Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case–control study

Glioma-related seizures in relation to histopathological subtypes: a report from the glioma... Background The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. Methods The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demograph- ics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. Results Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. Conclusions Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma. Keywords Observational study (cohort, case–control) · Epileptic seizures · Primary brain tumor · Glioma-related seizures Introduction bilateral, convulsive seizures [2, 3]. The etiology of glioma- related seizures is complex and not completely understood, Epileptic seizures are among the most common presenting but patients diagnosed with low-grade gliomas (LGGs) have symptom in patients with glioma [1]. Glioma-related sei- a higher risk for developing medically refractory epileptic zures may occur at different time points during the course seizures than those with higher tumor grades (i.e., anaplastic of a patients’ illness, and can present either as focal seizures glioma and glioblastoma) [1]. An imbalance between the with or without impairment of consciousness or evolving to excessive release of neuroexcitatory glutamate and impaired GABAergic inhibition in the microenvironment surrounding the tumor has been suggested as one possible mechanism in Shala G. Berntsson and Ryan T. Merrell contributed equally to this glioma-related seizure development [4–7]. work. Treatment with antiepileptic drugs (AEDs) is critical Melissa L. Bondy and Beatrice S. Melin co-last authors. for care of glioma patients, and good seizure control is an essential factor for improved quality of life. First-genera- * Shala G. Berntsson tion AEDs, such as phenytoin, carbamazepine, and valproic shala.berntsson@neuro.uu.se acid, have largely been replaced by newer AEDs, such as Extended author information available on the last page of the article Vol:.(1234567890) 1 3 Journal of Neurology (2018) 265:1432–1442 1433 levetiracetam, lacosamide, and lamotrigine [8]. These newer questionnaire collected information on demographic charac- drugs are characterized by lower hepatic enzyme inducing teristics, past medical/medication history, and occupational properties, fewer drug–drug interactions, and more favorable history. Questionnaires were administered in person and/ tolerability profiles. or by phone, or through mailed self-administered forms. The goal of the current study was threefold: (1) evalu- Eight sites administered the full version of the question- ate the distribution of glioma-related seizures at the time of naire (The University of Texas MD Anderson Cancer Center, tumor diagnosis with respect to tumor- and patient-related Danish Cancer Society Research Centre, Memorial Sloan characteristics; (2) assess epileptic seizure frequency in Kettering Cancer Center, Brigham and Women’s Hospital, relation to AED therapy and glioma treatment (surgery and Case Western Reserve University, Mayo Clinic, NorthShore radiotherapy); (3) compare seizure history preceding tumor University HealthSystem and Umeå University). Some sites diagnosis for cases and study enrollment for controls. (Duke University, University of California, San Francisco, Institute of Cancer Research, UK, Gertner Institute, Israel, Columbia University, and University of Southern Califor- Materials and methods nia) opted not to collect detailed seizure history [9]. All cases were asked if they had ever been diagnosed with sei- Study population zures, convulsions, or epilepsy and the age at which they were diagnosed. In addition, at the sites that administered The Glioma International Case–Control study (GICC) the full questionnaire, the glioma cases were asked if they recruited 4533 cases and 4171 controls from 14 centers in had childhood seizures (febrile or not), when their epilepsy the US, Europe, and Israel. Details on the GICC study popu- was diagnosed in relation to their brain tumor, if they had lation and methodology have previously been published [9]. ever had an impairment of consciousness during a seizure, Cases were between 18 and 80 years old at diagnosis, were or bilateral convulsive epileptic seizures (grand mal), how histologically confirmed, and were recruited within 1 year many seizures they had had in the last 2 months, and if they of diagnosis of glioma. were currently taking AED, and if so, what type of AED. For Supratentorial and infratentorial gliomas were classified our analysis, we defined glioma-related seizures as seizures according to the 2007 WHO classification of brain tumors that began ≤ 2 years before diagnosis. as follows: fibrillary astrocytoma (9420/3), protoplasmic astrocytoma (9410/3), gemistocytic astrocytoma (9411/3), Statistical analyses oligodendroglioma (9450/3), oligoastrocytoma (9382/3), anaplastic astrocytoma (9401/3), anaplastic oligodendro- The overall GICC analysis plan and a detailed table of demo- glioma (9451/3), anaplastic oligoastrocytoma (9382/3), graphics by study site are described elsewhere [9]. The main gliosarcoma (9442/3), or glioblastoma (9440/3) [10]. WHO parameters of interest were history of seizures, the relative grade I gliomas, which are usually low-proliferation, often- timing of the first epileptic seizure in relation to glioma curable tumors were not included in this study. Thus, low- diagnosis, age at epilepsy diagnosis, and epileptic seizure grade glioma (LGG) refers to WHO grade II tumors, includ- characteristics including impairment or loss of conscious- ing the following subtypes: astrocytoma, oligodendroglioma, ness evolving to bilateral convulsive seizures, AED use, and and oligoastrocytoma. Anaplastic glioma refers to WHO seizure control (defined as recurrent epileptic seizures in grade III gliomas, including astrocytomas, oligodendroglio- spite of AED use and the subsequent frequency of seizures) mas, and oligoastrocytomas, whereas glioblastoma refers to during the last 2 months before the interview. WHO grade IV glioma, the most malignant type included Case-only analyses were conducted using multino- in this study. A pathology review was performed on partici- mial models. For the case–control analyses, we calculated pants in the first year of the study and demonstrated good adjusted odds ratios (ORs), along with their corresponding concordance of the histopathology [9]. 95% Wald confidence intervals (CIs), using unconditional All recruitment sites received Institutional Review Board logistic regression. We decided a priori to control for age (IRB) or ethical board approval to conduct the study, and and sex, glioma subtype, and study site in all multivariable informed consent was obtained from participants. models. Despite our large sample size, some strata were sparse within the histologic subtypes (Table 2). As a result, Data collection we pooled the data from all sites rather than conducting meta-analysis. While we acknowledge that pooling has limi- Every site administered a common study protocol and ques- tations because of the inter-site heterogeneity present in our tionnaire (full or abbreviated version), and data were stored consortium, the pooled analyses are exploratory, and there- in a centralized web-based database. The questionnaire was fore, allowed us to evaluate whether there might be some only administered at one time point. The GICC risk factor implication of an effect that should be examined in future 1 3 1434 Journal of Neurology (2018) 265:1432–1442 studies of larger subgroups. Sensitivity analyses included (Table 5). Glioma occurred more frequently in males than running models with and without proxy responses (~ 8% of females (59 vs. 41%), both in the entire sample and by tumor the cases). subtypes. Patients with LGG were younger at diagnosis (30–39 years) than patients with anaplastic glioma (40–59 years) or glioblastoma (50–69 years). Approximately, one- third of all glioma cases (28.5%) reported diagnosis of Results seizures, convulsions, or epilepsy (Table 1). Among cases reporting the relative timing of their r fi st seizures ( n = 1376), Descriptive statistics for glioma cases (overall and by his- there were cases who, reported uncertainty about the time tologic subtypes) and controls are presented in Table  1. interval (n = 112), leaving a total of 1264 cases for the analy- Median time interval from diagnosis to questionnaire was sis. Epileptic seizures occurred most commonly within 2 3.2 months for GBM, 4.6 months for anaplastic astrocytoma years prior to glioma diagnosis (n = 1158) (Table 1). Table 1 Selected population characteristics from the glioma international case–control study by case–control status and glioma histology group Glioma cases Controls Glioblastoma Anaplastic Anaplastic LGG Astrocy- LGG Oligo- Other astrocytoma oligodendro- toma dendroglioma/ glioma/oli- oligoastrocy- goastrocytoma toma N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Sex  Male 2679 (59.1) 2351 (56.37) 1727 (62.3) 294 (55.58) 142 (51.64) 199 (53.35) 241 (53.44) 76 (57.14)  Female 1854 (40.9) 1820 (43.63) 1045 (37.7) 235 (44.42) 133 (48.36) 174 (46.65) 210 (46.56) 57 (42.86) Age at diagnosis/enrollment  18–29 years 308 (6.79) 294 (7.05) 62 (2.24) 68 (12.85) 25 (9.09) 65 (17.43) 70 (15.52) 18 (13.53)  30–39 years 521 (11.49) 473 (11.34) 108 (3.9) 115 (21.74) 54 (19.64) 99 (26.54) 122 (27.05) 23 (17.29)  40–49 years 813 (17.94) 680 (16.3) 417 (15.04) 110 (20.79) 63 (22.91) 89 (23.86) 114 (25.28) 20 (15.04)  50–59 years 1150 (25.3) 1079 (25.87) 795 (28.68) 90 (17.01) 64 (23.27) 67 (17.96) 98 (21.73) 36 (27.07)  60–69 years 1239 (27.3) 1098 (26.32) 993 (35.82) 94 (17.77) 52 (18.91) 40 (10.72) 37 (8.2) 23 (17.29)  70–80 years 502 (11.07) 547 (13.11) 397 (14.32) 52 (9.83) 17 (6.18) 13 (3.49) 10 (2.22) 13 (9.77) Seizure history  Glioma-related 1158 (28.5) – 527 (21.11) 186 (39.74) 84 (36.68) 150 (43.35) 188 (45.30) 23 (19.83) seizures (sei- zures ≤ 2 years of diagnosis)  Non-glioma- 106 (2.60) – 55 (8.86) 15 (6.79) 2 (2.15) 13 (7.22) 14 (6.20) 7 (20.00) related seizures (seizure initiation started > 2 years before diagnosis  Cases with 112 (2.75) – 39 (6.28) 20 (9.05) 7 (7.53) 17 (9.44) 24 (10.62) 5 (14.29) seizures where time of seizure initiation not reported  No seizures 2568 (63.1) – 1792 (71.79) 233 (49.79) 130 (56. (77) 157 (45.38) 179 (43.13) 77 (66.38)  Missing 126 (3.1) – 83 (3.33) 14 (2.99) 6 (2.62) 9 (2.6) 10 (2.41) 4 (3.45) LGG low-grade glioma UK did not answer this section and was excluded. ORs adjusted for sex and age and oligodendroglioma and finally 4.2 months for patients There was a significant difference in history of ever hav - with low-grade gliomas. ing been diagnosed with epileptic seizures (including seizure 3944 of the 4533 (87%) glioma cases and 3244 of the diagnoses within 2 years prior to tumor diagnosis) between 4171 (78%) controls completed the full questionnaire patients with glioblastoma (26%) and those with low-grade 1 3 Journal of Neurology (2018) 265:1432–1442 1435 oligodendroglioma/oligoastrocytoma (56%) or low-grade seizure risk and the growth rate of the tumor. Patients with astrocytoma (53%) (Table 2). Grade II oligodendroglioma/ LGGs, and particularly oligodendroglial tumors, are there- oligoastrocytoma patients were 3 times more likely to have fore, generally more prone to seizures than patients with had a history of epileptic seizures compared to glioblastoma high-grade gliomas [3, 14, 15]. The mechanisms behind patients (OR = 3.03; CI 2.41–3.82, p < 0.0001) (Table 2). seizure development in slow-growing tumors are different Patients with grade II oligodendroglioma/oligoastro- from high-grade tumors. Chronic deafferentation and dis- cytoma, grade II astrocytoma, and anaplastic astrocytoma connection of functionally isolated regions of cortex, caus- were more likely to have generalized epileptic seizures than ing a denervation hypersensitivity is connected to seizure cases with glioblastoma and anaplastic oligodendroglioma risk in LGGs, whereas the direct effects of tissue damage in (p < 0.0001) (Table 2). There were a higher proportion of fast-growing high-grade gliomas by disturbed microvascu- LGG patients who had recurrent epileptic seizures than larization and peritumoral ischemia are thought to be causa- cases with anaplastic glioma and glioblastoma, despite tive factors [16, 17]. treatment with AEDs. Low-grade astrocytoma cases were We also found that patients with low-grade astrocytoma about 1.6 times more likely to have recurrent epileptic sei- patients had significantly more recurrent seizures in spite zures compared to glioblastoma cases (OR = 1.55; 95% CI of combined antiepileptic treatments. These differences in 1.03–2.33 p = 0.15) (Table 2). seizure control may reflect the differences in tumor locations Overall, 83% of cases with epileptic seizures were pre- of the glioma subtypes. Astrocytomas are more frequently scribed one AED; 12% were on two AEDs; and 3% used associated with location in temporal or insular areas, while 3–5 AEDs. Levetiracetam was the AED of choice in 71% oligodendroglial tumors are more often located in frontal of cases (Table 3). areas [14, 18]. Treatment information in terms of type of surgery (gross Refractory seizures in patients with LGGs is a major total resection vs. subtotal resection/biopsy) and radio- concern in clinical neuro-oncology practice [19]. The epi- therapy (yes or no) was only available in a subset of cases leptogenic zone of LGGs, especially in tumors located in (23%). Gross total resection (GTR) was strongly associated temporal and paralimbic areas, involves not only the tumor with reduced frequency of epileptic seizures; glioma cases itself but also extra-tumoral cortical areas, explaining the who had GTR were 72% less likely to have reported > 10 poor seizure control in 15–20% of patients after gross total seizures during the 2 months immediately prior to the inter- tumor resection. Improved postoperative seizure control view, compared with cases that underwent subtotal resection was achieved in cases where the resection involved both the or biopsy (n = 255) (OR = 0.28; CI 0.11–0.73, p < 0.009). tumor and the epileptogenic zone surrounding the tumor Radiotherapy, during first-line treatment, was not associated [20–24]. with epileptic seizure control (p < 0.85) (Table 4). Moreover, the treatment of glioma-related epilepsy Glioma cases were as likely as controls to experience with AED is complex. Cognitive side effects, interactions febrile (OR = 1.13; 95% CI 0.73–1.75, p = 0.59) and non- between AEDs and between AED treatment and chemo- febrile seizures (OR = 1.61; 95% CI 0.93–2.76, p = 0.09) therapy are important aspects that need to be considered. during childhood (Table 5). Increased susceptibility to the cognitive side effects of AEDs was much more frequent than the side effects of radiotherapy in patients with LGGs [25]. Finally, the difficulties of obtain- Discussion ing good seizure control in spite of optimal AED and tumor treatment also illustrate the natural course of LGGs as a Our study is one of the largest studies to date of glioma- progressive and eventually fatal disease. related seizures in relation to proximity of diagnosis, glioma Our data demonstrate that patients with LGG, particu- histology, and treatment by AEDs, as well as tumor treat- larly low-grade astrocytoma, should be closely monitored ment by resection and radiotherapy. Our results confirms a for seizures. lower mean age at onset in patients with LGGs compared to Recently, a large multicenter French study provided anaplastic glioma and glioblastoma, as well as a higher rate detailed information on approximately 1500 LGGs, and of epileptic seizures as a presenting symptom, a phenom- identified male sex and tumor location in functional areas enon that has been well established in other large epidemio- as independent predictors for tumor-related epileptic sei- logical studies [11–13]. We also observed a higher frequency zures [12]. The correlation between glioma-related sei- of seizures among low-grade oligodendroglioma/oligoastro- zures and male sex was not confirmed in the present study. cytoma cases compared to glioblastoma cases, consistent In addition, among LGGs, the prevalence of self-reported with previous reports. Our data confirm the relatively long glioma-related seizures was slightly lower in our study time interval that is needed for the development of tumor- than in previous studies [1, 12, 14, 26]. A potential reason related seizures in the brain and the association between is the possible poor recall of events. Patients may only 1 3 1436 Journal of Neurology (2018) 265:1432–1442 1 3 Table 2 Characteristics of seizures in glioma cases according to histology subtype Glioblastoma ORs Anaplastic astrocytoma Anaplastic oligo/oligoastro- LGG astrocytoma LGG oligo/oligoastrocytoma Other Trend p value [Ref] cytoma N (%) N (%) OR (95% CI) N (%) OR (95% CI) N (%) OR (95% CI) N (%) OR (95% CI) N (%) Ever diagnosed < 0.0001 with seizure, convulsions, or epilepsy No [ref] 1792 (74.3) Ref 233 (51.3) 130 (58.3) 157 (46.6) 179 (44.2) 77 (68.8) Yes 621 (25.7) Ref 221 (48.7) 2.44 (1.98–3.02) 93 (41.7) 1.84 (1.38–2.45) 180 (53.4) 2.77 (2.17–3.54) 226 (55.8) 3.03 (2.41–3.82) 35 (31.3) Ever lost < 0.0001 consciousness while having a seizure No [ref] 658 (71.8) Ref 132 (56.9) 74 (61.7) 83 (49.1) 119 (51.7) 30 (60.0) Yes 258 (28.2) Ref 100 (43.1) 1.53 (1.12–2.08) 46 (38.3) 1.30 (0.87–1.95) 86 (50.9) 1.89 (1.33–2.69) 111 (48.3) 1.62 (1.18–2.23) 20 (40.0) Currently taking < 0.0001 medications including prevention No [ref] 690 (51.3) Ref 100 (34.5) 59 (39.1) 60 (27.9) 87 (33.6) 29 (42.0) Yes 655 (48.7) Ref 190 (65.5) 1.63 (1.24–2.15) 92 (60.9) 1.35 (0.95–1.92) 155 (72.1) 1.97 (1.42–2.75) 172 (66.4) 1.46 (1.08–1.97) 40 (58.0) Recurrent seizure 0.1462 in spite of medication No [ref] 355 (69.5) Ref 115 (69.7) 57 (73.1) 80 (56.7) 101 (63.1) 23 (71.9) Yes 156 (30.5) Ref 50 (30.3) 0.90 (0.60–1.34) 21 (26.9) 0.78 (0.45–1.34) 61 (43.3) 1.55 (1.03–2.33) 59 (36.9) 1.17 (0.78–1.75) 9 (28.1) Oligo is oligodendroglioma. LGG is low-grade Glioma UK did not answer this section and was excluded. ORs adjusted for sex and age and site Duke, UCSF, UK, Israel, Columbia and USC did not answer this section and were excluded. ORs adjusted for sex and age Duke, UCSF, UK, Israel, Columbia and USC did not answer this section and were excluded Journal of Neurology (2018) 265:1432–1442 1437 Table 3 Seizure information and use of medication for seizure in glioma cases) by glioma histology group Glioblastoma N (%) Anaplastic Anaplastic oligo/ LGG LGG oligo/oli- Other N (%) Total N (%) astrocytoma oligoastrocytoma astrocytoma goastrocytoma N (%) N (%) N (%) N (%) As a child ever had seizures with high f ever Yes 22 (1.53) 10 (3.27) 2 (1.24) 4 (1.79) 4 (1.5) 1 (1.37) 43 (1.74) No 1365 (94.92) 285 (93.14) 158 (98.14) 212 (94.64) 253 (94.76) 68 (93.15) 2341 (94.82) Missing 51 (3.55) 11 (3.59) 1 (0.62) 8 (3.57) 10 (3.75) 4 (5.48) 85 (3.44) Has a child ever had seizure not caused by high fever Yes 18 (1.25) 5 (1.63) 0 4 (1.79) 5 (1.87) 4 (5.48) 36 (1.46) No 1374 (95.55) 290 (94.77) 156 (96.89) 216 (96.43) 252 (94.38) 65 (89.04) 2353 (95.3) Missing 46 (3.2) 11 (3.59) 5 (3.11) 4 (1.79) 10 (3.75) 4 (5.48) 80 (3.24) Ever had a bilateral convulsive seizure Yes 124 (28.18) 59 (35.33) 31 (37.8) 52 (36.36) 61 (36.53) 13 (41.94) 340 (33.01) No 245 (55.68) 85 (50.9) 37 (45.12) 69 (48.25) 79 (47.31) 15 (48.39) 530 (51.46) Missing 71 (16.14) 23 (13.77) 14 (17.07) 22 (15.39) 27 (16.17) 3 (9.68) 160 (15.54) No of seizure medications 1 339 (85.18) 126 (80.77) 68 (89.47) 104 (77.61) 120 (79.47) 23 (88.46) 780 (82.89) 2 44 (11.06) 23 (14.74) 5 (6.58) 21 (15.67) 20 (13.25) 3 (11.54) 116 (12.33) 3 5 (1.26) 3 (1.92) 1 (1.32) 8 (5.97) 8 (5.3) 0 25 (2.66) 4 0 1 (0.64) 0 1 (0.75) 1 (0.66) 0 3 (0.32) 5 1 (0.25) 0 0 0 0 0 1 (0.11) Missing 9 (2.26) 3 (1.92) 2 (2.63) 0 2 (1.32) 0 16 (1.7) Ever taken levetiracetam Yes 301 (75.63) 112 (71.79) 49 (64.47) 90 (67.16) 98 (64.9) 18 (69.23) 668 (70.99) No 97 (24.37) 44 (28.21) 27 (35.53) 44 (32.84) 53 (35.1) 8 (30.77) 273 (29.01) Oligo is oligodendroglioma, LGG is low-grade glioma MDA, Denmark, MSK, Brigham and Women, Case Western, Mayo, Northshore and Sweden provided this information Duke, UCSF, UK, Israel, Columbia and USC did not ask these questions report more dramatic seizure episodes, such as secondary Somatic isocitrate–dehydrogenase 1 (IDH1) mutations generalized seizures, and due to cognitive decline, may are common in LGGs, leading to the production of D-2 fail to recall less severe focal seizures, such as left-hemi- hydroxyglutarate, a metabolite that bears structural similari- spheric temporal lobe seizures. In our study, data were col- ties to glutamate [27]. Thus, the IDH1 mutation in the tumor lected through self-reported questionnaires, as opposed to cells renders the tumor in a higher excitatory state and may clinical observation or medical record abstraction, which be directly involved in the pathogenesis of tumor-related could be one of the reasons for differences in the rates of seizures in LGGs [28]. Routine testing of IDH1 mutational epileptic seizures between the studies. status was not performed at the time of our data collection. Furthermore, LGGs and anaplastic astrocytomas were However, given that the frequency of IDH mutation in LGG more commonly associated with generalized seizures than approaches 80% and its possible role in epileptogenesis, a glioblastoma. These findings support the existence of differ - partial explanation for the observed higher frequency of ent epileptogenic pathways for LGG and high-grade gliomas epileptic seizures in LGGs could be due to IDH1 mutation [17, 24]. From an epileptogenic point of view, this finding status [29]. reinforces the general concept that slow-growing tumors In this study, we only have data from time of study have a lower epileptic threshold than fast-growing lesions enrollment/diagnosis, and no follow-up data was collected. [1]. Glioma patients who presented with other tumor-related 1 3 1438 Journal of Neurology (2018) 265:1432–1442 Table 4 Association between seizure frequency during the last 2 months and glioma case subtype Seizure free; 1–5 seizures 6–10 seizures > 10 seizures Total N 1–5 seizures 6–10 seizures > 10 seizures P value ref; N (%) N (%) N (%) N (%) OR (95% CI) OR (95% CI) OR (95% CI) Glioma sub- 0.7461 type Glioblastoma 380 (80.34) 70 (14.80) 6 (1.27) 17 (3.59) 473 1.00 1.00 1.00 [ref] Anaplastic 51 (78.46) 10 (15.38) 1 (1.54) 3 (4.62) 65 0.95 (0.45– 0.82 (0.09– 1.14 (0.31– oligo/oli- 2.00) 7.48) 4.16) goastrocy- toma Anaplastic 92 (74.80) 24 (19.51) 1 (0.81) 6 (4.88) 123 1.24 (0.72– 0.42 (0.05– 1.22 (0.45– astrocytoma 2.14) 3.87) 3.30) LGG, astrocy- 65 (70.65) 13 (14.13) 3 (3.26) 11 (11.96) 92 0.90 (0.44– 1.86 (0.36– 3.25 (1.27– toma 1.85) 9.61) 8.29) LGG, oligo/ 87 (72.50) 23 (19.17) 3 (2.50) 7 (5.83) 120 1.16 (0.60– 1.35 (0.23– 1.47 (0.49– oligoastro- 2.23) 7.78) 4.39) cytoma Other 22 (78.57) 3 (10.71) 1 (3.57) 2 (7.14) 28 0.63 (0.18– 1.93 (0.19– 1.73 (0.35– 2.22) 19.67) 8.40) Sex 0.1522 Male [ref] 411 (78.74) 84 (16.09) 4 (0.77) 23 (4.41) 522 1.00 1.00 1.00 Female 286 (75.46) 59 (15.57) 11 (2.90) 23 (6.07) 379 0.96 (0.67– 3.54 (1.10– 1.31 (0.71– 1.40) 11.39) 2.41) Gross total 0.009 resection No [ref] 481 (74.46) 111 (17.18) 13 (2.01) 41 (6.35) 646 1.00 1.00 1.00 Yes 216 (84.71) 32 (12.55) 2 (0.78) 5 (1.96) 255 0.64 (0.42– 0.36 (0.08– 0.28 (0.11– 0.99) 1.64) 0.73) Radiotherapy 0.8558 No [ref] 149 (73.40) 36 (17.73) 4 (1.97) 14 (6.90) 203 1.00 1.00 1.00 Yes 548 (78.51) 107 (15.33) 11 (1.58) 32 (4.58) 698 0.83 (0.50– 1.17 (0.30– 0.82 (0.38– 1.38) 4.64) 1.76) Mean age 52.7 51.2 46.7 50.3 0.99 (0.98– 0.98 (0.94– 1.00 (0.98– 0.6138 at glioma 1.01) 1.02) 1.03) diagnosis Total 697 143 15 46 Duke, UCSF, UK, Israel, Columbia, and USC did not take part in this section and were excluded. ORs adjusted for sex, age, gross total resection status (yes/no) and radiotherapy within 6 months (yes/no) symptoms may not have an initial seizure until much later monotherapy with efficacy of 70–100% in gliomas, and is in course of their disease. Thus, these cases may not have one of the drugs of choice for glioma-related seizures due been recognized as tumor-related seizures occurring post- to its favorable tolerability profile [28, 31, 32]. However, glioma diagnosis. the standard of care for epileptic seizure prophylaxis may Levetiracetam was the most commonly used AED to be different between the recruitment sites. treat patients in our study. Levetiracetam is a newer genera- Although we only had data from a subset of the popu- tion AED that has predictable pharmacokinetics with less lation, which may not be representative of the population concern for interaction with chemotherapeutic drugs, as is as a whole, we observed a significant correlation between the case with the first-generation enzyme-inducing drugs, reduced seizure frequency and gross total resection, which phenytoin and carbamazepine [30]. Newer generation AEDs is also consistent with previous studies where the extent such as levetiracetam do not induce or inhibit hepatic P450 of surgical resection is recognized as an independent pre- enzymes. For this reason, the first-generation AEDs are dictor of controlled epileptic seizures after oncological often prohibited from being used in glioma patients who treatment [14, 20, 33]. are enrolled in clinical trials. Although not more effective Based on the patient’s status and specific characteris- than first-generation AEDs, levetiracetam has been used as tics, however, maximal surgery may have to be postponed, 1 3 Journal of Neurology (2018) 265:1432–1442 1439 Table 5 Association between Case N (%) Control N (%) Multivariate models P value seizure diagnosis and case– ORs (95% CI) control status Ever diagnosed with seizure < 0.0001 No [ref] 2568 (65.11) 3141 (93.82) 1.00 Yes 1376 (34.89) 103 (3.18) 18.97 (15.32–23.48) Non-glioma-related seizures (seizure 0.221 initiation started > 2 years before diagnosis) No [ref] 3838 (97.31) 3141 (96.82) 1.00 Yes 106 (2.69) 103 (3.18) 0.93 (0.69–1.24) Febrile seizures as a c hild 0.5944 No [ref] 2341 (98.20) 2413 (98.29) 1.00 Yes 43 (1.80) 42 (1.71) 1.13 (0.73–1.75) Non-febrile seizure as a child 0.0874 No [ref] 2353 (98.49) 2474 (99.08) 1.00 Yes 36 (1.51) 23 (0.92) 1.61 (0.93–2.76) UK did not answer this section and was excluded. ORs adjusted for sex, glioma subtype, diagnosis age, and study sites Duke, UCSF, UK, Israel, Columbia and USC did not answer this section and were excluded. Ref reference condition. Those with missing data were excluded from OR calculations particularly if the mass is situated in the eloquent areas of that grouping data from different centers that may have differ - the brain. ent standards of care may introduce a potential bias when inter- Oncological treatment of the tumor is essential for preting the results. Furthermore, the results are based entirely glioma-related seizure control, and previous studies on a one-time questionnaire completion and some centers have reported improved seizure control in patients with opted out of full questionnaire completion. Another limitation LGGs after radiotherapy [34–36]. Moreover, two series of our study is related to the lack of information on the exact of patients with low-grade gliomas have shown a signifi- location of the tumor and volume estimates at surgery, vari- cant lower seizure frequency following interstitial brachy- ables that have been associated with seizure risk and control in therapy [37, 38]. gliomas [12, 24]. Additionally, a significant limitation is that However, we were not able to confirm this in our study, we did not have access to detailed oncological treatment data, most likely because the interviews were conducted soon as the primary aim of the GICC was to analyze potential epi- after the patient’s diagnosis (median 3.6  months post- demiological associations and gene-environment interactions. diagnosis), when improvement of seizure control by radio- In addition to what has been reported for the effects of radio- therapy may not yet be achieved. therapy on seizure control, prior studies have found positive There was no significant difference in the incidence ee ff cts of chemotherapy on epileptic seizure control. Our study of epileptic seizures > 2 years before diagnosis or in the was not primarily aimed at looking at these clinical factors, so history of seizures during childhood between cases and we have limited data on treatment-related variables with the controls. A causal relationship between increased glioma possibility of potential bias in the reported conclusions. risk and a history of epilepsy and/or exposure to AEDs Our cases were diagnosed prior to the 2016 WHO clas- long before brain tumor diagnosis has not been established sification so they are not classified with IDH mutation and [40–42]. Our study does not show that childhood seizures 1p/19q co-deletion status [43]. Future studies within the con- are risk factors for glioma-related seizures. sortium will determine if there are genes that may lead to increased susceptibility to glioma-related seizures. Limitations of the study This study was a retrospective analysis of the GICC epidemio- Conclusion logical study and an extensive medical chart review was not part of the analysis. One limitation common to all case–control In conclusion, our large case series demonstrates a pattern of studies is the potential for recall bias; although in this study, it epileptic seizure prevalence and seizure control in patients is more likely that cases under-reported seizures due to poor with gliomas that confirms previous reports. Our study also memory related to cognitive impairment. We also acknowledge 1 3 1440 Journal of Neurology (2018) 265:1432–1442 credit to the original author(s) and the source, provide a link to the confirms the strong association between epileptic seizures Creative Commons license, and indicate if changes were made. and slowly growing tumors. No relationship was found between a history of febrile seizures and glioma-related epi- leptic seizures, suggesting that remote seizure may not be a risk factor for developing glioma-related seizures or glioma. 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J Neurooncol 104(1):205–214 Affiliations 1 2 3 3 4 Shala G. Berntsson  · Ryan T. Merrell  · E. Susan Amirian  · Georgina N. Armstrong  · Daniel Lachance  · 1,20 3,4 3 5 6 7 Anja Smits  · Renke Zhou  · Daniel I. Jacobs  · Margaret R. Wrensch  · Sara H. Olson  · Dora Il’yasova  · 8 9 10 11,12 13,14 Elizabeth B. Claus  · Jill S. Barnholtz‑Sloan  · Joellen Schildkraut  · Siegal Sadetzki  · Christoffer Johansen  · 15,16 16 6 17 18 Richard S. Houlston  · Robert B. Jenkins  · Jonine L. Bernstein  · Rose Lai  · Sanjay Shete  · 3 3 19 Christopher I. Amos  · Melissa L. Bondy  · Beatrice S. Melin 1 2 Department of Neuroscience, Neurology, Uppsala Department of Neurology, NorthShore University University, 751 85 Uppsala, Sweden HealthSystem, Evanston, IL, USA 1 3 1442 Journal of Neurology (2018) 265:1432–1442 3 13 Division of Medicine, Dan L. Duncan Cancer Center, Baylor Institute of Cancer Epidemiology, Danish Cancer Society, College of Medicine, Houston, TX, USA Copenhagen, Denmark 4 14 Department of Neurology, Mayo Clinic Comprehensive Rigshospitalet, University of Copenhagen, Copenhagen, Cancer Center, Mayo Clinic, Rochester, MN, USA Denmark 5 15 Department of Neurological Surgery, University Section of Cancer Genetics, Institute of Cancer Research, of California, San Francisco, San Francisco, CA, USA Sutton, London, Surrey, UK 6 16 Department of Epidemiology and Biostatistics, Memorial Department of Laboratory Medicine and Pathology, Sloan-Kettering Cancer Center, New York, NY, USA Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA Department of Epidemiology and Biostatistics, Georgia State University School of Public Health, Atlanta, Georgia Departments of Neurology, Neurosurgery, and Preventive Medicine, The University of Southern California Keck Department of Epidemiology and Public Health, Yale School of Medicine, Los Angeles, CA, USA University School of Medicine, New Haven, CT, USA Department of Epidemiology, The University of Texas MD Case Comprehensive Cancer Center, Case Western Reserve Anderson Cancer Center, Houston, TX, USA University School of Medicine, Cleveland, OH, USA Department of Radiation Sciences Oncology, Umeå Department of Public Health Sciences, University University, Umeå, Sweden of Virginia, Charlottesville, VA, USA Department of Clinical Neuroscience, Institute Cancer and Radiation Epidemiology Unit, Gertner Institute, of Neuroscience and Physiology, Sahlgrenska Academy, Chaim Sheba Medical Center, Tel Hashomer, Israel University of Gothenburg, Gothenburg, Sweden Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neurology Springer Journals

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Abstract

Background The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. Methods The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demograph- ics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. Results Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. Conclusions Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma. Keywords Observational study (cohort, case–control) · Epileptic seizures · Primary brain tumor · Glioma-related seizures Introduction bilateral, convulsive seizures [2, 3]. The etiology of glioma- related seizures is complex and not completely understood, Epileptic seizures are among the most common presenting but patients diagnosed with low-grade gliomas (LGGs) have symptom in patients with glioma [1]. Glioma-related sei- a higher risk for developing medically refractory epileptic zures may occur at different time points during the course seizures than those with higher tumor grades (i.e., anaplastic of a patients’ illness, and can present either as focal seizures glioma and glioblastoma) [1]. An imbalance between the with or without impairment of consciousness or evolving to excessive release of neuroexcitatory glutamate and impaired GABAergic inhibition in the microenvironment surrounding the tumor has been suggested as one possible mechanism in Shala G. Berntsson and Ryan T. Merrell contributed equally to this glioma-related seizure development [4–7]. work. Treatment with antiepileptic drugs (AEDs) is critical Melissa L. Bondy and Beatrice S. Melin co-last authors. for care of glioma patients, and good seizure control is an essential factor for improved quality of life. First-genera- * Shala G. Berntsson tion AEDs, such as phenytoin, carbamazepine, and valproic shala.berntsson@neuro.uu.se acid, have largely been replaced by newer AEDs, such as Extended author information available on the last page of the article Vol:.(1234567890) 1 3 Journal of Neurology (2018) 265:1432–1442 1433 levetiracetam, lacosamide, and lamotrigine [8]. These newer questionnaire collected information on demographic charac- drugs are characterized by lower hepatic enzyme inducing teristics, past medical/medication history, and occupational properties, fewer drug–drug interactions, and more favorable history. Questionnaires were administered in person and/ tolerability profiles. or by phone, or through mailed self-administered forms. The goal of the current study was threefold: (1) evalu- Eight sites administered the full version of the question- ate the distribution of glioma-related seizures at the time of naire (The University of Texas MD Anderson Cancer Center, tumor diagnosis with respect to tumor- and patient-related Danish Cancer Society Research Centre, Memorial Sloan characteristics; (2) assess epileptic seizure frequency in Kettering Cancer Center, Brigham and Women’s Hospital, relation to AED therapy and glioma treatment (surgery and Case Western Reserve University, Mayo Clinic, NorthShore radiotherapy); (3) compare seizure history preceding tumor University HealthSystem and Umeå University). Some sites diagnosis for cases and study enrollment for controls. (Duke University, University of California, San Francisco, Institute of Cancer Research, UK, Gertner Institute, Israel, Columbia University, and University of Southern Califor- Materials and methods nia) opted not to collect detailed seizure history [9]. All cases were asked if they had ever been diagnosed with sei- Study population zures, convulsions, or epilepsy and the age at which they were diagnosed. In addition, at the sites that administered The Glioma International Case–Control study (GICC) the full questionnaire, the glioma cases were asked if they recruited 4533 cases and 4171 controls from 14 centers in had childhood seizures (febrile or not), when their epilepsy the US, Europe, and Israel. Details on the GICC study popu- was diagnosed in relation to their brain tumor, if they had lation and methodology have previously been published [9]. ever had an impairment of consciousness during a seizure, Cases were between 18 and 80 years old at diagnosis, were or bilateral convulsive epileptic seizures (grand mal), how histologically confirmed, and were recruited within 1 year many seizures they had had in the last 2 months, and if they of diagnosis of glioma. were currently taking AED, and if so, what type of AED. For Supratentorial and infratentorial gliomas were classified our analysis, we defined glioma-related seizures as seizures according to the 2007 WHO classification of brain tumors that began ≤ 2 years before diagnosis. as follows: fibrillary astrocytoma (9420/3), protoplasmic astrocytoma (9410/3), gemistocytic astrocytoma (9411/3), Statistical analyses oligodendroglioma (9450/3), oligoastrocytoma (9382/3), anaplastic astrocytoma (9401/3), anaplastic oligodendro- The overall GICC analysis plan and a detailed table of demo- glioma (9451/3), anaplastic oligoastrocytoma (9382/3), graphics by study site are described elsewhere [9]. The main gliosarcoma (9442/3), or glioblastoma (9440/3) [10]. WHO parameters of interest were history of seizures, the relative grade I gliomas, which are usually low-proliferation, often- timing of the first epileptic seizure in relation to glioma curable tumors were not included in this study. Thus, low- diagnosis, age at epilepsy diagnosis, and epileptic seizure grade glioma (LGG) refers to WHO grade II tumors, includ- characteristics including impairment or loss of conscious- ing the following subtypes: astrocytoma, oligodendroglioma, ness evolving to bilateral convulsive seizures, AED use, and and oligoastrocytoma. Anaplastic glioma refers to WHO seizure control (defined as recurrent epileptic seizures in grade III gliomas, including astrocytomas, oligodendroglio- spite of AED use and the subsequent frequency of seizures) mas, and oligoastrocytomas, whereas glioblastoma refers to during the last 2 months before the interview. WHO grade IV glioma, the most malignant type included Case-only analyses were conducted using multino- in this study. A pathology review was performed on partici- mial models. For the case–control analyses, we calculated pants in the first year of the study and demonstrated good adjusted odds ratios (ORs), along with their corresponding concordance of the histopathology [9]. 95% Wald confidence intervals (CIs), using unconditional All recruitment sites received Institutional Review Board logistic regression. We decided a priori to control for age (IRB) or ethical board approval to conduct the study, and and sex, glioma subtype, and study site in all multivariable informed consent was obtained from participants. models. Despite our large sample size, some strata were sparse within the histologic subtypes (Table 2). As a result, Data collection we pooled the data from all sites rather than conducting meta-analysis. While we acknowledge that pooling has limi- Every site administered a common study protocol and ques- tations because of the inter-site heterogeneity present in our tionnaire (full or abbreviated version), and data were stored consortium, the pooled analyses are exploratory, and there- in a centralized web-based database. The questionnaire was fore, allowed us to evaluate whether there might be some only administered at one time point. The GICC risk factor implication of an effect that should be examined in future 1 3 1434 Journal of Neurology (2018) 265:1432–1442 studies of larger subgroups. Sensitivity analyses included (Table 5). Glioma occurred more frequently in males than running models with and without proxy responses (~ 8% of females (59 vs. 41%), both in the entire sample and by tumor the cases). subtypes. Patients with LGG were younger at diagnosis (30–39 years) than patients with anaplastic glioma (40–59 years) or glioblastoma (50–69 years). Approximately, one- third of all glioma cases (28.5%) reported diagnosis of Results seizures, convulsions, or epilepsy (Table 1). Among cases reporting the relative timing of their r fi st seizures ( n = 1376), Descriptive statistics for glioma cases (overall and by his- there were cases who, reported uncertainty about the time tologic subtypes) and controls are presented in Table  1. interval (n = 112), leaving a total of 1264 cases for the analy- Median time interval from diagnosis to questionnaire was sis. Epileptic seizures occurred most commonly within 2 3.2 months for GBM, 4.6 months for anaplastic astrocytoma years prior to glioma diagnosis (n = 1158) (Table 1). Table 1 Selected population characteristics from the glioma international case–control study by case–control status and glioma histology group Glioma cases Controls Glioblastoma Anaplastic Anaplastic LGG Astrocy- LGG Oligo- Other astrocytoma oligodendro- toma dendroglioma/ glioma/oli- oligoastrocy- goastrocytoma toma N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Sex  Male 2679 (59.1) 2351 (56.37) 1727 (62.3) 294 (55.58) 142 (51.64) 199 (53.35) 241 (53.44) 76 (57.14)  Female 1854 (40.9) 1820 (43.63) 1045 (37.7) 235 (44.42) 133 (48.36) 174 (46.65) 210 (46.56) 57 (42.86) Age at diagnosis/enrollment  18–29 years 308 (6.79) 294 (7.05) 62 (2.24) 68 (12.85) 25 (9.09) 65 (17.43) 70 (15.52) 18 (13.53)  30–39 years 521 (11.49) 473 (11.34) 108 (3.9) 115 (21.74) 54 (19.64) 99 (26.54) 122 (27.05) 23 (17.29)  40–49 years 813 (17.94) 680 (16.3) 417 (15.04) 110 (20.79) 63 (22.91) 89 (23.86) 114 (25.28) 20 (15.04)  50–59 years 1150 (25.3) 1079 (25.87) 795 (28.68) 90 (17.01) 64 (23.27) 67 (17.96) 98 (21.73) 36 (27.07)  60–69 years 1239 (27.3) 1098 (26.32) 993 (35.82) 94 (17.77) 52 (18.91) 40 (10.72) 37 (8.2) 23 (17.29)  70–80 years 502 (11.07) 547 (13.11) 397 (14.32) 52 (9.83) 17 (6.18) 13 (3.49) 10 (2.22) 13 (9.77) Seizure history  Glioma-related 1158 (28.5) – 527 (21.11) 186 (39.74) 84 (36.68) 150 (43.35) 188 (45.30) 23 (19.83) seizures (sei- zures ≤ 2 years of diagnosis)  Non-glioma- 106 (2.60) – 55 (8.86) 15 (6.79) 2 (2.15) 13 (7.22) 14 (6.20) 7 (20.00) related seizures (seizure initiation started > 2 years before diagnosis  Cases with 112 (2.75) – 39 (6.28) 20 (9.05) 7 (7.53) 17 (9.44) 24 (10.62) 5 (14.29) seizures where time of seizure initiation not reported  No seizures 2568 (63.1) – 1792 (71.79) 233 (49.79) 130 (56. (77) 157 (45.38) 179 (43.13) 77 (66.38)  Missing 126 (3.1) – 83 (3.33) 14 (2.99) 6 (2.62) 9 (2.6) 10 (2.41) 4 (3.45) LGG low-grade glioma UK did not answer this section and was excluded. ORs adjusted for sex and age and oligodendroglioma and finally 4.2 months for patients There was a significant difference in history of ever hav - with low-grade gliomas. ing been diagnosed with epileptic seizures (including seizure 3944 of the 4533 (87%) glioma cases and 3244 of the diagnoses within 2 years prior to tumor diagnosis) between 4171 (78%) controls completed the full questionnaire patients with glioblastoma (26%) and those with low-grade 1 3 Journal of Neurology (2018) 265:1432–1442 1435 oligodendroglioma/oligoastrocytoma (56%) or low-grade seizure risk and the growth rate of the tumor. Patients with astrocytoma (53%) (Table 2). Grade II oligodendroglioma/ LGGs, and particularly oligodendroglial tumors, are there- oligoastrocytoma patients were 3 times more likely to have fore, generally more prone to seizures than patients with had a history of epileptic seizures compared to glioblastoma high-grade gliomas [3, 14, 15]. The mechanisms behind patients (OR = 3.03; CI 2.41–3.82, p < 0.0001) (Table 2). seizure development in slow-growing tumors are different Patients with grade II oligodendroglioma/oligoastro- from high-grade tumors. Chronic deafferentation and dis- cytoma, grade II astrocytoma, and anaplastic astrocytoma connection of functionally isolated regions of cortex, caus- were more likely to have generalized epileptic seizures than ing a denervation hypersensitivity is connected to seizure cases with glioblastoma and anaplastic oligodendroglioma risk in LGGs, whereas the direct effects of tissue damage in (p < 0.0001) (Table 2). There were a higher proportion of fast-growing high-grade gliomas by disturbed microvascu- LGG patients who had recurrent epileptic seizures than larization and peritumoral ischemia are thought to be causa- cases with anaplastic glioma and glioblastoma, despite tive factors [16, 17]. treatment with AEDs. Low-grade astrocytoma cases were We also found that patients with low-grade astrocytoma about 1.6 times more likely to have recurrent epileptic sei- patients had significantly more recurrent seizures in spite zures compared to glioblastoma cases (OR = 1.55; 95% CI of combined antiepileptic treatments. These differences in 1.03–2.33 p = 0.15) (Table 2). seizure control may reflect the differences in tumor locations Overall, 83% of cases with epileptic seizures were pre- of the glioma subtypes. Astrocytomas are more frequently scribed one AED; 12% were on two AEDs; and 3% used associated with location in temporal or insular areas, while 3–5 AEDs. Levetiracetam was the AED of choice in 71% oligodendroglial tumors are more often located in frontal of cases (Table 3). areas [14, 18]. Treatment information in terms of type of surgery (gross Refractory seizures in patients with LGGs is a major total resection vs. subtotal resection/biopsy) and radio- concern in clinical neuro-oncology practice [19]. The epi- therapy (yes or no) was only available in a subset of cases leptogenic zone of LGGs, especially in tumors located in (23%). Gross total resection (GTR) was strongly associated temporal and paralimbic areas, involves not only the tumor with reduced frequency of epileptic seizures; glioma cases itself but also extra-tumoral cortical areas, explaining the who had GTR were 72% less likely to have reported > 10 poor seizure control in 15–20% of patients after gross total seizures during the 2 months immediately prior to the inter- tumor resection. Improved postoperative seizure control view, compared with cases that underwent subtotal resection was achieved in cases where the resection involved both the or biopsy (n = 255) (OR = 0.28; CI 0.11–0.73, p < 0.009). tumor and the epileptogenic zone surrounding the tumor Radiotherapy, during first-line treatment, was not associated [20–24]. with epileptic seizure control (p < 0.85) (Table 4). Moreover, the treatment of glioma-related epilepsy Glioma cases were as likely as controls to experience with AED is complex. Cognitive side effects, interactions febrile (OR = 1.13; 95% CI 0.73–1.75, p = 0.59) and non- between AEDs and between AED treatment and chemo- febrile seizures (OR = 1.61; 95% CI 0.93–2.76, p = 0.09) therapy are important aspects that need to be considered. during childhood (Table 5). Increased susceptibility to the cognitive side effects of AEDs was much more frequent than the side effects of radiotherapy in patients with LGGs [25]. Finally, the difficulties of obtain- Discussion ing good seizure control in spite of optimal AED and tumor treatment also illustrate the natural course of LGGs as a Our study is one of the largest studies to date of glioma- progressive and eventually fatal disease. related seizures in relation to proximity of diagnosis, glioma Our data demonstrate that patients with LGG, particu- histology, and treatment by AEDs, as well as tumor treat- larly low-grade astrocytoma, should be closely monitored ment by resection and radiotherapy. Our results confirms a for seizures. lower mean age at onset in patients with LGGs compared to Recently, a large multicenter French study provided anaplastic glioma and glioblastoma, as well as a higher rate detailed information on approximately 1500 LGGs, and of epileptic seizures as a presenting symptom, a phenom- identified male sex and tumor location in functional areas enon that has been well established in other large epidemio- as independent predictors for tumor-related epileptic sei- logical studies [11–13]. We also observed a higher frequency zures [12]. The correlation between glioma-related sei- of seizures among low-grade oligodendroglioma/oligoastro- zures and male sex was not confirmed in the present study. cytoma cases compared to glioblastoma cases, consistent In addition, among LGGs, the prevalence of self-reported with previous reports. Our data confirm the relatively long glioma-related seizures was slightly lower in our study time interval that is needed for the development of tumor- than in previous studies [1, 12, 14, 26]. A potential reason related seizures in the brain and the association between is the possible poor recall of events. Patients may only 1 3 1436 Journal of Neurology (2018) 265:1432–1442 1 3 Table 2 Characteristics of seizures in glioma cases according to histology subtype Glioblastoma ORs Anaplastic astrocytoma Anaplastic oligo/oligoastro- LGG astrocytoma LGG oligo/oligoastrocytoma Other Trend p value [Ref] cytoma N (%) N (%) OR (95% CI) N (%) OR (95% CI) N (%) OR (95% CI) N (%) OR (95% CI) N (%) Ever diagnosed < 0.0001 with seizure, convulsions, or epilepsy No [ref] 1792 (74.3) Ref 233 (51.3) 130 (58.3) 157 (46.6) 179 (44.2) 77 (68.8) Yes 621 (25.7) Ref 221 (48.7) 2.44 (1.98–3.02) 93 (41.7) 1.84 (1.38–2.45) 180 (53.4) 2.77 (2.17–3.54) 226 (55.8) 3.03 (2.41–3.82) 35 (31.3) Ever lost < 0.0001 consciousness while having a seizure No [ref] 658 (71.8) Ref 132 (56.9) 74 (61.7) 83 (49.1) 119 (51.7) 30 (60.0) Yes 258 (28.2) Ref 100 (43.1) 1.53 (1.12–2.08) 46 (38.3) 1.30 (0.87–1.95) 86 (50.9) 1.89 (1.33–2.69) 111 (48.3) 1.62 (1.18–2.23) 20 (40.0) Currently taking < 0.0001 medications including prevention No [ref] 690 (51.3) Ref 100 (34.5) 59 (39.1) 60 (27.9) 87 (33.6) 29 (42.0) Yes 655 (48.7) Ref 190 (65.5) 1.63 (1.24–2.15) 92 (60.9) 1.35 (0.95–1.92) 155 (72.1) 1.97 (1.42–2.75) 172 (66.4) 1.46 (1.08–1.97) 40 (58.0) Recurrent seizure 0.1462 in spite of medication No [ref] 355 (69.5) Ref 115 (69.7) 57 (73.1) 80 (56.7) 101 (63.1) 23 (71.9) Yes 156 (30.5) Ref 50 (30.3) 0.90 (0.60–1.34) 21 (26.9) 0.78 (0.45–1.34) 61 (43.3) 1.55 (1.03–2.33) 59 (36.9) 1.17 (0.78–1.75) 9 (28.1) Oligo is oligodendroglioma. LGG is low-grade Glioma UK did not answer this section and was excluded. ORs adjusted for sex and age and site Duke, UCSF, UK, Israel, Columbia and USC did not answer this section and were excluded. ORs adjusted for sex and age Duke, UCSF, UK, Israel, Columbia and USC did not answer this section and were excluded Journal of Neurology (2018) 265:1432–1442 1437 Table 3 Seizure information and use of medication for seizure in glioma cases) by glioma histology group Glioblastoma N (%) Anaplastic Anaplastic oligo/ LGG LGG oligo/oli- Other N (%) Total N (%) astrocytoma oligoastrocytoma astrocytoma goastrocytoma N (%) N (%) N (%) N (%) As a child ever had seizures with high f ever Yes 22 (1.53) 10 (3.27) 2 (1.24) 4 (1.79) 4 (1.5) 1 (1.37) 43 (1.74) No 1365 (94.92) 285 (93.14) 158 (98.14) 212 (94.64) 253 (94.76) 68 (93.15) 2341 (94.82) Missing 51 (3.55) 11 (3.59) 1 (0.62) 8 (3.57) 10 (3.75) 4 (5.48) 85 (3.44) Has a child ever had seizure not caused by high fever Yes 18 (1.25) 5 (1.63) 0 4 (1.79) 5 (1.87) 4 (5.48) 36 (1.46) No 1374 (95.55) 290 (94.77) 156 (96.89) 216 (96.43) 252 (94.38) 65 (89.04) 2353 (95.3) Missing 46 (3.2) 11 (3.59) 5 (3.11) 4 (1.79) 10 (3.75) 4 (5.48) 80 (3.24) Ever had a bilateral convulsive seizure Yes 124 (28.18) 59 (35.33) 31 (37.8) 52 (36.36) 61 (36.53) 13 (41.94) 340 (33.01) No 245 (55.68) 85 (50.9) 37 (45.12) 69 (48.25) 79 (47.31) 15 (48.39) 530 (51.46) Missing 71 (16.14) 23 (13.77) 14 (17.07) 22 (15.39) 27 (16.17) 3 (9.68) 160 (15.54) No of seizure medications 1 339 (85.18) 126 (80.77) 68 (89.47) 104 (77.61) 120 (79.47) 23 (88.46) 780 (82.89) 2 44 (11.06) 23 (14.74) 5 (6.58) 21 (15.67) 20 (13.25) 3 (11.54) 116 (12.33) 3 5 (1.26) 3 (1.92) 1 (1.32) 8 (5.97) 8 (5.3) 0 25 (2.66) 4 0 1 (0.64) 0 1 (0.75) 1 (0.66) 0 3 (0.32) 5 1 (0.25) 0 0 0 0 0 1 (0.11) Missing 9 (2.26) 3 (1.92) 2 (2.63) 0 2 (1.32) 0 16 (1.7) Ever taken levetiracetam Yes 301 (75.63) 112 (71.79) 49 (64.47) 90 (67.16) 98 (64.9) 18 (69.23) 668 (70.99) No 97 (24.37) 44 (28.21) 27 (35.53) 44 (32.84) 53 (35.1) 8 (30.77) 273 (29.01) Oligo is oligodendroglioma, LGG is low-grade glioma MDA, Denmark, MSK, Brigham and Women, Case Western, Mayo, Northshore and Sweden provided this information Duke, UCSF, UK, Israel, Columbia and USC did not ask these questions report more dramatic seizure episodes, such as secondary Somatic isocitrate–dehydrogenase 1 (IDH1) mutations generalized seizures, and due to cognitive decline, may are common in LGGs, leading to the production of D-2 fail to recall less severe focal seizures, such as left-hemi- hydroxyglutarate, a metabolite that bears structural similari- spheric temporal lobe seizures. In our study, data were col- ties to glutamate [27]. Thus, the IDH1 mutation in the tumor lected through self-reported questionnaires, as opposed to cells renders the tumor in a higher excitatory state and may clinical observation or medical record abstraction, which be directly involved in the pathogenesis of tumor-related could be one of the reasons for differences in the rates of seizures in LGGs [28]. Routine testing of IDH1 mutational epileptic seizures between the studies. status was not performed at the time of our data collection. Furthermore, LGGs and anaplastic astrocytomas were However, given that the frequency of IDH mutation in LGG more commonly associated with generalized seizures than approaches 80% and its possible role in epileptogenesis, a glioblastoma. These findings support the existence of differ - partial explanation for the observed higher frequency of ent epileptogenic pathways for LGG and high-grade gliomas epileptic seizures in LGGs could be due to IDH1 mutation [17, 24]. From an epileptogenic point of view, this finding status [29]. reinforces the general concept that slow-growing tumors In this study, we only have data from time of study have a lower epileptic threshold than fast-growing lesions enrollment/diagnosis, and no follow-up data was collected. [1]. Glioma patients who presented with other tumor-related 1 3 1438 Journal of Neurology (2018) 265:1432–1442 Table 4 Association between seizure frequency during the last 2 months and glioma case subtype Seizure free; 1–5 seizures 6–10 seizures > 10 seizures Total N 1–5 seizures 6–10 seizures > 10 seizures P value ref; N (%) N (%) N (%) N (%) OR (95% CI) OR (95% CI) OR (95% CI) Glioma sub- 0.7461 type Glioblastoma 380 (80.34) 70 (14.80) 6 (1.27) 17 (3.59) 473 1.00 1.00 1.00 [ref] Anaplastic 51 (78.46) 10 (15.38) 1 (1.54) 3 (4.62) 65 0.95 (0.45– 0.82 (0.09– 1.14 (0.31– oligo/oli- 2.00) 7.48) 4.16) goastrocy- toma Anaplastic 92 (74.80) 24 (19.51) 1 (0.81) 6 (4.88) 123 1.24 (0.72– 0.42 (0.05– 1.22 (0.45– astrocytoma 2.14) 3.87) 3.30) LGG, astrocy- 65 (70.65) 13 (14.13) 3 (3.26) 11 (11.96) 92 0.90 (0.44– 1.86 (0.36– 3.25 (1.27– toma 1.85) 9.61) 8.29) LGG, oligo/ 87 (72.50) 23 (19.17) 3 (2.50) 7 (5.83) 120 1.16 (0.60– 1.35 (0.23– 1.47 (0.49– oligoastro- 2.23) 7.78) 4.39) cytoma Other 22 (78.57) 3 (10.71) 1 (3.57) 2 (7.14) 28 0.63 (0.18– 1.93 (0.19– 1.73 (0.35– 2.22) 19.67) 8.40) Sex 0.1522 Male [ref] 411 (78.74) 84 (16.09) 4 (0.77) 23 (4.41) 522 1.00 1.00 1.00 Female 286 (75.46) 59 (15.57) 11 (2.90) 23 (6.07) 379 0.96 (0.67– 3.54 (1.10– 1.31 (0.71– 1.40) 11.39) 2.41) Gross total 0.009 resection No [ref] 481 (74.46) 111 (17.18) 13 (2.01) 41 (6.35) 646 1.00 1.00 1.00 Yes 216 (84.71) 32 (12.55) 2 (0.78) 5 (1.96) 255 0.64 (0.42– 0.36 (0.08– 0.28 (0.11– 0.99) 1.64) 0.73) Radiotherapy 0.8558 No [ref] 149 (73.40) 36 (17.73) 4 (1.97) 14 (6.90) 203 1.00 1.00 1.00 Yes 548 (78.51) 107 (15.33) 11 (1.58) 32 (4.58) 698 0.83 (0.50– 1.17 (0.30– 0.82 (0.38– 1.38) 4.64) 1.76) Mean age 52.7 51.2 46.7 50.3 0.99 (0.98– 0.98 (0.94– 1.00 (0.98– 0.6138 at glioma 1.01) 1.02) 1.03) diagnosis Total 697 143 15 46 Duke, UCSF, UK, Israel, Columbia, and USC did not take part in this section and were excluded. ORs adjusted for sex, age, gross total resection status (yes/no) and radiotherapy within 6 months (yes/no) symptoms may not have an initial seizure until much later monotherapy with efficacy of 70–100% in gliomas, and is in course of their disease. Thus, these cases may not have one of the drugs of choice for glioma-related seizures due been recognized as tumor-related seizures occurring post- to its favorable tolerability profile [28, 31, 32]. However, glioma diagnosis. the standard of care for epileptic seizure prophylaxis may Levetiracetam was the most commonly used AED to be different between the recruitment sites. treat patients in our study. Levetiracetam is a newer genera- Although we only had data from a subset of the popu- tion AED that has predictable pharmacokinetics with less lation, which may not be representative of the population concern for interaction with chemotherapeutic drugs, as is as a whole, we observed a significant correlation between the case with the first-generation enzyme-inducing drugs, reduced seizure frequency and gross total resection, which phenytoin and carbamazepine [30]. Newer generation AEDs is also consistent with previous studies where the extent such as levetiracetam do not induce or inhibit hepatic P450 of surgical resection is recognized as an independent pre- enzymes. For this reason, the first-generation AEDs are dictor of controlled epileptic seizures after oncological often prohibited from being used in glioma patients who treatment [14, 20, 33]. are enrolled in clinical trials. Although not more effective Based on the patient’s status and specific characteris- than first-generation AEDs, levetiracetam has been used as tics, however, maximal surgery may have to be postponed, 1 3 Journal of Neurology (2018) 265:1432–1442 1439 Table 5 Association between Case N (%) Control N (%) Multivariate models P value seizure diagnosis and case– ORs (95% CI) control status Ever diagnosed with seizure < 0.0001 No [ref] 2568 (65.11) 3141 (93.82) 1.00 Yes 1376 (34.89) 103 (3.18) 18.97 (15.32–23.48) Non-glioma-related seizures (seizure 0.221 initiation started > 2 years before diagnosis) No [ref] 3838 (97.31) 3141 (96.82) 1.00 Yes 106 (2.69) 103 (3.18) 0.93 (0.69–1.24) Febrile seizures as a c hild 0.5944 No [ref] 2341 (98.20) 2413 (98.29) 1.00 Yes 43 (1.80) 42 (1.71) 1.13 (0.73–1.75) Non-febrile seizure as a child 0.0874 No [ref] 2353 (98.49) 2474 (99.08) 1.00 Yes 36 (1.51) 23 (0.92) 1.61 (0.93–2.76) UK did not answer this section and was excluded. ORs adjusted for sex, glioma subtype, diagnosis age, and study sites Duke, UCSF, UK, Israel, Columbia and USC did not answer this section and were excluded. Ref reference condition. Those with missing data were excluded from OR calculations particularly if the mass is situated in the eloquent areas of that grouping data from different centers that may have differ - the brain. ent standards of care may introduce a potential bias when inter- Oncological treatment of the tumor is essential for preting the results. Furthermore, the results are based entirely glioma-related seizure control, and previous studies on a one-time questionnaire completion and some centers have reported improved seizure control in patients with opted out of full questionnaire completion. Another limitation LGGs after radiotherapy [34–36]. Moreover, two series of our study is related to the lack of information on the exact of patients with low-grade gliomas have shown a signifi- location of the tumor and volume estimates at surgery, vari- cant lower seizure frequency following interstitial brachy- ables that have been associated with seizure risk and control in therapy [37, 38]. gliomas [12, 24]. Additionally, a significant limitation is that However, we were not able to confirm this in our study, we did not have access to detailed oncological treatment data, most likely because the interviews were conducted soon as the primary aim of the GICC was to analyze potential epi- after the patient’s diagnosis (median 3.6  months post- demiological associations and gene-environment interactions. diagnosis), when improvement of seizure control by radio- In addition to what has been reported for the effects of radio- therapy may not yet be achieved. therapy on seizure control, prior studies have found positive There was no significant difference in the incidence ee ff cts of chemotherapy on epileptic seizure control. Our study of epileptic seizures > 2 years before diagnosis or in the was not primarily aimed at looking at these clinical factors, so history of seizures during childhood between cases and we have limited data on treatment-related variables with the controls. A causal relationship between increased glioma possibility of potential bias in the reported conclusions. risk and a history of epilepsy and/or exposure to AEDs Our cases were diagnosed prior to the 2016 WHO clas- long before brain tumor diagnosis has not been established sification so they are not classified with IDH mutation and [40–42]. Our study does not show that childhood seizures 1p/19q co-deletion status [43]. Future studies within the con- are risk factors for glioma-related seizures. sortium will determine if there are genes that may lead to increased susceptibility to glioma-related seizures. Limitations of the study This study was a retrospective analysis of the GICC epidemio- Conclusion logical study and an extensive medical chart review was not part of the analysis. One limitation common to all case–control In conclusion, our large case series demonstrates a pattern of studies is the potential for recall bias; although in this study, it epileptic seizure prevalence and seizure control in patients is more likely that cases under-reported seizures due to poor with gliomas that confirms previous reports. Our study also memory related to cognitive impairment. We also acknowledge 1 3 1440 Journal of Neurology (2018) 265:1432–1442 credit to the original author(s) and the source, provide a link to the confirms the strong association between epileptic seizures Creative Commons license, and indicate if changes were made. and slowly growing tumors. No relationship was found between a history of febrile seizures and glioma-related epi- leptic seizures, suggesting that remote seizure may not be a risk factor for developing glioma-related seizures or glioma. 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Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, approval; BSM: study concept, collecting data, drafting manuscript, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO revising manuscript, accepts responsibility for conduct of research and classification of tumours of the central nervous system. Acta Neu- final approval ropathol 114(2):97–109 11. Ohgaki H, Kleihues P (2005) Population-based studies on inci- dence, survival rates, and genetic alterations in astrocytic and oli- Compliance with ethical standards godendroglial gliomas. J Neuropathol Exp Neurol 64(6):479–489 12. Pallud J, Audureau E, Blonski M, Sanai N, Bauchet L, Fontaine Funding This work was supported by Grants from the NIH, Bethesda, D, Mandonnet E, Dezamis E, Psimaras D, Guyotat J et al (2014) MD:R01CA139020 (to M.L. Bondy), R01CA52689, P50CA97257 (to Epileptic seizures in diffuse low-grade gliomas in adults. Brain M.R. Wrensch). All authors received support from R01CA139020 (to 137(Pt 2):449–462 M.L. Bondy). Additional support was provided by the McNair Medical 13. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS (2002) Epi- Institute and the Population Sciences Biorepository at Baylor College demiology of primary brain tumors: current concepts and review of Medicine (P30CA125123). of the literature. Neuro Oncol 4(4):278–299 14. Chang EF, Potts MB, Keles GE, Lamborn KR, Chang SM, Bar- baro NM, Berger MS (2008) Seizure characteristics and control Conflicts of interest The authors declare no competing financial in- following resection in 332 patients with low-grade gliomas. J Neu- terests. rosurg 108(2):227–235 15. Lote K, Stenwig AE, Skullerud K, Hirschberg H (1998) Preva- Informed consent Written informed consent was obtained from each lence and prognostic significance of epilepsy in patients with subject or from his or her guardian. Approval from local institutional gliomas. Eur J Cancer 34(1):98–102 review boards was received at each Gliogene participating institution. 16. 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J Neurooncol 104(1):205–214 Affiliations 1 2 3 3 4 Shala G. Berntsson  · Ryan T. Merrell  · E. Susan Amirian  · Georgina N. Armstrong  · Daniel Lachance  · 1,20 3,4 3 5 6 7 Anja Smits  · Renke Zhou  · Daniel I. Jacobs  · Margaret R. Wrensch  · Sara H. Olson  · Dora Il’yasova  · 8 9 10 11,12 13,14 Elizabeth B. Claus  · Jill S. Barnholtz‑Sloan  · Joellen Schildkraut  · Siegal Sadetzki  · Christoffer Johansen  · 15,16 16 6 17 18 Richard S. Houlston  · Robert B. Jenkins  · Jonine L. Bernstein  · Rose Lai  · Sanjay Shete  · 3 3 19 Christopher I. Amos  · Melissa L. Bondy  · Beatrice S. Melin 1 2 Department of Neuroscience, Neurology, Uppsala Department of Neurology, NorthShore University University, 751 85 Uppsala, Sweden HealthSystem, Evanston, IL, USA 1 3 1442 Journal of Neurology (2018) 265:1432–1442 3 13 Division of Medicine, Dan L. Duncan Cancer Center, Baylor Institute of Cancer Epidemiology, Danish Cancer Society, College of Medicine, Houston, TX, USA Copenhagen, Denmark 4 14 Department of Neurology, Mayo Clinic Comprehensive Rigshospitalet, University of Copenhagen, Copenhagen, Cancer Center, Mayo Clinic, Rochester, MN, USA Denmark 5 15 Department of Neurological Surgery, University Section of Cancer Genetics, Institute of Cancer Research, of California, San Francisco, San Francisco, CA, USA Sutton, London, Surrey, UK 6 16 Department of Epidemiology and Biostatistics, Memorial Department of Laboratory Medicine and Pathology, Sloan-Kettering Cancer Center, New York, NY, USA Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA Department of Epidemiology and Biostatistics, Georgia State University School of Public Health, Atlanta, Georgia Departments of Neurology, Neurosurgery, and Preventive Medicine, The University of Southern California Keck Department of Epidemiology and Public Health, Yale School of Medicine, Los Angeles, CA, USA University School of Medicine, New Haven, CT, USA Department of Epidemiology, The University of Texas MD Case Comprehensive Cancer Center, Case Western Reserve Anderson Cancer Center, Houston, TX, USA University School of Medicine, Cleveland, OH, USA Department of Radiation Sciences Oncology, Umeå Department of Public Health Sciences, University University, Umeå, Sweden of Virginia, Charlottesville, VA, USA Department of Clinical Neuroscience, Institute Cancer and Radiation Epidemiology Unit, Gertner Institute, of Neuroscience and Physiology, Sahlgrenska Academy, Chaim Sheba Medical Center, Tel Hashomer, Israel University of Gothenburg, Gothenburg, Sweden Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 1 3

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Journal of NeurologySpringer Journals

Published: Apr 23, 2018

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