An analysis of 170 glioma patients and systematic review to investigate the association between IDH-1 mutations and preoperative glioma-related epilepsy

Seizure is a common presenting symptom of glioma, and many biomarkers have been suggested to be associated with preoperative seizure; however, the relationships between IDH (isocitrate dehydrogenase) mutations and glioma-related epilepsy only recently been studied. The authors aimed to examine the correlations between IDH mutations in glioma patients with preoperative seizures and tumor location. A series of 170 glioma samples were analyzed for IDH1 R132H mutations (amino acid change from arginine to histidine at codon 132) with immunohistochemistry (IHC) staining and for IDH mutations with direct DNA sequencing when the IHC results were negative. If either the IHC or direct DNA sequencing result was positive, the IDH status was defined as mutated. The results of the IDH mutation examinations were used to analyze the relationship between mutations and glioma-related epilepsy. The study population consisted of 64 (37.6%) World Health Organization (WHO) grade II gliomas, 58 (34.1%) grade III, and 48 (28.3%) grade IV gliomas. A total of 84 samples with IDH1 mutations were observed in our study, and 54 of these presented with seizures as the initial symptoms, whereas 28 of the patients with wild-type IDH status presented with seizures (p = 0.043 for the WHO grade II gliomas, p = 0.002 for the grade III gliomas and p = 0.942 for the grade IV gliomas, chi-squared tests). Among the WHO grade II and III gliomas, IDH1 mutations were significantly associated with preoperative seizures, but no significant relationship between IDH mutations and preoperative seizures was found with glioblastoma multiforme.     

KPNA2 predicts long term survival in patients with anaplastic oligoastrocytomas

The family of karyopherins comprises importins and exportins which are both involved in nucleocytoplasmic shuttling. Increased levels of karyopherin a2/importin 1 (KPNA2) and chromosome region maintenance protein 1/exportin 1 (CRM1) have been associated with poorer prognosis in patients with infiltrative astrocytomas. Isocitrate dehydrogenase 1 gene (IDH1) R132H mutation status was also recently identified as a prognostic factor for malignant gliomas. We evaluated KPNA2 and CRM1, as well as the IDH1 mutation status, as possible novel biomarkers for World Health Organization grade III anaplastic oligoastrocytomas (AOA). We analyzed nuclear expression of KPNA2 by immunohistochemistry in 72 primary anaplastic gliomas (29 AOA, 24 anaplastic astrocytomas, 19 anaplastic oligodendrogliomas). The IDH1 mutation status was also determined in patients with anaplastic astrocytomas and AOA, and AOA patients were additionally evaluated for CRM1 nuclear expression. Long term survivors (LTS; >8 years) with AOA showed lower KPNA2 expression levels compared to non-LTS (p = 0.005). KPNA2 expression (⩾5% versus <5%, 1–<5%, median) was found to correlate inversely with overall survival (OS) and progression-free survival (PFS) in our overall series as well as in the AOA group (anaplastic gliomas: OS p = 0.017; PFS p = 0.033; AOA: OS p = 0.017, PFS p = 0.040). Mutant IDH1-R132H was detected in 69% of the AOA cohort; a combination of KPNA2 low expression and mutant IDH1-R132H was only seen in LTS (p = 0.050). No differences between the histological subtypes were observed in terms of KPNA2 expression and IDH1-R132H mutation status. To our knowledge this is the first time it has been shown that KPNA2 expression may have potential as a prognostic biomarker for AOA as well.     

IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom

IntroductionSeizures are the most common initial symptom in patients with low-grade glioma and their occurrence strongly depends on the tumor location. The majority of low-grade gliomas reveal mutations in the genes encoding isocitrate-dehydrogenase 1 (IDH1) or 2 (IDH2). These mutations are associated with metabolic changes that are potentially epileptogenic. We investigated the correlation between IDH1/2 mutations and tumor localization and seizure as the initial symptom.Materials and methodsThis retrospective study included patients with a diagnosis of WHO grade II astrocytoma and cortical infiltration and in whom initial symptoms were documented and biopsy tissue was available for IDH1/2 analysis. IDH1/2 mutation analysis was performed by direct sequencing or by immunohistochemistry with an antibody which detects mutated protein IDH1 R132H. Sequencing was carried out if immunohistochemistry was negative. IDH1/2 status was defined as mutated if either of these investigations were positive.ResultsSeventy-nine patients were included. IDH1 or IDH2 mutation was present in 63 (80%) patients who on average were younger than patients without IDH1/2 mutation (40 vs. 47 years, p = 0.0331, t-test). IDH1/2 mutations were associated with frontal tumor location (p = 0.0202). All 12 tumors in the insula revealed IDH1/2 mutations. Seizure as the initial symptom was recorded in 57 (72%) patients and was associated with IDH1 or IDH2 mutation by multivariate analysis (OR 22.563, p = 0.0019).ConclusionIn WHO grade II astrocytomas, IDH1/2 mutations mostly occur in tumors infiltrating the frontal lobe. Seizure as the initial symptom is associated with IDH1 or IDH2 mutation.     

Reliability of noncontrast-enhancing tumor as a biomarker of IDH1 mutation status in glioblastoma

Isocitrate dehydrogenase 1 (IDH1) mutations in gliomas have been associated with a frontal lobe location and a greater proportion of noncontrast-enhancing tumour (nCET). The purpose of our study was to validate the utility of MRI imaging features in predicting IDH1 mutations in glioblastomas. Pre-operative MRIs of new glioblastoma patients, consisting of at least FLAIR and T1-weighted post-contrast sequences, were reviewed by a neuroradiologist based primarily on the VASARI feature set. IDH1 mutation testing was performed on all patients using immunohistochemistry. 153 patients met the inclusion criteria, of whom five had IDH1 mutations (3.3%). A frontal lobe location had equivalent frequency in both the IDH1-mutated and IDH1-wildtype cohorts (p = 1.000). Three (60%) of the IDH1-mutated tumours had >33% nCET, compared to 21% of IDH1-wildtype (p = 0.073). 12 tumours had a frontal lobe epicentre and >33% nCET, all being IDH1-wildtype. All five IDH1-mutated tumours had either a frontal lobe epicentre or >33% nCET, but none had both these features. Our results question the strength of the association between frontal lobe glioblastomas with substantial nCET and IDH1 mutations, as these features are also relatively frequent in IDH1-wildtype tumours, which are much more common. MRI is thus more useful for ruling out an IDH1 mutation rather than strongly suggesting its presence: if a particular glioblastoma does not have a frontal lobe epicentre and has less than 33% nCET, it can be predicted to be IDH1-wildtype with a high degree of confidence.     

BRAF V600E mutation is a significant prognosticator of the tumour regrowth rate in brainstem gangliogliomas

BRAF V600E mutations are progression factors in paediatric low-grade gliomas. Furthermore, a high percentage of paediatric brainstem gangliogliomas have BRAF V600E mutations. However, their clinical significance, including possible connections between the biomarkers and ganglioglioma’s clinical features, especially a brainstem counterpart, is unclear. To identify potential molecular features predictive of brainstem ganglioglioma’s clinical outcomes, a retrospective cohort of 28 World Health Organization (WHO) grade I brainstem gangliogliomas was analysed for BRAF V600E, IDH1 R132H, and IDH2 R172K mutations, TERT C228T/C250T promoter mutation, H3F3A K27M mutation and MGMT methylation. The volume of tumours was calculated accurately by using 3D Slicer software. The clinical data of these patients were retrospectively analysed. In tumours with BRAF V600E mutations, the tumour regrowth rate was significantly faster than that of the wild type group (p = 0.001). Moreover, the BRAF V600E mutant group had shorter progression-free survival (PFS) compared with wild type (p = 0.012). On multivariate analysis, no factor was found to be an independent prognostic factor; however, tumours with faster regrowth rates had a strong trend towards an increased risk for shorter PFS (HR = 1.027, p = 0.056). No statistical analysis could be performed to evaluate factors affecting overall survival (OS). These data suggest that BRAF V600E can predict the regrowth rate of brainstem gangliogliomas after microsurgery, and a BRAF V600E-targeted therapeutic may be a promising early intervention measure for patients who harbour BRAF V600E mutation after microsurgery.     

IDH1 mutation may not be prognostically favorable in glioblastoma when controlled for tumor location: A case-control study

Isocitrate dehydrogenase 1 (IDH1) mutation is a known prognostic factor in glioblastoma multiforme (GBM). It has been well documented that patients with IDH1 mutant (IDH1-mu) GBM have a better outcome compared to patients with IDH1 wild-type (IDH1-WT) GBM. IDH1-mu tumors have been shown to be more commonly located in the frontal lobe, and less likely to be in multiple lobes. It is unclear whether differential location is part of the prognostically favorable profile of these tumors. We performed a case-control study, matching IDH1-mu GBMs to IDH1-WT GBMs that are controlled for age, sex and tumor location. There were 21 IDH1-mu tumors and 21 matched IDH1-WT tumors. Age, sex and tumor location were matched between the two groups. After controlling for the factors described, the IDH1-mu tumors were more likely to be secondary GBM (61.9% secondary vs. 14.3%, p = 0.004). There was an insignificant trend towards smaller tumor volume in the IDH1-mu group (28.13 ± 6.56 vs. 41.8 ± 7.33 cm³, p = 0.173). Extent of surgical resection was similar in both groups (mean 84.49% vs. 89.89%, p = 0.419). There was no survival advantage for IDH1-mu tumors when controlled for location: 25.2 months overall survival for IDH1-mu patients and 23.6 for IDH1-WT patients, p = 0.794. IDH1 mutation may provide part of its prognostic significance by differential localization of tumor, both making IDH1-mu tumors more amenable to gross total resection and placing these tumors in less eloquent areas, thereby lowering neurological morbidity.     

Selective acquisition of <Emphasis Type="Italic">IDH1</Emphasis> R132C mutations in astrocytomas associated with Li-Fraumeni syndrome

Mutations of the IDH1 gene are frequent in gliomas, with R132H (CGT → CAT) being the most common (>85%). In astrocytomas, IDH1 mutations are typically co-present with, or precede, TP53 mutations. We assessed IDH1 mutations in brain tumors diagnosed in patients from three families with Li-Fraumeni syndrome. We identified IDH1 mutations in five astrocytomas that developed in carriers of a TP53 germline mutation. Without exception, all were R132C (CGT → TGT), which in sporadic astrocytomas accounts for <5% of IDH1 mutations. This remarkably selective occurrence of R132C mutations may reflect differences in the sequence of genetic events, with a preference for R132C mutations in astrocytes or precursor cells that already carry a germline TP53 mutation.     

Value and limitations of immunohistochemistry and gene sequencing for detection of the IDH1-R132H mutation in diffuse glioma biopsy specimens

To assess the value of anti-isocitrate dehydrogenase 1 (IDH1) immunohistochemistry for evaluating diffuse gliomas, we analyzed anti-IDH1-R132H immunohistochemistry using monoclonal antibodies DIA-H09 and IMab-1 and IDH1 gene sequencing in formalin-fixed and paraffin-embedded biopsy samples of 95 diffuse gliomas. We found concordant immunostaining results using the 2 antibodies in 94 (98.9%) of the 95 cases, but DIA-H09 generally showed a higher signal-to-background ratio than IMab-1 did. Fifty-five percent of cases showed anti-IDH1-R132H immunostaining of virtually all tumor cells and 15% of only a fraction of tumor cells. All cases with complete or partial immunostaining of the tumor tissue carried the IDH1-R132H mutation. In all cases with negative immunostaining results (approximately 30%), genetic analysis showed IDH1 wild-type or non-R132H-IDH1 mutations. In a single tiny biopsy, both anti-IDH1-R132H antibodies showed immunoreactivity, but genetic testing was inconclusive. Our data confirm anti-IDH1-R132H immunostaining as a reliable method for evaluation of IDH1 gene mutation status. They also suggest the following: (i) in some cases, nonspecific background staining or regional heterogeneity of IDH1-R132H protein expression may necessitate confirmatory genetic analysis; (ii) for individual cases, anti-IDH1-R132H immunostaining may not reliably identify infiltrating tumor cells admixed with preexisting or reactive glial cells; and (iii) in tiny biopsies, immunohistochemistry may be more sensitive for detection of IDH1-R132H mutation than genetic analysis.     

IDH1 R132H突变对不同级别胶质瘤的影响及相关因素分析

目的 检测人脑不同级别胶质瘤组织中IDH1 R132H突变及胶质瘤细胞系IDH1表达情况,探讨IDH1 R132H突变对不同级别胶质瘤的影响.方法 采用q-PCR法检测U87、U251、LN-229、HS683、U118等胶质瘤细胞系中IDH1表达情况,回顾性收集70例经手术切除、病理确诊的胶质瘤组织标本(实验组)及同...     

Quality of life,mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group

ObjectiveBrain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated.Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n = 19) treated with Levetiracetam as an add-on.MethodsWe recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3 months and at 6 months.This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28–70) with uncontrolled partial-onset seizures treated with LEV as add-on.The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency.ResultsTwelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400 mg/die (mean final dose 300 mg/die). Four patients dropped out due to poor compliance and 1 for inefficacy.In the historical control group treated with LEV (mean final dose 2000 mg/die) 12 patients had high-grade gliomas, and 7 had low grade gliomas. Thirteen patients were in monotherapy and 6 in polytherapy with AEDs.In the 22 patients evaluable of 25 patients treated with LCM, we observed at final follow-up 7 patients seizure free, 12 with a significant reduction of seizures ≥ 50%, 2 stable and 1 patient with number of seizures increased.Mean seizure frequency at baseline compared with baseline period: the mean number of seizures significantly decreased from baseline (9.4) to final follow-up (1.2) (P = 0.005). The Responder Rate was 86.4%.Comparing responder rate of 22 evaluable patients with LCM with responder rate of 19 patients with LEV we didn't observe significant differences (p = 0.31).In our patients treated with LCM we didn't observe significant difference at 3 and 6 months in QoL tests results; we observe a significant reduction in the mean score of Karnofsky Performance Status (KPS) and Barthel Index (BI) between baseline and 6 months of follow-up (KPS p = 0.003; BI p = 0.007).No clinical side effects were observed.ConclusionComparing the LCM with the historical group treated with LEV in add-on, we observed that LCM seems to have a higher clinical efficacy than LEV.In our patients, we did not observe any significant changes in QoL tests, indicating stability in all quality of life domains explored, despite the objective worsening in their functional status. Although this is a small series with a relatively short follow-up, our data indicates that LCM in add-on in patients with BTRE appears to be as effective as LEV in add-on, without impact on mood and quality of life.     

IDH1R132H抗体在测定人脑胶质瘤中IDH1突变的意义

目的研究IDH1R132H抗体(IMab-1)在测定人脑胶质瘤中IDH1突变中的作用。方法使用IDH1R132H抗体,通过免疫组织化学及Western-Blot方法检测97例人脑胶质瘤及9例其他中枢神经系统肿瘤,10例对照组脑组织的IDH1突变情况,比较其与采用基因片段测序方法检测结果的差异。结果 IDH1基因阳性测定结果:免疫组织化学方法为46例,Western-blot方法为49例,基因片段测序方法为52例,三者在统计学上无差异性。结论使用IDH1R132H抗体,通过免疫组织化学及Western-Blot方法检测人脑胶质瘤中IDH1突变情况,虽然有一定的假阴性,但准确率较高,操作方便,为一种便捷良好的检测IDH1突变的方法。     

Ki-67 overexpression in WHO grade II gliomas is associated with poor postoperative seizure control

PurposeSeizures are the most common initial symptom in patients with low-grade gliomas, and approximately 30% of these patients still suffer from epilepsy after gross-total resection of the tumour. We examined the relationship between the overexpression of ki-67 in WHO grade II gliomas and seizure control.MethodsA series of 93 histologically confirmed WHO grade II glioma tissues were analysed through immunohistochemical staining for ki-67 expression. Follow-up visits regarding seizure control were scheduled at 12 months. The Engel classification was used to categorise patients’ seizure status.ResultsOf the 93 patients analysed, 65 (66.3%) patients initially presented with seizures. A total of 36 patients were diagnosed with WHO grade II oligodendrogliomas, 29 patients had oligoastrocytomas and 28 patients had astrocytomas. Ki-67 was over-expressed in 15 patients. One year after surgery poor seizure control was observed in 11 of these patients. In contrast, low ki-67 expression (<10%) was found in 78 patients. Poor seizure control was observed in 36 patients (difference between ki-67 over- and low expression groups P = 0.002). Logistic regression analysis revealed that patients with gross-total resection achieved better seizure control while ki-67 overexpression and age below 38 years were poor seizure control factors explained of the variance of seizure outcome (OR: 0.382, 4.354 and 1.822, respectively).ConclusionsIn WHO grade II gliomas, Ki-67 is a molecular marker which predicts poor seizure control of glioma patients after the resection of the tumour. Gross-total resection, ki-67 overexpression and age below 38 years significantly affect seizure prognosis.     

Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas

Somatic mutations in the IDH1 gene encoding cytosolic NADP+-dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas and oligoastrocytomas of WHO grades II and III. IDH2 encoding mitochondrial NADP+-dependent isocitrate dehydrogenase is also mutated in these tumors, albeit at much lower frequencies. Preliminary data suggest an importance of IDH1 mutation for prognosis showing that patients with anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas harboring IDH1 mutations seem to fare much better than patients without this mutation in their tumors. To determine mutation types and their frequencies, we examined 1,010 diffuse gliomas. We detected 716 IDH1 mutations and 31 IDH2 mutations. We found 165 IDH1 (72.7%) and 2 IDH2 mutations (0.9%) in 227 diffuse astrocytomas WHO grade II, 146 IDH1 (64.0%) and 2 IDH2 mutations (0.9%) in 228 anaplastic astrocytomas WHO grade III, 105 IDH1 (82.0%) and 6 IDH2 mutations (4.7%) in 128 oligodendrogliomas WHO grade II, 121 IDH1 (69.5%) and 9 IDH2 mutations (5.2%) in 174 anaplastic oligodendrogliomas WHO grade III, 62 IDH1 (81.6%) and 1 IDH2 mutations (1.3%) in 76 oligoastrocytomas WHO grade II and 117 IDH1 (66.1%) and 11 IDH2 mutations (6.2%) in 177 anaplastic oligoastrocytomas WHO grade III. We report on an inverse association of IDH1 and IDH2 mutations in these gliomas and a non-random distribution of the mutation types within the tumor entities. IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations predominantly occur in oligodendroglial tumors. In addition, patients with anaplastic glioma harboring IDH1 mutations were on average 6 years younger than those without these alterations.     

Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

Cerebellar high‐grade gliomas are rare, and likely to affect younger patients compared with those of cerebral origin. Recent genetic analyses have revealed that isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas. In this paper, we report two elderly cases of IDH‐mutated cerebellar high‐grade glioma with unusual histological features and uncommon patient ages. One case was an 83‐year‐old man, whose tumor was predominantly composed of densely packed round‐to‐polygonal epithelioid cells. The other was a 75‐year‐old woman's high‐grade astrocytoma characterized by cord‐like structures and the perivascular papillary arrangements with varying amounts of myxoid matrix. The former harbored IDH1 R132H mutation, whereas the latter had IDH2 R172K mutation. According to our literature review, eight cases of IDH‐mutated infratentorial gliomas including the present cases have been reported, and four had mutations other than IDH1 R132H. Moreover, we herein report the first elderly case of IDH2‐mutation. Although the number is limited, IDH‐mutant infratentorial diffuse gliomas may have clinical, histological and genetic features different from supratentorial cases.     

IDH2 mutation in gliomas including novel mutation

Glioblastomas (GBMs) are the most aggressive type of primary brain tumors and provide a dismal prognosis. Thus far, several key genes have been identified in GBMs as prognostic and therapeutic targets. Mutations in two isocitrate dehydrogenase (IDH) genes, IDH1 and IDH2, commonly occur in low‐grade gliomas and secondary high‐grade gliomas, but are rare in primary GBMs. These mutations alter the catalytic activity of IDH proteins, promoting gliomagenesis. Gliomas with IDH1 or IDH2 mutation have better outcomes than do gliomas with wild‐type IDH. The hot spots of IDH1 mutations (R132) and IDH2 mutations (R140 and R172) are well known and are considered as a possible biochemical explanation for the differing clinical characteristics of primary and secondary GBMs. We sought to find the incidence of IDH2 mutation and the characteristics of the gliomas with IDH2 mutation. Among 134 gliomas, which were operated in our hospital consecutively, we studied IDH1 and IDH2 mutations by Sanger sequencing and IDH2 mutation was identified in seven cases (5.2%, four oligodendrogliomas and three GBMs). IDH2 mutation was found in 3.3% of GBMs (3/90 cases) and 9.0% (4/44) of grades II to III gliomas. Here, we report the clinicopathological characteristics of the gliomas with IDH2 mutations including two cases of primary GBM carrying a novel missense IDH2 mutation (c. 484C>T, p. P162S).     

Spinal cord glioblastoma: 25 years of experience from a single institution

Accounting for less than 0.2% of all glioblastomas, high grade gliomas of the spinal cord are very rare. Here, we discuss our approach to managing patients with high grade spinal cord glioma and review the literature on the subject. Six patients with high grade spinal cord gliomas who presented to our institution between 1990 and 2015 were reviewed. Each patient underwent subtotal surgical resection, with a subset receiving adjuvant chemotherapy and radiation. Our primary outcomes of interest were pre-operative and post-operative functional status. One year survival rate was 100%. All patients had stable or improved American Spine Injury Association score immediately after surgery, which was maintained at 3 months in 83.3% of patients. Karnofsky Performance Status (KPS) was stable at 3 month follow up in 50% of patients, but all had decreased KPS 1 year after surgery. A subset of patients received post-operative radiation and chemotherapy with 0% tumor recurrence rate at 3 months. We assessed the molecular profiles of tumors from two patients in our series and found that each had mutations in TP53, but had wildtype BRAF, IDH-1, and MGMT. Taken together, our data show that patients with high grade spinal cord gliomas have an excellent survival at 1 year, but with some decline in functional status within this period. Further studies are needed to elucidate the natural history of the disease and to explore the role of adjuvant targeted molecular therapies.     

Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: A randomized,placebo-controlled Phase III study

PurposeThe purpose of this study was to evaluate the efficacy and safety of adjunctive retigabine/ezogabine (RTG/EZG) therapy in Asian adults with partial-onset seizures.MethodsA Phase III, randomized, double-blind, placebo-controlled, parallel-group study was conducted at 26 centers in Asia. Eligible patients were randomized in a 1:1:1 ratio to receive RTG/EZG 600 mg/day (200 mg 3 times daily), RTG/EZG 900 mg/day (300 mg 3 times daily), or placebo. The study consisted of an 8-week screening/baseline phase, followed by a 16-week treatment phase (4-week titration phase and 12-week maintenance phase).ResultsThe study was terminated early because of emerging safety information on RTG/EZG (i.e., retinal pigmentation and skin/mucosal discoloration) from long-term trials. Of 132 patients screened and 76 randomized, 75 (placebo, n = 25; RTG/EZG 600 mg/day, n = 26; RTG/EZG 900 mg/day, n = 24) received at least 1 dose of the study drug and were included in the safety and intent-to-treat populations. The responder rate (≥ 50% reduction in 28-day total partial-onset seizure frequency) was 31% with RTG/EZG 600 mg/day and 17% with RTG/EZG 900 mg/day versus 0% with placebo. Median percent change from baseline in 28-day total partial-onset seizure frequency during the maintenance phase was − 33.90% and − 22.46% with RTG/EZG 600 and 900 mg/day, respectively, versus − 22.21% with placebo. No new safety concerns were identified.ConclusionsInsufficient data were obtained to permit definitive conclusions. However, the results appear to be broadly in line with those from previous studies that included primarily Caucasian patients.     

Long-term seizure outcome in patients with juvenile absence epilepsy; a retrospective study in a tertiary referral center

PurposeThe study aim was to evaluate pharmacotherapy effects and long-term seizure outcomes in patients with juvenile absence epilepsy (JAE) during a five-year follow-up period. The secondary aim was to identify factors from patient history and determine their influence on seizure control.MethodWe retrospectively studied 46 patients with JAE in the period between 2006 and 2011. The age at seizure onset, onset seizure type, family history of epilepsy, status epilepticus in history, medication history, and the rate of seizure control were studied.ResultsThere were 30 females (65.2%) and 16 males (34.8%) in the study. The mean age at seizure onset was 12.9 ± 5.6 years (ranged from 3 to 28 years). In 30 patients (65.2%), seizure onset was with absences, in 15 patients (32.6%) with generalized tonic-clonic seizure (GTCS), and in 1 patient (2.2%) with absence status. In 43 patients (93.5%), GTCS occurred in the course of the disease. Family history for epilepsy was positive in 10 patients (21.7%). In the five-year follow-up period, seizure freedom (Group 1) was achieved in 7 patients (15.2%). In total, 22 patients (47.8%) were classified into the groups involving very poor seizure control and antiepileptic drug resistance (Groups 5 and 6). The mean number of antiepileptic drugs (AEDs) used in the course of the disease in appropriate therapeutic doses was 3.8 ± 2.3 (1–10 AEDs).ConclusionThe study results show that almost half of JAE patients have poor seizure control with a high rate of pharmacoresistance. The outcome of JAE can be very uncertain.     

Outcome after cortico-amygdalo-hippocampectomy in patients with temporal lobe epilepsy and normal MRI

RationaleWe describe seizure and neuropsychological outcome obtained after CAH in patients with TLE and normal MRI evaluated in the modern imaging era.MethodsForty-five adult consecutive patients with TLE and normal MRI were studied. All patients had neuropsychological testing, interictal and ictal EEG recordings and MRI. They were divided into two groups: Group 1 (n = 18), included patients in whom non-invasive neurophysiological evaluation was lateralizing and Group 2 (n = 27) included patients with non-lateralizing neurophysiological data who were submitted to invasive recordings.ResultsSeventy-seven percent of the Group 1 patients were rated as Engel I; 11% were rated as Engel II and 11% as Engel III. In Group 2, there were 57% of patients seizure-free, 26% in Engel II and 14% in Engel III. Pre-operatively, mean general IQ was 82 and 78 in Groups1 and 2, respectively; post-operatively, mean general IQ was respectively 86 and 71. Some degree of verbal memory decline was noted in all patients submitted to dominant temporal lobe resection in both Groups 1 and 2. At last follow-up visit, 22% of Group 1 and 11% of Group 2 patients were receiving no antiepileptic drugs (AED).ConclusionsOur data showed that patients with TLE and normal MRI could get good surgical results after CAH although 60% of them would need invasive recordings and their results regarding seizure control and cognition were worse than those obtained in patients with MRI defined temporal lobe lesions. Caution should be taken in offering dominant temporal lobe resection to this subset of patients.     

A two-year retrospective evaluation of perampanel in patients with highly drug-resistant epilepsy and cognitive impairment

PurposeThe objective of this work was to review systematically the efficacy and tolerability of perampanel (PER) in residential patients of an epilepsy center.MethodWe adopted an industry-independent noninterventional retrospective evaluation on the basis of the paper and electronic records complemented by personal information on the part of the treating neurologists. All patients (N = 26, 15 females, mean age: 30, range 21–55 years) started on PER from its introduction to the market in September 2012 until December 15th 2013 were included. Evaluation was carried out after 6, 12, and 24 months of PER treatment. Changes in seizure frequency were calculated as the number of seizures during three months on PER compared to a three-month baseline period. The Clinical Global Impression Scale served as an instrument to record changes in seizure intensity beyond numerical values. Adverse effects were documented by means of the Liverpool Adverse Events Profile.ResultsMost patients had structural or metabolic epilepsy, 2 patients suffered from Lennox-Gastaut syndrome, 2 from other symptomatic generalized epilepsy. All patients had grade III drug-resistant epilepsy. All patients had additional cognitive deficits of different degree.The retention rates were 61.5% after 6 months, 46.2% after 12 months, and 42.3% after 24 months. The responder rates were 11.5% after 6 months, 23.1% after 12 months, and 7.7% after 24 months. Partial responders (positive CGI and/or seizure reduction < 50%) included, the respective values were 26.9%, 38.5%, and 23.1%. Only 1 patient was seizure free at 12 months (but not at 24 months). A loss of efficacy in the second year of treatment was suspected but the decrease of the responder rate could also be ascribed to a number of different circumstances. Adverse effects in the psychiatric field like irritability, aggression, increased sensitivity, and suicidal ideation/behavior occurred in 50% of the patients. They were the main reason to discontinue PER.ConclusionsAfter one year of treatment PER showed reasonable efficacy in a particularly difficult-to-treat population. Psychiatric adverse effects forced discontinuation in many cases.