Low prevalence of neural autoantibodies in perioperative cerebrospinal fluid samples of epilepsy surgery patients: A multicenter prospective study.

OBJECTIVE: Refractory epilepsy may have an underlying autoimmune etiology. Our aim was to assess the prevalence of neural autoantibodies in a multicenter national prospective cohort of patients with drug-resistant epilepsy undergoing epilepsy surgery utilizing comprehensive clinical, serologic, and histopathological analyses. METHODS: We prospectively recruited patients undergoing epilepsy surgery for refractory focal epilepsy not caused by a brain tumor from epilepsy surgery centers in the Czech Republic. Perioperatively, we collected cerebrospinal fluid (CSF) and/or serum samples and performed comprehensive commercial and in-house assays for neural autoantibodies. Clinical data were obtained from the patients' medical records, and histopathological analysis of resected brain tissue was performed. RESULTS: Seventy-six patients were included, mostly magnetic resonance imaging (MRI)-lesional cases (74%). Mean time from diagnosis to surgery was 21 ± 13 years. Only one patient (1.3%) had antibodies in the CSF and serum (antibodies against glutamic acid decarboxylase 65) in relevant titers; histology revealed focal cortical dysplasia (FCD) III (FCD associated with hippocampal sclerosis [HS]). Five patients' samples displayed CSF-restricted oligoclonal bands (OCBs; 6.6%): three cases with FCD (one with FCD II and two with FCD I), one with HS, and one with negative histology. Importantly, eight patients (one of them with CSF-restricted OCBs) had findings on antibody testing in individual serum and/or CSF tests that could not be confirmed by complementary tests and were thus classified as nonspecific, yet could have been considered specific without confirmatory testing. Of these, two had FCD, two gliosis, and four HS. No inflammatory changes or lymphocyte cuffing was observed histopathologically in any of the 76 patients. SIGNIFICANCE: Neural autoantibodies are a rare finding in perioperatively collected serum and CSF of our cohort of mostly MRI-lesional epilepsy surgery patients. Confirmatory testing is essential to avoid overinterpretation of autoantibody-positive findings.

Ultrasound-Navigated Multiple Hippocampal Transections: An Anatomical Study.

BACKGROUND: Multiple hippocampal transection (MHT) is a surgical technique used for the treatment of drug-resistant mesial temporal lobe epilepsy in situations where standard procedures would pose a high risk for memory deterioration. During MHT, the longitudinal fibers of the hippocampus, implicated in epilepsy spreading, are interrupted, while the transverse memory circuits are spared. The extent of MHT is governed by intraoperative electrocorticography; abolition of epileptic discharges serves as an end point to terminate the transection. In other words, the aim of MHT is not the anatomical completeness of hippocampal transection. In contrast, we hypothesize that only the complete transection of hippocampal cross-section is needed to durably terminate epilepsy, avoiding possible postoperative reorganization of longitudinal pathways. Here, we report an anatomical study designed to evaluate the feasibility of complete transection of hippocampus with the aid of ultrasound neuronavigation and we propose new instruments to reach this goal. METHODS: Five cadaveric brains were analyzed in this study. MHT was performed on both sides of each brain either with or without ultrasound neuronavigation. The percentage of transected cross-section of the hippocampus was measured using magnetic resonance imaging (MRI) and both sides were compared. RESULTS: The ultrasound-guided MHTs were more likely to achieve complete hippocampal transection compared with the nonnavigated MHT transection (73 vs 58%; p < 0.01). Our study also allowed us to propose specialized transectors to minimize invasivity of this procedure. CONCLUSION: Completeness of MHT can be better reached with the aid of an ultrasound neuronavigation system; modified instruments for this procedure were also designed.

One-year neuropsychological outcome after temporal lobe epilepsy surgery in large Czech sample: Search for factors contributing to memory decline.

Background: Assessment of cognitive functions is an integral part of the evaluation the efficacy of temporal resections. We studied postoperative neuropsychological changes and factors contributing to worse memory outcomes in patients who experienced a significant decline using reliable change indices. Methods: We prospectively studied 110 patients in whom we indicated anteromesial temporal resection (AMTR) and 46 patients who underwent selective amygdalohippocampectomy (SAHE). We administrated Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, and the Verbal Fluency Test before and 1 year after the operation. Results: At a group level, we did not observe any statistically significant changes in global, verbal, and visual MQ in either the AMTR or the SAHE group. At an individual level, we found a mean decrease of verbal MQ after left-sided AMTR by -4.43 points (P = 0.01). We detected no significant differences between the left and right side of surgery in the SAHE group. In patients with significant postoperative memory decline, we found either pre-existing extrahippocampal deficits/postoperative complications or incomplete hippocampal resection or a combination of these factors. Conclusion: In addition to the side of surgery, structural integrity and functional adequacy of resected hippocampus and volume of resected tissue and preoperative extrahippocampal lesions/postoperative complications also contribute to postoperative memory decline after temporal lobe epilepsy surgery.

Eighteen years' experience with tumor treating fields in the treatment of newly diagnosed glioblastoma.

Introduction: The prognosis of glioblastoma remains unfavorable. TTFields utilize low intensity electric fields (frequency 150-300 kHz) that disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields are delivered via transducer arrays placed on the patients' scalp. Methods: Between the years 2004 and 2022, 55 patients (20 female), aged 21.9-77.8 years (mean age 47.3±11.8 years; median 47.6 years) were treated with TTFields for newly-diagnosed GBM, and compared to 54 control patients (20 females), aged 27.0-76.7 years (mean age 51.4±12.2 years; median 51.7 years) (p=0.08). All patients underwent gross total or partial resection of GBM. One patient had biopsy only. When available, MGMT promoter methylation status and IDH mutation was detected. Results: Patients on TTFields therapy demonstrated improvements in PFS and OS relative to controls (hazard ratio: 0.64, p=0.031; and 0.61, p=0.028 respectively). TTFields average time on therapy was 74.8% (median 82%): median PFS of these patients was 19.75 months. Seven patients with TTFields usage ≤60% (23-60%, mean 46.3%, median 53%) had a median PFS of 7.95 months (p=0.0356). Control patients with no TTFields exposure had a median PFS of 12.45 months. Median OS of TTF patients was 31.67 months compared to 24.80 months for controls. Discussion: This is the most extensive study on newly-diagnosed GBM patients treated with TTFields, covering a period of 18 years at a single center and presenting not only data from clinical trials but also a group of 36 patients treated with TTFields as a part of routine clinical practice.

Evidences for a Role of Gut Microbiota in Pathogenesis and Management of Epilepsy.

Epilepsy as a chronic neurological disorder is characterized by recurrent, unprovoked epileptic seizures. In about half of the people who suffer from epilepsy, the root cause of the disorder is unknown. In the other cases, different factors can cause the onset of epilepsy. In recent years, the role of gut microbiota has been recognized in many neurological disorders, including epilepsy. These data are based on studies of the gut microbiota-brain axis, a relationship starting by a dysbiosis followed by an alteration of brain functions. Interestingly, epileptic patients may show signs of dysbiosis, therefore the normalization of the gut microbiota may lead to improvement of epilepsy and to greater efficacy of anticonvulsant drugs. In this descriptive review, we analyze the evidences for the role of gut microbiota in epilepsy and hypothesize a mechanism of action of these microorganisms in the pathogenesis and treatment of the disease. Human studies revealed an increased prevalence of Firmicutes in patients with refractory epilepsy. Exposure to various compounds can change microbiota composition, decreasing or exacerbating epileptic seizures. These include antibiotics, epileptic drugs, probiotics and ketogenic diet. Finally, we hypothesize that physical activity may play a role in epilepsy through the modulation of the gut microbiota.

Magnetic resonance markers of bilateral neuronal metabolic dysfunction in patients with unilateral internal carotid artery occlusion.

OBJECTIVES: To evaluate cerebral hemodynamic, metabolic and anatomic changes occurring in patients with unilateral occlusion of the internal carotid artery (ICA). MATERIALS AND METHODS: Twenty-two patients with unilateral occlusion of ICA and twenty age and sex matched healthy subjects were included in the study. Single voxel proton magnetic resonance spectroscopy (1H-MRS) of the centrum semiovale, semi-automated hippocampal volumetry in T1-weighted scans and transcranial Doppler examination (TCD) with calculation of Breath Holding Index (BHI) were performed in both groups. Metabolic, anatomic, and hemodynamic features were compared between the two groups. RESULTS: The N-acetylaspartate (NAA)/choline (Cho) ratio was significantly lower in both hemispheres of enrolled patients compared to controls (p = 0.005 for the side with occlusion, p = 0.04 for the side without occlusion). The hippocampus volume was significantly reduced bilaterally in patients compared to healthy subjects (p = 0.049). A statistically significant difference in BHI values was observed between the side with occlusion and without occlusion (p = 0.037) of the patients, as well as between BHI values of the side with occlusion and healthy volunteers (p = 0.014). DISCUSSION: Patients with unilateral ICA occlusion have reduced NAA/Cho ratio in the white matter of both hemispheres and have bilateral atrophy of hippocampus. The alteration of hemodynamics alone cannot explain these changes.

Ruptured Thoracolumbar Perimedullary Arteriovenous Fistula during Pregnancy Complicated by Cerebral Subarachnoid Hemorrhage and Brainstem Hematoma: A Case Report.

Intradural spinal arteriovenous fistulas (sAVF) are spinal vascular lesions that usually manifest due to myelopathy or local symptoms caused by venous congestion and ischemia. In addition, perimedullary arteriovenous fistulas (PMAVF) in particular may rupture and cause subarachnoid or intramedullary hemorrhage along with relevant symptoms. Subarachnoid hemorrhage (SAH) can propagate into cranial space with clinically dominant symptoms and signs of typical aneurysmal intracranial SAH. The standard workup for cerebral SAH, after excluding an intracranial source of hemorrhage, is usually limited to a cervical spine MRI; therefore, thoracolumbar sources of hemorrhage can be missed, or their diagnosis may be delayed. Here we present a case of a pregnant patient who presented with cerebral SAH. The source of hemorrhage was not initially identified, leading to a presumptive diagnosis of benign pretruncal non-aneurysmal SAH. The correct diagnosis of spinal thoracolumbar PMAVF was revealed 2.5 months later due to the progression of local symptoms. While the diagnosis was being refined and endovascular treatment was being planned (but delayed due to pregnancy), there was a recurrence of intraconal hemorrhage followed by brainstem hemorrhage. This led to significant clinical deterioration. The PMAVF was then treated microsurgically and the patient experienced partial recovery.

Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE: Tumor-treating fields (TTFields) therapy improves both progression-free and overall survival in patients with glioblastoma. There is a need to assess the influence of TTFields on patients' health-related quality of life (HRQoL). OBJECTIVE: To examine the association of TTFields therapy with progression-free survival and HRQoL among patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of EF-14, a phase 3 randomized clinical trial, compares TTFields and temozolomide or temozolomide alone in 695 patients with glioblastoma after completion of radiochemotherapy. Patients with glioblastoma were randomized 2:1 to combined treatment with TTFields and temozolomide or temozolomide alone. The study was conducted from July 2009 until November 2014, and patients were followed up through December 2016. INTERVENTIONS: Temozolomide, 150 to 200 mg/m2/d, was given for 5 days during each 28-day cycle. TTFields were delivered continuously via 4 transducer arrays placed on the shaved scalp of patients and were connected to a portable medical device. MAIN OUTCOMES AND MEASURES: Primary study end point was progression-free survival; HRQoL was a predefined secondary end point, measured with questionnaires at baseline and every 3 months thereafter. Mean changes from baseline scores were evaluated, as well as scores over time. Deterioration-free survival and time to deterioration were assessed for each of 9 preselected scales and items. RESULTS: Of the 695 patients in the study, 639 (91.9%) completed the baseline HRQoL questionnaire. Of these patients, 437 (68.4%) were men; mean (SD) age, 54.8 (11.5) years. Health-related quality of life did not differ significantly between treatment arms except for itchy skin. Deterioration-free survival was significantly longer with TTFields for global health (4.8 vs 3.3 months; P < .01); physical (5.1 vs 3.7 months; P < .01) and emotional functioning (5.3 vs 3.9 months; P < .01); pain (5.6 vs 3.6 months; P < .01); and leg weakness (5.6 vs 3.9 months; P < .01), likely related to improved progression-free survival. Time to deterioration, reflecting the influence of treatment, did not differ significantly except for itchy skin (TTFields worse; 8.2 vs 14.4 months; P < .001) and pain (TTFields improved; 13.4 vs 12.1 months; P < .01). Role, social, and physical functioning were not affected by TTFields. CONCLUSIONS AND RELEVANCE: The addition of TTFields to standard treatment with temozolomide for patients with glioblastoma results in improved survival without a negative influence on HRQoL except for more itchy skin, an expected consequence from the transducer arrays. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

Late morphological changes after radiosurgery of brain arteriovenous malformations: an MRI study.

BACKGROUND: Radiosurgery by Gamma Knife (GK) is an effective treatment for brain arteriovenous malformations (AVM). The aim of the present study was to evaluate late, radiation-induced changes detectable by MRI after AVM radiosurgery in patients treated minimally 10 years prior, with AVM obliteration proven by angiography. METHODS: Thirty-five patients with 37 AVMs were included. AVMs were irradiated 16.6 ± 3.5 years prior with AVM obliteration proven 13 ± 4 years prior. All patients underwent recent MRI examinations, including application of gadolinium-based contrast. RESULTS: In one case, post-irradiative cystic formation with mass effect and signs of hemorrhage requiring surgery was found. Post-gadolinium enhancement at the site of obliterated nidi was apparent in 28 of 37 cases (76 %). In all cases except one, the mean volume of enhancement at the time of review was clearly lower than the volume of the originally irradiated AVM (88 ± 20 %; median 92 %); in one case the extent was 142 % greater than the irradiated AVM. When we compared enhancing and non-enhancing nidi, we found that enhancing nidi were significantly larger than non-enhancing nidi at the time of radiosurgery (4.39 ± 3.35 cc vs. 0.89 ± 0.79 cc, p = 0.004). Enhancement was not influenced by total radiation dose, patient age at the time of irradiation, duration since radiosurgery, or the number of irradiations. Wallerian degeneration was found in nine of 37 cases (24 %); in six cases the optical tracts were affected and visual field defects were proven. In five of nine cases (55.6 %) with Wallerian degeneration previous hemorrhage was present. Dual vascular pathology was found in eight of 35 patients (23 %). CONCLUSIONS: GK radiosurgery for AVM is a safe treatment method although delayed complications may occur. Post-gadolinium enhancement of obliterated nidi may indicate an active post-irradiative process.

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

Relationship between remnant hippocampus and amygdala and memory outcomes after stereotactic surgery for mesial temporal lobe epilepsy.

BACKGROUND AND PURPOSE: Mesial temporal structures play an important role in human memory. In mesial temporal lobe epilepsy (MTLE), seizure activity is generated from the same structures. Surgery is the definitive treatment for medically intractable MTLE. In addition to standard temporal lobe microsurgical resection, stereotactic radiofrequency amygdalohippocampectomy (SAHE) is used as an alternative MTLE treatment. While memory impairments after standard epilepsy surgery are well known, it has been shown that memory decline is not a feature of SAHE. The aim of the present study was to correlate the volume of the remnant hippocampus and amygdala in patients treated by SAHE with changes in memory parameters. MATERIALS AND METHODS: Thirty-seven MTLE patients treated by SAHE (ten right, 27 left) were included. Patients underwent magnetic resonance imaging examinations including hippocampal and amygdalar volumetry and neuropsychological evaluation preoperatively and 1 year after surgery. RESULTS: Using Spearman correlation analyses, larger left-sided hippocampal reductions were associated with lower verbal memory performance (ρ=-0.46; P=0.02). On the contrary, improvement of global memory quotient (MQ) was positively correlated with larger right-sided hippocampal reduction (ρ=0.66; P=0.04). Similarly, positive correlations between the extent of right amygdalar reduction and verbal MQ (ρ=0.74; P=0.02) and global MQ change (ρ=0.69; P=0.03) were found. Thus, larger right hippocampal and amygdalar reduction was associated with higher global and verbal MQ change after SAHE. CONCLUSION: Larger left-sided hippocampal reductions were associated with lower verbal memory performance. This finding is in accordance with the material-specific model of human memory, which states that the dominant hemisphere is specialized for the learning and recall of verbal information. We hypothesize that larger right-sided ablations enable the left temporal lobe to support memory more effectively, perhaps as a consequence of epileptiform discharges spreading from remnants of right mesiotemporal structures to the left.

Morphological changes after radiosurgery for mesial temporal lobe epilepsy.

BACKGROUND: To review our experience with morphological developments during the long-term follow-up of patients treated by Gamma Knife radiosurgery for mesial temporal lobe epilepsy. METHOD: Between 1995 and 1999, we treated 14 patients with marginal doses of 24 Gy (n = 6) and 18-20 Gy (n = 8). Nine of these were operated on for insufficient seizure control. We reviewed seizure outcome and magnetic resonance images in both operated and unoperated patients and also re-examined histopathology specimens. RESULTS: Of the nine operated patients, two were Engel IIIA, one was IVA, five were IVB, and one was Engel IVC prior to surgery. At their final visit, five cases had become Engel class IA, one patient was ID, and two were IIC. In one patient the follow-up was not long enough for classification. Of the five unoperated patients, one was Engel class IB, one was IIIA, one IIB and one IVB at their final visit. Radionecrosis developed in 11 patients, occurring more often and earlier in those treated with higher doses. Collateral edema reached outside the temporal lobe in six patients, caused uncal herniation in two and intracranial hypertension in three. During longer follow-up, postnecrotic pseudocysts developed in 9 patients, and postcontrast enhancement persisted for 2.5-16 years after GKRS in all 14 patients. In five of them we detected its progression between 2 and 16 years after treatment. Signs of neoangiogenesis were found in two patients and microbleeds could be seen in five. Histopathology revealed blood vessel proliferation and macrophage infiltration. CONCLUSIONS: Early delayed complications and morphological signs suggesting a risk of development of late delayed complications are frequent after radiosurgery for mesial temporal lobe epilepsy. Together with its unproven antiseizure efficacy, these issues should be taken into account when planning future studies of this method.

Different surgical approaches for mesial temporal epilepsy: resection extent, seizure, and neuropsychological outcomes.

BACKGROUND: Surgical therapy of intractable mesial temporal lobe epilepsy (MTLE) is an effective and well-established treatment. OBJECTIVES: We compared two different surgical approaches, standard microsurgical anterior temporal resection (ATL) and stereotactic radiofrequency amygdalohippocampectomy (SAHE) for MTLE, with respect to the extent of resection or destruction, clinical outcomes, and complications. MATERIAL AND METHODS: 75 MTLE patients were included: 41 treated by SAHE (11 right sided, 30 left sided) and 34 treated by ATL (21 right sided, 13 left sided). RESULTS: SAHE and ATL seizure control were comparable (Engel I in 75.6 and 76.5% 2 years after surgery and 79.3 and 76.5% 5 years after procedures, respectively). The neuropsychological results of SAHE patients were better than in ATL. In SAHE patients, no memory deficit was found. Hippocampal (60.6 ± 18.7%) and amygdalar (50.3 ± 21.9%) volume reduction by SAHE was significantly lower than by ATL (86.0 ± 12.7% and 80.2 ± 20.9%, respectively). The overall rate of surgical nonsilent complications without permanent neurological deficit after ATL was 11.8%, and another 8.8% silent infarctions were found on MRI. The rate of clinically manifest complications after SAHE was 4.9%. The rate of visual field defects after SAHE was expectably less frequent than after ATL. CONCLUSION: Seizure control by SAHE was comparable to ATL. However, SAHE was safer with better neuropsychological results.

Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields.

Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor, and has a median survival of only 10 to 14 months with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only five to seven months with optimal therapy. Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence.