Prevalence of Liver Steatosis in Tuberous Sclerosis Complex Patients: A Retrospective Cross-Sectional Study.

Introduction: Tuberous sclerosis complex (TSC) is a genetic disease caused by pathogenetic variants in either the TSC1 or TSC2 genes. Consequently, the mechanistic target of the rapamycin complex 1 (mTORC1) pathway, a regulator of cell growth, metabolism, and survival, becomes inappropriately activated, leading to the development of benign tumors in multiple organs. The role of mTORC1 in lipid metabolism and liver steatosis in TSC patients has not been well-studied, and clinical data on liver involvement in this population are scarce. Methods: We conducted a retrospective, cross-sectional study to compare liver steatosis in TSC patients with age-, sex-, BMI-, and diabetes status-matched controls. Participants with a definite diagnosis of TSC were recruited from the TSC clinic at UZ Brussel. Liver steatosis was quantified using the fat signal fraction from in-phase and out-of-phase MRI, with a threshold of ≥5% defining the presence of steatosis. We also evaluated the prevalence of liver angiomyolipomata in the TSC group and analyzed risk factors for both liver steatosis and angiomyolipomata. Results: The study included 59 TSC patients and 59 matched controls. The mean fat signal fraction was 4.0% in the TSC group and 3.9% in the controls, showing no significant difference (two-tailed Wilcoxon signed ranks test, p = 0.950). Liver steatosis was observed in 15.3% of TSC patients compared to 23.7% of the controls, which was not statistically significant (two-tailed McNemar test, p = 0.267). Liver angiomyolipomata were identified in 13.6% of the TSC cohort. Conclusions: Our study, describing in detail the liver phenotype of TSC patients, did not reveal a significant difference in the prevalence of MRI-assessed liver steatosis in a large cohort of TSC patients compared to a closely matched control group.

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method.

BACKGROUND: Epileptic seizures are an established comorbidity of Alzheimer's disease (AD). Subclinical epileptiform activity (SEA) as detected by 24-h electroencephalography (EEG) or magneto-encephalography (MEG) has been reported in temporal regions of clinically diagnosed AD patients. Although epileptic activity in AD probably arises in the mesial temporal lobe, electrical activity within this region might not propagate to EEG scalp electrodes and could remain undetected by standard EEG. However, SEA might lead to faster cognitive decline in AD. AIMS: 1. To estimate the prevalence of SEA and interictal epileptic discharges (IEDs) in a well-defined cohort of participants belonging to the AD continuum, including preclinical AD subjects, as compared with cognitively healthy controls. 2. To evaluate whether long-term-EEG (LTM-EEG), high-density-EEG (hd-EEG) or MEG is superior to detect SEA in AD. 3. To characterise AD patients with SEA based on clinical, neuropsychological and neuroimaging parameters. METHODS: Subjects (n = 49) belonging to the AD continuum were diagnosed according to the 2011 NIA-AA research criteria, with a high likelihood of underlying AD pathophysiology. Healthy volunteers (n = 24) scored normal on neuropsychological testing and were amyloid negative. None of the participants experienced a seizure before. Subjects underwent LTM-EEG and/or 50-min MEG and/or 50-min hd-EEG to detect IEDs. RESULTS: We found an increased prevalence of SEA in AD subjects (31%) as compared to controls (8%) (p = 0.041; Fisher's exact test), with increasing prevalence over the disease course (50% in dementia, 27% in MCI and 25% in preclinical AD). Although MEG (25%) did not withhold a higher prevalence of SEA in AD as compared to LTM-EEG (19%) and hd-EEG (19%), MEG was significantly superior to detect spikes per 50 min (p = 0.002; Kruskall-Wallis test). AD patients with SEA scored worse on the RBANS visuospatial and attention subset (p = 0.009 and p = 0.05, respectively; Mann-Whitney U test) and had higher left frontal, (left) temporal and (left and right) entorhinal cortex volumes than those without. CONCLUSION: We confirmed that SEA is increased in the AD continuum as compared to controls, with increasing prevalence with AD disease stage. In AD patients, SEA is associated with more severe visuospatial and attention deficits and with increased left frontal, (left) temporal and entorhinal cortex volumes. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04131491. 12/02/2020.

Low-Dose Bevacizumab for the Treatment of Focal Radiation Necrosis of the Brain (fRNB): A Single-Center Case Series.

Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5-7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation.

Accurate detection of typical absence seizures in adults and children using a two-channel electroencephalographic wearable behind the ears.

OBJECTIVE: Patients with absence epilepsy sensitivity <10% of their absences. The clinical gold standard to assess absence epilepsy is a 24-h electroencephalographic (EEG) recording, which is expensive, obtrusive, and time-consuming to review. We aimed to (1) investigate the performance of an unobtrusive, two-channel behind-the-ear EEG-based wearable, the Sensor Dot (SD), to detect typical absences in adults and children; and (2) develop a sensitive patient-specific absence seizure detection algorithm to reduce the review time of the recordings. METHODS: We recruited 12 patients (median age = 21 years, range = 8-50; seven female) who were admitted to the epilepsy monitoring units of University Hospitals Leuven for a 24-h 25-channel video-EEG recording to assess their refractory typical absences. Four additional behind-the-ear electrodes were attached for concomitant recording with the SD. Typical absences were defined as 3-Hz spike-and-wave discharges on EEG, lasting 3 s or longer. Seizures on SD were blindly annotated on the full recording and on the algorithm-labeled file and consequently compared to 25-channel EEG annotations. Patients or caregivers were asked to keep a seizure diary. Performance of the SD and seizure diary were measured using the F1 score. RESULTS: We concomitantly recorded 284 absences on video-EEG and SD. Our absence detection algorithm had a sensitivity of .983 and false positives per hour rate of .9138. Blind reading of full SD data resulted in sensitivity of .81, precision of .89, and F1 score of .73, whereas review of the algorithm-labeled files resulted in scores of .83, .89, and .87, respectively. Patient self-reporting gave sensitivity of .08, precision of 1.00, and F1 score of .15. SIGNIFICANCE: Using the wearable SD, epileptologists were able to reliably detect typical absence seizures. Our automated absence detection algorithm reduced the review time of a 24-h recording from 1-2 h to around 5-10 min.

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial.

BACKGROUND: Patients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30-39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated. METHODS: Within 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue. RESULTS: Twenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1-4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2-152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029). CONCLUSION: IC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS. TRIAL REGISTRATION: NCT03233152.

Anti-NMDA-receptor encephalitis: an unusual treatable cause of chronic insomnia?

We describe an unusual case of severe and chronic insomnia that proved to be eminently treatable. Initially presumed to be of primary psychiatric/toxicological origin, certain clinical and paraclinical clues led us to the diagnosis of NMDA-receptor encephalitis, an immune-mediated disease of the brain. Our patient responded dramatically to immunotherapy, effectively regaining normal sleep habits and significantly improving his general and mental health after 25 years of insomnia and drug abuse. Immune-mediated encephalopathies should be considered in the differential diagnosis of severe sleep disorders that present with additional neurological signs and symptoms, even when chronic.

Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx).

BACKGROUND: No treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB. METHODS: Adult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint. RESULTS: Between June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0-1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events. CONCLUSION: The combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.

Encephalitis associated with the SARS-CoV-2 virus: A case report.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) usually causes fever, respiratory symptoms, malaise and myalgia. Recent observations suggested possible neurological complications of COVID-19, including the first report of suspected viral encephalitis. We report a case of a 29-year-old male with -on nasopharyngeal testing- confirmed SARS-CoV-2 infection with severe respiratory symptoms, followed by clinical and radiological signs of encephalitis. Magnetic resonance imaging (MRI) of the brain showed an asymmetric FLAIR-hyperintensity of the left medial temporal cortex associated with mild gyral expansion. Lumbar puncture was normal and PCR's for SARS-CoV-2 virus on CSF were negative. Clinicians treating SARS-CoV-2 infected patients should be aware of possible neurological complications, like encephalitis. The diagnosis of SARS-CoV-2 encephalitis is difficult as CSF analysis may be normal.

Optimized preoperative motor cortex mapping in brain tumors using advanced processing of transcranial magnetic stimulation data.

BACKGROUND AND OBJECTIVE: Transcranial magnetic stimulation (TMS) is a useful technique to help localize motor function prior to neurosurgical procedures. Adequate modelling of the effect of TMS on the brain is a prerequisite to obtain reliable data. METHODS: Twelve patients were included with perirolandic tumors to undergo TMS-based motor mapping. Several models were developed to analyze the mapping data, from a projection to the nearest brain surface to motor evoked potential (MEP) amplitude informed weighted average of the induced electric fields over a multilayer detailed individual head model. The probability maps were compared with direct cortical stimulation (DCS) data in all patients for the hand and in three for the foot. The gold standard was defined as the results of the DCS sampling (with on average 8 DCS-points per surgery) extrapolated over the exposed cortex (of the tailored craniotomy), and the outcome parameters were based on the similarity of the probability maps with this gold standard. RESULTS: All models accurately gauge the location of the motor cortex, with point-cloud based mapping algorithms having an accuracy of 83-86%, with similarly high specificity. To delineate the whole area of the motor cortex representation, the model based on the weighted average of the induced electric fields calculated with a realistic head model performs best. The optimal single threshold to visualize the field based maps is 40% of the maximal value for the anisotropic model and 50% for the isotropic model, but dynamic thresholding adds information for clinical practice. CONCLUSIONS: The method with which TMS mapping data are analyzed clearly affects the predicted area of the primary motor cortex representation. Realistic electric field based modelling is feasible in clinical practice and improves delineation of the motor cortex representation compared to more simple point-cloud based methods.

Early-Onset Creutzfeldt-Jakob Disease Mimicking Immune-Mediated Encephalitis.

OBJECTIVES: The objective of this study is to explore the clinical, radiological, and pathological manifestations of a rare subtype of prion disease and their implication for differential diagnosis in case of an early onset neuropsychiatric deterioration. METHODS: We discuss a patients' clinical history, as well as the string of investigations and symptomatological evolution that finally led to a pathological diagnosis. RESULTS: Our patient had the extremely rare VV1 type sporadic Creutzfeldt-Jakob disease (sCJD). We explain the differential diagnosis of progressive encephalomyelitis with rigidity and myoclonus and its implications for treatment. CONCLUSION: sCJD, especially the VV1 subtype, can present at an early age with an insidious psychiatric onset. Classical findings of prion disease-14-3-3 protein, PSWC on electroencephalography, and magnetic resonance imaging patterns-are not always present. The presence of neural autoantibodies does not always implicate pathogenicity in the presence of other neurological/neurodegenerative conditions.

Publisher Correction: Using high-amplitude and focused transcranial alternating current stimulation to entrain physiological tremor.

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Correlation of neuropsychological and metabolic changes after epilepsy surgery in patients with left mesial temporal lobe epilepsy with hippocampal sclerosis.

BACKGROUND: Epilepsy surgery often causes changes in cognition and cerebral glucose metabolism. Our aim was to explore relationships between pre- and postoperative cerebral metabolism as measured with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological test scores in patients with left mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), who were rendered seizure-free after epilepsy surgery. RESULTS: Thirteen patients were included. All had neuropsychological testing and an interictal FDG-PET scan of the brain pre- and postoperative. Correlations between changes in neuropsychological test scores and metabolism were examined using statistical parametric mapping (SPM). There were no significant changes in the neuropsychological test scores pre- and postoperatively at the group level. Decreased metabolism was observed in the left mesial temporal regions and occipital lobe. Increased metabolism was observed in the bi-frontal and right parietal lobes, temporal lobes, occipital lobes, thalamus, cerebellum, and vermis. In these regions, we did not find a correlation between changes in metabolism and neuropsychological test scores. A significant negative correlation, however, was found between metabolic changes in the precuneus and Boston Naming Test (BNT) scores. CONCLUSIONS: There are significant metabolic decreases in the left mesial temporal regions and increases in the bi-frontal lobes; right parietal, temporal, and occipital lobes; right thalamus; cerebellum; and vermis in patients with left MTLE-HS who were rendered seizure-free after epilepsy surgery. We could not confirm that these changes translate into significant cognitive changes. A significant negative correlation was found between changes in confrontation naming and changes in metabolism in the precuneus. We speculate that the precuneus may play a compensatory role in patients with postoperative naming difficulties after left TLE surgery. Understanding of these neural mechanisms may aid in designing cognitive rehabilitation strategies.

Using high-amplitude and focused transcranial alternating current stimulation to entrain physiological tremor.

Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation method that can entrain physiological tremor in healthy volunteers. We conducted two experiments to investigate the effectiveness of high-amplitude and focused tACS montages at entraining physiological tremor. Experiment 1 used saline-soaked sponge electrodes with an extra-cephalic return electrode and compared the effects of a motor (MC) and prefrontal cortex (PFC) electrode location. Average peak-amplitude was 1.925 mA. Experiment 2 used gel-filled cup-electrodes in a 4 × 1 focused montage and compared the effects of MC and occipital cortex (OC) tACS. Average peak-amplitude was 4.45 mA. Experiment 1 showed that unfocused MC and PFC tACS both produced phosphenes and significant phase entrainment. Experiment 2 showed that focused MC and OC tACS produced no phosphenes but only focused MC tACS caused significant phase entrainment. At the group level, tACS did not have a significant effect on tremor amplitude. However, with focused tACS there was a significant correlation between phase entrainment and tremor amplitude modulation: subjects with higher phase entrainment showed more tremor amplitude modulation. We conclude that: (1) focused montages allow for high-amplitude tACS without phosphenes and (2) high amplitude focused tACS can entrain physiological tremor.

Electrocorticography of Spatial Shifting and Attentional Selection in Human Superior Parietal Cortex.

Spatial-attentional reorienting and selection between competing stimuli are two distinct attentional processes of clinical and fundamental relevance. In the past, reorienting has been mainly associated with inferior parietal cortex. In a patient with a subdural grid covering the upper and lower bank of the left anterior and middle intraparietal sulcus (IPS) and the superior parietal lobule (SPL), we examined the involvement of superior parietal cortex using a hybrid spatial cueing paradigm identical to that previously applied in stroke and in healthy controls. In SPL, as early as 164 ms following target onset, an invalidly compared to a validly cued target elicited a positive event-related potential (ERP) and an increase in intertrial coherence (ITC) in the theta band, regardless of the direction of attention. From around 400-650 ms, functional connectivity [weighted phase lag index (wPLI) analysis] between SPL and IPS briefly inverted such that SPL activity was driving IPS activity. In contrast, the presence of a competing distracter elicited a robust change mainly in IPS from 300 to 600 ms. Within superior parietal cortex reorienting of attention is associated with a distinct and early electrophysiological response in SPL while attentional selection is indexed by a relatively late electrophysiological response in the IPS. The long latency suggests a role of IPS in working memory or cognitive control rather than early selection.

Randomized crossover sham-controlled clinical trial of targeted low-frequency transcranial magnetic stimulation comparing a figure-8 and a round coil to treat refractory neocortical epilepsy.

OBJECTIVE: Determine the efficacy and side effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) to treat refractory neocortical epilepsy and study differences in effect between a figure-8 and round coil type. METHODS: This single-center randomized sham-controlled crossover trial (NCT01745952 on ClinicalTrials.gov) included 11 patients with well-defined focal epilepsy. rTMS (0.5 Hz) was targeted to the focus during three treatment conditions consisting of 1,500 stimulations/day for 10 weekdays at 90% of resting motor threshold (rMT) followed by a 10-week observation period. Patients were randomized for the order in which the figure-8, round, and sham coil were used. Outcome assessors and patients were blinded to the type of coil used. The primary outcome measure was the percentage of seizure reduction after active rTMS treatment. Other outcome measures were responder rate, quality of life, and side effects. RESULTS: There was no difference between a figure-8 and round coil. None of the patients achieved an overall 50% seizure reduction. One patient responded during 1 month after treatment with either active coil, followed by a significant increase in seizure frequency. Another patient had a fourfold increase in seizure frequency during rTMS treatment. SIGNIFICANCE: This study provides evidence that rTMS is on average not effective for reducing seizure frequency. No difference in effectiveness between the different coil types was observed. It can, however, exacerbate seizures during treatment and lead to a rebound in seizure frequency after an initial reduction.