SAS Institute Inc, Cary, North Carolina) and Excel 2010 (Microsoft Corp, Redmond, Washington). Statistical significance was assumed for P values ≤ .05. RESULTS Participants and Descriptive Data Overall, 143 pediatric patients were eligible for the study out of 813 children who received a craniotomy for supratentorial lesion in the considered period (they account only for less than 20% due to the adopted exclusion criteria). Their main characteristics are summarized in Table 1. TABLE 1. Main Characteristics of the 2 Groups   Group A (cases)  Group B (controls)  P value  No. of patients  68  75  .9  M/F ratio  1.12 (36/32)  1.27 (42/33)  .71  Mean age at surgery (years)  10.4 (range: 1 mo-18 yr)  11.3 (range: 3 mo-18 yr)  .48  Infants (≤3 yr)  15 (22%)  26 (34.5%)  .09  Type of lesion          Astrocytoma: 23 (34%)  Craniopharyngioma: 31 (41.5%)      Ganglioglioma/DNET: 5 (7%)  Pituitary adenoma: 8 (10.5%)      Choroid plexus tumors: 13 (19%)  Optic glioma: 14 (19%)      Ependymoma: 11 (16%)  Pineal tumors: 10 (13.5%)      Cavernous angioma: 10 (15%)  Arachnoid cyst: 8 (10.5%)      Other: 6 (9%)  Other: 4 (5%)    Location          Ventricles: 25 (37%)  Sellar/suprasellar: 53 (71%)      Frontal lobe: 15 (22%)  Pineal region: 10 (13.5%)      Parieto-occipital lobe: 10 (15%)  Middle cranial fossa: 7 (9%)      Temporal lobe: 6 (9%)  Dural/intracranial: 3 (4%)      Thalamus: 12 (17%)  Interhemispheric fissure: 2 (2.5%)    Tumor diameter         ≤3 cm  32 (47%)  24 (32%)  .22   >3 cm  36 (53%)  51 (68%)  .36  Extent of tumor removal         Gross total  52 (76%)  43 (64%)a  .18   Subtotal  10 (15%)  15 (22.5%)a  .40   Partial/biopsy  6 (9%)  9 (13.5%)a  .55  Mean corticotomic surface         ≤3 cm2  30 (44%)  /     >3 cm2  38 (66%)  /      Group A (cases)  Group B (controls)  P value  No. of patients  68  75  .9  M/F ratio  1.12 (36/32)  1.27 (42/33)  .71  Mean age at surgery (years)  10.4 (range: 1 mo-18 yr)  11.3 (range: 3 mo-18 yr)  .48  Infants (≤3 yr)  15 (22%)  26 (34.5%)  .09  Type of lesion          Astrocytoma: 23 (34%)  Craniopharyngioma: 31 (41.5%)      Ganglioglioma/DNET: 5 (7%)  Pituitary adenoma: 8 (10.5%)      Choroid plexus tumors: 13 (19%)  Optic glioma: 14 (19%)      Ependymoma: 11 (16%)  Pineal tumors: 10 (13.5%)      Cavernous angioma: 10 (15%)  Arachnoid cyst: 8 (10.5%)      Other: 6 (9%)  Other: 4 (5%)    Location          Ventricles: 25 (37%)  Sellar/suprasellar: 53 (71%)      Frontal lobe: 15 (22%)  Pineal region: 10 (13.5%)      Parieto-occipital lobe: 10 (15%)  Middle cranial fossa: 7 (9%)      Temporal lobe: 6 (9%)  Dural/intracranial: 3 (4%)      Thalamus: 12 (17%)  Interhemispheric fissure: 2 (2.5%)    Tumor diameter         ≤3 cm  32 (47%)  24 (32%)  .22   >3 cm  36 (53%)  51 (68%)  .36  Extent of tumor removal         Gross total  52 (76%)  43 (64%)a  .18   Subtotal  10 (15%)  15 (22.5%)a  .40   Partial/biopsy  6 (9%)  9 (13.5%)a  .55  Mean corticotomic surface         ≤3 cm2  30 (44%)  /     >3 cm2  38 (66%)  /    aArachnoid cyst excluded / = none View Large Group A consists of 68 children (mean age at surgery: 10.4 yr) prevalently affected by lesions located within the cerebral hemispheres (46%) or the supratentorial ventricles (37%). A gross total removal (GTR) of the lesion was achieved in 76% of cases. The corticotomy area at the end of the operation ranged from 1 × 1 cm to 4.5 × 3 cm, meanly 2 × 1.5 (3 cm2; Figures 1 and 2). FIGURE 1. View largeDownload slide A and B, T2-weighted A and T1-weighted B after gadolinium administration brain MRI showing a solid-cystic, left parietal pilocytic astrocytoma in an 8-yr-old boy. C, Approach through a 1.5 × 0.5 cm corticotomy. FIGURE 1. View largeDownload slide A and B, T2-weighted A and T1-weighted B after gadolinium administration brain MRI showing a solid-cystic, left parietal pilocytic astrocytoma in an 8-yr-old boy. C, Approach through a 1.5 × 0.5 cm corticotomy. FIGURE 2. View largeDownload slide A and B, T1-weighted sagittal A and axial B brain MRI after gadolinium of a 12-yr-old girl showing a huge, solid, left temporo-parieto-occipital pilocytic astrocytoma. C, The corticotomy at the end of the operation is 4 × 2 cm. FIGURE 2. View largeDownload slide A and B, T1-weighted sagittal A and axial B brain MRI after gadolinium of a 12-yr-old girl showing a huge, solid, left temporo-parieto-occipital pilocytic astrocytoma. C, The corticotomy at the end of the operation is 4 × 2 cm. Group B is composed of 75 children (mean age at surgery: 11.2 yr) with lesions of the sellar/suprasellar region (71%), the pineal region, and the middle cranial fossa. GTR in this group was as high as 64% (arachnoid cysts are excluded from this count because they were treated by microsurgical fenestration alone). No patient received corticotomy. No statistical differences were found between the 2 groups as far as patients’ age and sex, size of the lesion, and extent of lesion resection were concerned. Outcome Data and Main Results PSs occurred in 8 children (11.7%) in group A and 11 children (14.5%) in group B (see also Table 2). No statistical differences between the 2 groups were recorded as far as PSs and late epilepsy are concerned. Both groups showed a homogeneous distribution of immediate, early, and late seizures. TABLE 2. Postoperative Seizures and Late Epilepsy   Group A (cases)  Group B (controls)  Total  P value  No. of patients  68  75  143              Immediate seizures  3 (4.5%)  3 (4%)  6 (4.2%)  .90  Early seizures  3 (4.5%)  5 (6.5%)  8 (5.6%)  .55  Late seizures  2 (3%)  3 (4%)  5 (3.5%)  .73  Type of seizure           Focal  5/8  7/11  12/19 (63%)  .25   Generalized  3/8  4/11  7/19 (37%)  .25    Tonic-clonic  /  1/4  1/7      Tonic  1/3  /  1/7      Absence  2/3  3/4  5/7              Epilepsy  3 (4.5%)  5 (6.5%)  8 (5.6%)  .55  Mean time from surgery  90 d  67 d  78.5 d  .57  Type of epilepsy           Focal  2/3  3/5  5/8 (62.5%)  .92   Generalized  1/3  2/5  3/8 (37.5%)  .92    Tonic-clonic  /  1/2  1/3      Tonic  1/3  /  1/3      Absence  /  1/2  1/3      Group A (cases)  Group B (controls)  Total  P value  No. of patients  68  75  143              Immediate seizures  3 (4.5%)  3 (4%)  6 (4.2%)  .90  Early seizures  3 (4.5%)  5 (6.5%)  8 (5.6%)  .55  Late seizures  2 (3%)  3 (4%)  5 (3.5%)  .73  Type of seizure           Focal  5/8  7/11  12/19 (63%)  .25   Generalized  3/8  4/11  7/19 (37%)  .25    Tonic-clonic  /  1/4  1/7      Tonic  1/3  /  1/7      Absence  2/3  3/4  5/7              Epilepsy  3 (4.5%)  5 (6.5%)  8 (5.6%)  .55  Mean time from surgery  90 d  67 d  78.5 d  .57  Type of epilepsy           Focal  2/3  3/5  5/8 (62.5%)  .92   Generalized  1/3  2/5  3/8 (37.5%)  .92    Tonic-clonic  /  1/2  1/3      Tonic  1/3  /  1/3      Absence  /  1/2  1/3    / = none View Large Five of 8 children in group A experienced isolated seizures while the remaining 3 had multiple seizures. Transient AED treatment was required in 2 cases. Three children (4.5%) finally developed epilepsy requiring continued medical treatment. On average, epilepsy started 3 mo after surgery (ranging from 20 d to 6 mo). After a 6.8-yr mean follow-up, 2 of these children still require AEDs while the remaining 1 is seizure-free and drug-free. Five of 11 children in group B developed isolated seizures while 6 had multiple focal or absence seizures (requiring transient AEDs in 5 cases). Five children (6.5%) developed epilepsy about 2 mo after surgery (range: 8 d-3.6 mo). At late follow-up (6.8 yr), all of them still receive AEDs. In both groups, no statistical correlation was found between the occurrence of PSs/postoperative epilepsy (PE) and all the variables considered (sex, age less or more than 3 yr, tumor less or more than 3 cm, GTR vs subtotal/partial resection). No correlation was found between PSs/PE and extent of corticotomy (≤3 cm2 vs >3 cm2). DISCUSSION Seizures occur immediately (within 24 h), early (within 1 wk), or late (more than 1 wk) after head injuries or neurosurgical operations.15 Immediate and early seizures are the most commonly experienced by neurosurgical patients.1,16 However, only late seizures are considered as “true” epilepsy because of the risk of epileptic focus formation.11 The incidence of PSs ranges from 10% to 20% in adults and from 5% to 15% in children, the estimated frequency of PE being about 5% to 7%.1,2,4,9,17-19 The underreporting of very early and isolated seizures, the presence of preoperative seizures or preoperative electrolytic imbalance, and the use of AED prophylaxis makes it hard to assess the real frequency of PSs. The present study provides a confirmation of the rates of PSs (PSs: 13.2%; PE: 5.6%) without the bias of the aforementioned limitations. As observed by other authors,2,11 epilepsy meanly started 78.5 d after surgery (in no cases after 1 yr) and was mainly characterized by focal or “absence” generalized seizures Key Results and Interpretation The goal of the present paper was to investigate the role of the surgical cortical “damage” as possible etiological factor for seizures. PSs can result from a multifactorial process including brain lesion, patient comorbidities (namely, hyponatremia or fever), and surgical damage. Both clinical and experimental observations suggest that seizures may arise from acute cortical damage: more than 20% of subjects with head injury-related cortical damage present seizures within 2 yr from the trauma20 as a possible result of oxidative stress and free radical formation (extravascular leakage of blood components) and membrane ion imbalance (hypoxic-ischemic injury).11,21-23 Similarly, the microhemorrhages due to the cortical incision and the local ischemic damage resulting from coagulation and/or brain retraction (edema) can induce those alterations in neurosurgical patients. To the best of our knowledge, this is the first time that this problem is specifically addressed and the first time that only children without preoperative seizures are considered. Our results show that the cortical incision and the extent of the corticotomy are not adjunctive risk factors for PSs. Actually, children of group A (corticotomy) showed even a reduced rate of PSs and late epilepsy compared with those of group B (noncorticotomic way, as sylvian or interhemispheric or suboccipital transtentorial route), being 11.7% and 4.5% vs 14.5% and 6.5%, respectively. Moreover, the risk of seizures in group A was equally distributed between the patients with ≤3 cm2 and those with >3 cm2 corticotomy. These results can be considered conclusive because of the length of the mean follow-up (6.8 yr) and the absence of other influencing factors (sex, age, type and location of tumor, extent of tumor resection). Such a “missing” epileptogenesis could result, at least in part, also from the progress in neurosurgical technique and technology and from the attention paid by the neurosurgeon to neuroprotection during the operation. Indeed, nonepileptic complications (cerebrospinal fluid leakage, infection, fever, bleeding, electrolytic imbalance, neurological deficits) are more frequent than PSs.24,25 Generalizability The main explanation for these results could be the predominant role of other risk factors. Low-grade glioma, meningioma, vascular (arteriovenous malformation and aneurysm) and infectious lesions (brain abscess) are considered important risk factors for PSs in adults.5,7 Abscess and vascular lesions in particular are associated with up to 90% and 50% risk for PE, respectively. Moreover, the comorbidities of adult patients significantly contribute to PSs7,11 because even patients undergoing evacuation of subdural chronic collection with burr holes present important rates of PSs (15%-18%).8,26 In children, on the other hand, no significant correlation between type of lesion and PSs can be found. Indeed, the only study available on this topic was provided by Hardesty et al9 (223 children; PE: 7.4%), who pointed out supratentorial location, age < 2 yr, and hyponatremia as independent factors associated with perioperative seizures, while histotype, affected lobe, length of surgery, and blood loss were not.9 Our experience reinforces these observations (no correlation between PSs and tumor type, size and location, and extent of tumor resection) except for age that was not significant in ours as well as in other series.13,19 Even children operated on for posterior fossa tumors show a high incidence of PSs (1.8%-6% in spite of AEDs prophylaxis) as a result of metabolic problems (acidosis, hyponatremia) or air embolism due to the sitting position.19,27 Hyponatremia seems to be the most important risk factors in the pediatric age because it occurs in about 12% of children undergoing a neurosurgical operation for brain tumors, causing seizures and mental status alteration in 21% and 41% of cases, respectively.28 In our series, hyponatremia was associated with PE in half of all cases (overall, 4 out of 8 patients). Four of 5 children in group B who developed epilepsy (2 with optic-hypothalamic astrocytoma and 2 with craniopharyngioma), indeed, presented postoperative hyponatremia due to SIADH (syndrome of inappropriate antidiuretic hormone secretion; 1 child with craniopharyngioma also had postoperative hemorrhagic infarction and 1 child with optic glioma had a right sylvian ischemia). The remaining patient (pineal tumor) developed postoperative occipital subcortical glio-malacic degeneration. This latter complication occurred also in 1 of the 3 children of group A who experienced PSs (Figure 3). The surgical brain retraction, which should be avoided to reduce the risk of postoperative edema, infarction, and cortical thinning,29 but which is sometimes required in children where the arachnoid cisterns are small and the brain is trophic and swollen, may explain the PSs in both groups because of the glio-malacic brain damage. Indeed, the brain manipulation is associated with an increased risk of PSs,30 while this risk drops up to 1% when brain manipulation or retraction can be avoided (eg, endoscopic transphenoidal approaches).31 FIGURE 3. View largeDownload slide A-C, T2-weighted axial A, B and sagittal C postoperative brain MRI of an 18-yr-old girl operated for an occipital pilocytic astrocytoma. The glio-malacic area 6 mo after the operation is about 3.5 × 5 cm. FIGURE 3. View largeDownload slide A-C, T2-weighted axial A, B and sagittal C postoperative brain MRI of an 18-yr-old girl operated for an occipital pilocytic astrocytoma. The glio-malacic area 6 mo after the operation is about 3.5 × 5 cm. Limitations We realized a single-institution, retrospective, observational study. Therefore, despite the number of patients, homogeneous population, and same surgical and neurological team over time, a selection bias was inherent to the type of study and the long period encompassed. Moreover, the strict exclusion criteria, adopted to “purify” as much as possible the cohorts from the biases resulting from preoperative seizures and/or perioperative AED administration, could have “flattened” them, thus explaining the absence of a statistical relevance. A further limitation (which is also the newest aspect of the study) is the absence of corresponding data from the literature to be compared with our results. Although our data suggest that a surgical corticotomy is not burdened by an increased risk of PSs/PE, a certain risk of false negative should be considered due to a missing statistically reliable null hypothesis. This results also from the use of 2 very different cohorts of patients that, however, were needed to have a reliable comparison between children where a cortical disruption was carried out and those where the cortical surface was definitely left intact. CONCLUSION The present study confirms the 5% to 6% rate of de novo onset epilepsy following pediatric neurosurgical operations in a context of a 13% rate of PSs. These rates are lower than in adults or head injury where comorbidities and severe brain damage play a predominant role, respectively. The surgical brain incision and the corticotomy do not increase the risk for PSs and PE in children where hyponatremia and, probably, brain retraction are the most important risk factors. The latter point is raised by the literature more than by our study alone. Due to the retrospective analysis and the selection of 2 distinct cohorts, our results cannot be considered as absolute. These data, indeed, should be validated either by series including adults or by prospective studies. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes The preliminary results of this paper were presented as oral presentation at the XV WFNS Congress, Seoul, Korea, 2013. REFERENCES 1. De Santis A, Villani R, Sinisi M, Stocchetti N, Perucca E. Add-om phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study. Epilepsia . 2002; 43: 175- 182. Google Scholar CrossRef Search ADS PubMed  2. Foy PM, Copeland GP, Shaw MDM. The incidence of postoperative seizures. Acta Neurochir (Wien) . 1981; 55: 253- 264. Google Scholar CrossRef Search ADS PubMed  3. Grobelny BT, Ducruet AF, Zacharia BE et al.   Preoperative antiepileptic drug administration and the incidence of postoperative seizures following bur hole–treated chronic subdural hematoma. J Neurosurg . 2009; 111: 1257- 1262. Google Scholar CrossRef Search ADS PubMed  4. 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Little AS, Liu S, Beeman S et al.   Brain retraction and thickness of cerebral neocortex: an automated technique for detecting retraction-induced anatomic changes using magnetic resonance imaging. Neurosurgery . 2010; 67( 3 Suppl Operative): 277- 282. 30. Conte V, Carrabba G, Magni L et al.   Risk of perioperative seizures in patients undergoing craniotomy with intraoperative brain mapping. Minerva Anestesiol . 2015; 81: 379- 388. Google Scholar PubMed  31. Lai L, Morgan MK, Trooboff S, Harvey RJ. A systematic review of published evidence on expanded endoscopic endonasal skull base surgery and the risk of postoperative seizure. J Clin Neurosci . 2013; 20: 197- 203. Google Scholar CrossRef Search ADS PubMed  COMMENTS In this retrospective study, the authors attempt to determine whether cortical incision during brain surgery is a risk factor for postoperative seizures or epilepsy. A highly-selected cohort of pediatric patients undergoing craniotomy were divided into 2 groups based on whether there was disruption of the cortex in order to approach a subcortical lesion (Group A, 68 patients) or no disruption to approach an extra-cortical lesion (Group B, 75 patients). They found that there were similar rates of postoperative seizures and epilepsy in both groups and conclude that cortical disruption does not lead to significantly higher risk of postoperative seizure activity. New seizures sometimes occur after craniotomy and the contribution of approach-related cortical disruption is unclear. This study represents a good effort to address this issue, although the pathology and operative site differ so substantially between the 2 groups that their comparability is questionable, and the lack of statistically significant differences precludes any firm conclusions. Nevertheless, the frequency of postoperative seizures in cases without any cortical involvement is strikingly high in this study, and this observation supports the concept that seizures and epilepsy after craniotomy can occur in the absence of focal cortical disruption. More research is necessary to identify the etiology of epileptic activity in these patients in order to design better prophylaxis and treatment. Jonathan P. Miller Cleveland, Ohio The authors analyzed a single-center experience with supratentorial lesions in pediatric patients - they found that incidence of postoperative seizures and subsequent development of epilepsy were not influenced by whether or not the surgery included corticotomy; both groups with and without brain incision had small but noticeable proportion of patients who developed postoperative seizures and epilepsy. The findings are interesting but not surprising - one would expect seeing epileptic activity with all kinds of brain manipulation. As a matter of fact, one may make an argument (and this data supports it) that the effect of brain retraction as observed in cases without corticotomy is more epileptogenic than the same retraction delivered through a brain incision. Similarly, one may hypothesize that cortical disruption in corticotomy has some antiepileptic effect, akin to subpial transections used in treatment of epilepsy. The concern of possible functional impairment has always prompted us to limit cortical disruption as much as possible - but this paper indicates that even in absence of cortical incision, brain retraction alone may result in development of detrimental postoperative seizures and epilepsy. Obviously, the importance of prompt correction (and prevention) of metabolic issues (hyponatremia, acidosis, etc) cannot be overestimated - but emphasizing avoidance or minimization of brain retraction may be just as important, particularly if one wants to reduce the incidence of epileptic complications. Konstantin Slavin Chicago, Illinois Copyright © 2017 by the Congress of Neurological Surgeons

Journal

NeurosurgeryOxford University Press

Published: Apr 1, 2018

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