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Study design Multicentre-observational study. Objectives The 6-minute walk test (6mWT) is an established assessment of walking function in individuals with spinal cord injury (SCI). However, walking 6 min can be demanding for severely impaired individuals. The 2-minute walk test (2mWT) could be an appropriate alternative that has already been validated in other neurological disorders. The aim of this study was to assess construct validity and test-rest reliability of the 2mWT in individuals with SCI. In addition, the influence of walking performance on sensitivity to change of the 2mWT was assessed. Setting Swiss Paraplegic Center Nottwil, Switzerland; Balgrist University Hospital, Zürich, Switzerland. Methods Fifty individuals (aged 18–79) with SCI (neurological level of injury: C1-L3, AIS: A-D) were assessed on two test days separated by 1 to 7 days. The first assessment consisted of a 2mWT familiarization, followed by a 2mWT and 10-meter walk test (10MWT) (including the Walking Index for Spinal Cord Injury (WISCI II)) in randomized order. The second assessment consisted of 2mWT and 6mWT in randomized order. Tests were separated by at least 30 min of rest. Results The interclass correlation coefficient between the 2mWT assessed on the first and second test day was excellent (r = 0.980, p r = 0.992, p r = 0.964, p r = 0.571, p Conclusion The 2mWT is a valid and reliable alternative to the 6mWT to measure walking function in individuals with SCI. Trial registration NCT04555759.

Background Life-space mobility is defined as the size of the area in which a person moves about within a specified period of time. Our study aimed to characterize life-space mobility, identify factors associated with its course, and detect typical trajectories in the first year after ischemic stroke. Methods MOBITEC-Stroke (ISRCTN85999967; 13/08/2020) was a cohort study with assessments performed 3, 6, 9 and 12 months after stroke onset. We applied linear mixed effects models (LMMs) with life-space mobility (Life-Space Assessment; LSA) as outcome and time point, sex, age, pre-stroke mobility limitation, stroke severity (National Institutes of Health Stroke Scale; NIHSS), modified Rankin Scale, comorbidities, neighborhood characteristics, availability of a car, Falls Efficacy Scale-International (FES-I), and lower extremity physical function (log-transformed timed up-and-go; TUG) as independent variables. We elucidated typical trajectories of LSA by latent class growth analysis (LCGA) and performed univariate tests for differences between classes. Results In 59 participants (mean age 71.6, SD 10.0 years; 33.9% women), mean LSA at 3 months was 69.3 (SD 27.3). LMMs revealed evidence (p ≤ 0.05) that pre-stroke mobility limitation, NIHSS, comorbidities, and FES-I were independently associated with the course of LSA; there was no evidence for a significant effect of time point. LCGA revealed three classes: “low stable”, “average stable”, and “high increasing”. Classes differed with regard to LSA starting value, pre-stroke mobility limitation, FES-I, and log-transformed TUG time. Conclusion Routinely assessing LSA starting value, pre-stroke mobility limitation, and FES-I may help clinicians identify patients at increased risk of failure to improve LSA.

Purpose Glioblastoma is the most common brain tumor in adults and is virtually incurable. Therefore, new therapeutic strategies are urgently needed. Over the last decade, multiple growth-promoting functions have been attributed to CD95, a prototypic death receptor well characterized as an apoptosis mediator upon CD95L engagement. Strategic targeting of non-apoptotic or apoptotic CD95 signaling may hold anti-glioblastoma potential. Due to its antithetic nature, understanding the constitutive role of CD95 signaling in glioblastoma is indispensable. Methods We abrogated constitutive Cd95 and Cd95l gene expression by CRISPR/Cas9 in murine glioma models and characterized the consequences of gene deletion in vitro and in vivo. Results Expression of canonical CD95 but not CD95L was identified in mouse glioma cells in vitro. Instead, a soluble isoform-encoding non-canonical Cd95l transcript variant was detected. In vivo, an upregulation of the membrane-bound canonical CD95L form was revealed. Cd95 or Cd95l gene deletion decreased cell growth in vitro. The growth-supporting role of constitutive CD95 signaling was validated by Cd95 re-transfection, which rescued growth. In vivo, Cd95 or Cd95l gene deletion prolonged survival involving tumor-intrinsic and immunological mechanisms in the SMA-497 model. In the GL-261 model, that expresses no CD95, only CD95L gene deletion prolonged survival, involving a tumor-intrinsic mechanism. Conclusion Non-canonical CD95L/CD95 interactions are growth-promoting in murine glioma models, and glioma growth and immunosuppression may be simultaneously counteracted by Cd95l gene silencing.

Background Sex-related differences in patients with aneurysmal subarachnoid hemorrhage (aSAH) exist. More females than males are affected. Aneurysm location is associated to sex. The relationship between sex and outcome, however, is unclear. Possible differences in management might influence the occurrence of primary and secondary brain injury and thus outcome. The study compares demographics, intensity of treatment, complications, and outcome among females and males with aSAH. Methods All consecutive patients with aSAH admitted to the neurocritical care unit, University Hospital Zurich over a 5-year period were eligible in this retrospective study. Patients’ characteristics, comorbidities, aSAH severity, frequency of vasospasm/delayed cerebral ischemia, frequency of invasive interventions, and 3-month outcome were compared by sex. Univariate analysis was performed with the data dichotomized by sex, and outcome. Multivariate analysis for prediction of outcomes was performed. Results Three hundred forty-eight patients were enrolled (64% females). Women were older than men. Comorbidities, scores at admission, and treatment modality were comparable among males and females. Vasospasm and DCI occurred similarly among females and males. Interventions and frequency of intraarterial spasmolysis were comparable between sexes. In the multivariate analysis, increasing age, female sex, increasing comorbidities, WFNS and Fisher grade, and presence of delayed cerebral ischemia were predictors of unfavorable outcome when considering all patients. However, after excluding death as a possible outcome, sex did not remain a predictor of unfavorable outcome. Conclusions In the study population, women with aSAH might have present a worse outcome at 3 months. However, no differences by sex that might explain this difference were found in intensity of treatment and management.

Objectives The manuscript serves as an update on the current management practices for infantile spasm syndrome (ISS). It includes a detailed summary of the level of current evidence of different treatment options for ISS and gives recommendations for the treatment and care of patients with ISS. Methods A literature search was performed using the Cochrane and Medline Databases (2014 to July 2020). All studies were objectively rated using the Scottish Intercollegiate Guidelines Network. For recommendations, the evidence from these studies was combined with the evidence from studies used in the 2014 guideline. Recommendations If ISS is suspected, electroencephalography (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatment should be evaluated clinically and electroencephalographically after 14 days. The preferred first-line treatment for ISS consists of either hormone-based monotherapy (AdrenoCorticoTropic Hormone [ACTH] or prednisolone) or a combination of hormone and vigabatrin. Children with tuberous sclerosis complex and those with contraindications against hormone treatment should be treated with vigabatrin. If first-line drugs are ineffective, second-line treatment options such as ketogenic dietary therapies, sulthiame, topiramate, valproate, zonisamide, or benzodiazepines should be considered. Children refractory to drug therapy should be evaluated early for epilepsy surgery, especially if focal brain lesions are present. Parents should be informed about the disease, the efficacy and adverse effects of the medication, and support options for the family. Regular follow-up controls are recommended.

Background: Favorable outcomes are seen in up to 50% of patients with World Federation of Neurosurgical Societies (WFNS) grade V aneurysmal subarachnoid hemorrhage. Therefore, the usefulness of the current WFNS grading system for identifying the worst scenarios for clinical studies and for making treatment decisions is limited. We previously modified the WFNS scale by requiring positive signs of brain stem dysfunction to assign grade V. This study aimed to validate the new herniation WFNS grading system in an independent prospective cohort. Methods: We conducted an international prospective multicentre study in poor-grade aneurysmal subarachnoid hemorrhage patients comparing the WFNS classification with a modified version—the herniation WFNS scale (hWFNS). Here, only patients who showed positive signs of brain stem dysfunction (posturing, anisocoric, or bilateral dilated pupils) were assigned hWFNS grade V. Outcome was assessed by modified Rankin Scale score 6 months after hemorrhage. The primary end point was the difference in specificity of the WFNS and hWFNS grading with respect to poor outcomes (modified Rankin Scale score 4–6). Results: Of the 250 patients included, 237 reached the primary end point. Comparing the WFNS and hWFNS scale after neurological resuscitation, the specificity to predict poor outcome increased from 0.19 (WFNS) to 0.93 (hWFNS) (McNemar, P P P P P Conclusions: The identification of objective positive signs of brain stem dysfunction significantly improves the specificity and positive predictive value with respect to poor outcome in grade V patients. Therefore, a simple modification—presence of brain stem signs is required for grade V—should be added to the WFNS classification. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT02304328.

Introduction: Fast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β-amyloidosis has raised the question of whether immune markers could be used as proxies for β-amyloid accumulation in the brain. Methods: Here, we apply multidimensional mass-cytometry combined with unbiased machine-learning techniques to immunophenotype peripheral blood mononuclear cells from a total of 251 participants in cross-sectional and longitudinal studies. Results: We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain β-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. Discussion: Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help identify and develop novel diagnostic tools for early AD assessment and better understand clinical outcomes., Alzheimer's & Dementia: The Journal of the Alzheimer's Association, ISSN:1552-5279, ISSN:1552-5260

ObjectivePreclinical studies have shown that cognitive impairments following spinal cord injury (SCI), such as impaired spatial memory, are linked to inflammation, neurodegeneration, and reduced neurogenesis in the right hippocampus. This cross-sectional study aims to characterize metabolic and macrostructural changes in the right hippocampus and their association to cognitive function in traumatic SCI patients.MethodsWithin this cross-sectional study, cognitive function was assessed in 28 chronic traumatic SCI patients and 18 age-, sex-, and education-matched healthy controls by a visuospatial and verbal memory test. A magnetic resonance spectroscopy (MRS) and structural MRI protocol was performed in the right hippocampus of both groups to quantify metabolic concentrations and hippocampal volume, respectively. Group comparisons investigated changes between SCI patients and healthy controls and correlation analyses investigated their relationship to memory performance.ResultsMemory performance was similar in SCI patients and healthy controls. The quality of the recorded MR spectra was excellent in comparison to the best-practice reports for the hippocampus. Metabolite concentrations and volume of the hippocampus measured based on MRS and MRI were not different between two groups. Memory performance in SCI patients and healthy controls was not correlated with metabolic or structural measures.ConclusionThis study suggests that the hippocampus may not be pathologically affected at a functional, metabolic, and macrostructural level in chronic SCI. This points toward the absence of significant and clinically relevant trauma-induced neurodegeneration in the hippocampus.

Pericytes are the mural cells of the microvascular network that are in close contact with underlying endothelial cells. Endothelial-secreted PDGFB leads to recruitment of pericytes to the vessel wall, but this is disrupted in Pdgfb(ret/ret) mice when the PDGFB retention motif is deleted. This results in severely reduced pericyte coverage on blood vessels. In this study, we investigated vascular abnormalities and hemodynamics in Pdgfb(ret/ret) mice throughout the cerebrovascular network and in different cortical layers by in vivo two-photon microscopy. We confirmed that Pdgfb(ret/ret) mice are severely deficient in pericytes throughout the vascular network, with enlarged brain blood vessels and a reduced number of vessel branches. Red blood cell velocity, linear density, and tube hematocrit were reduced in Pdgfb(ret/ret) mice, which may impair oxygen delivery to the tissue. We also measured intravascular PO2 and found that concentrations were higher in cortical Layer 2/3 in Pdgfb(ret/ret) mice, indicative of reduced blood oxygen extraction. Finally, we found that Pdgfb(ret/ret) mice had a reduced capacity for vasodilation in response to an acetazolamide challenge during functional MRI imaging. Taken together, these results suggest that severe pericyte deficiency can lead to vascular abnormalities and altered cerebral blood flow, reminiscent of pathologies such as arteriovenous malformations., Journal of Cerebral Blood Flow & Metabolism, 43 (5), ISSN:0271-678X, ISSN:1559-7016

Purpose Before the era of spinal imaging, presence of a spinal canal block was tested through gross changes in cerebrospinal fluid pressure (CSFP) provoked by manual compression of the jugular veins (referred to as Queckenstedt's test; QT). Beyond these provoked gross changes, cardiac-driven CSFP peak-to-valley amplitudes (CSFPp) can be recorded during CSFP registration. This is the first study to assess whether the QT can be repurposed to derive descriptors of the CSF pulsatility curve, focusing on feasibility and repeatability. Method Lumbar puncture was performed in lateral recumbent position in fourteen elderly patients (59.7±9.3 years, 6F) (NCT02170155) without stenosis of the spinal canal. CSFP was recorded during resting state and QT. A surrogate for the relative pulse pressure coefficient was computed from repeated QTs (i.e., RPPC-Q). Results Resting state mean CSFP was 12.3 mmHg (IQR 3.2) and CSFPp was 1.0 mmHg (0.5). Mean CSFP rise during QT was 12.5 mmHg (7.3). CSFPp showed an average 3-fold increase at peak QT compared to the resting state. Median RPPC-Q was 0.18 (0.04). There was no systematic error in the computed metrics between the first and second QT. Conclusion This technical note describes a method to reliably derive, beyond gross CSFP increments, metrics related to cardiac-driven amplitudes during QT (i.e., RPPC-Q). A study comparing these metrics as obtained by established procedures (i.e., infusion testing) and by QT is warranted.

Orbital metastases secondary to neuroendocrine tumors are exceedingly rare. We present a unique case of a 30-year-old female initially presenting with fever, chills, periorbital swelling, and painful proptosis. CT orbits revealed two ovoid-shaped ring-enhancing lesions in the right lateral and superior rectus muscles and clear sinuses, atypical for infectious post-septal cellulitis. Further work-up included serologic analysis, auto-immune panel, and MRI. Further imaging showed pseudocystic orbital lesions mimicking orbital cysticercosis. Additionally, given the bilateral nature of the lesions and patient’s country of origin, this parasitic process was highly suspected. A course of albendazole and steroids led to resolution of symptoms. With a presentation at age 30, this is by far the youngest case reported in literature to date.

Ataxia is one of the most common pediatric movement disorders and can be caused by a large number of congenital and acquired diseases affecting the cerebellum or the vestibular or sensory system. It is mainly characterized by gait abnormalities, dysmetria, intention tremor, dysdiadochokinesia, dysarthria, and nystagmus. In young children, ataxia may manifest as the inability or refusal to walk. The diagnostic approach begins with a careful clinical history including the temporal evolution of ataxia and the inquiry of additional symptoms, is followed by a meticulous physical examination, and, depending on the results, is complemented by laboratory assays, electroencephalography, nerve conduction velocity, lumbar puncture, toxicology screening, genetic testing, and neuroimaging. Neuroimaging plays a pivotal role in either providing the final diagnosis, narrowing the differential diagnosis, or planning targeted further workup. In this review, we will focus on the most common form of ataxia in childhood, cerebellar ataxia (CA). We will discuss and summarize the neuroimaging findings of either the most common or the most important causes of CA in childhood or present causes of pediatric CA with pathognomonic findings on MRI. The various pediatric CAs will be categorized and presented according to (a) the cause of ataxia (acquired/disruptive vs. inherited/genetic) and (b) the temporal evolution of symptoms (acute/subacute, chronic, progressive, nonprogressive, and recurrent). In addition, several illustrative cases with their key imaging findings will be presented.

Evidence on associations of lifestyle factors with Alzheimer's pathology and cognition are ambiguous, potentially because they rarely addressed inter-relationships of factors and sex effects. While considering these aspects, we examined the relationships of lifestyle factors with brain amyloid burden and cognition.We studied 178 cognitively normal individuals (women, 49%; 65.0 [7.6] years) and 54 individuals with mild cognitive impairment (women, 35%; 71.3 [8.3] years) enrolled in a prospective study of volunteers who completedOverall, higher cognitive activity was associated with better cognitive performance and higher physical activity was associated with lower amyloid burden. The latter association was weakened to a nonsignificant level after excluding multivariate outliers. Examination of the moderating effect of sex in the model revealed an inverse association of metabolic/vascular risk with cognition in men, whereas in women metabolic/vascular risk trended toward increased amyloid burden. Furthermore, a significant inverse association between physical activity and amyloid burden was found only in men. Inheritance of an APOE4 allele was associated with higher amyloid burden only in women.Sex modifies effects of certain lifestyle-related factors on amyloid burden and cognition. Notably, our results suggest that the negative impact of metabolic/vascular risk influences the risk of cognitive decline and Alzheimer's disease through distinct paths in women and men. ANN NEUROL 2022;92:451-463.

The circadian clock is synchronized to the 24 h day by environmental light which is transmitted from the retina to the suprachiasmatic nucleus (SCN) primarily via the retinohypothalamic tract (RHT). Circadian rhythm abnormalities have been reported in neurodegenerative disorders such as Alzheimer's disease (AD). Whether these AD-related changes are a result of the altered clock gene expression, retina degeneration, including the dysfunction in RHT transmission, loss of retinal ganglion cells and its electrophysiological capabilities, or a combination of all of these pathological mechanisms, is not known. Here, we evaluated transgenic APP/PS1 mouse model of AD and wild-type mice at 6- and 12-month-old, as early and late pathological stage, respectively. We noticed the alteration of circadian clock gene expression not only in the hypothalamus but also in two extra-hypothalamic brain regions, cerebral cortex and hippocampus, in APP/PS1 mice. These alterations were observed in 6-month-old transgenic mice and were exacerbated at 12 months of age. This could be explained by the reduced RHT projections in the SCN of APP/PS1 mice, correlating with downregulation of hypothalamic GABAergic response in APP/PS1 mice in advanced stage of pathology. Importantly, we also report retinal degeneration in APP/PS1 mice, including Aβ deposits and reduced choline acetyltransferase levels, loss of melanopsin retinal ganglion cells and functional integrity mainly of inner retina layers. Our findings support the theory that retinal degeneration constitutes an early pathological event that directly affects the control of circadian rhythm in AD.

Background Major retinal degenerative diseases, including age-related macular degeneration, diabetic retinopathy and retinal detachment, are associated with a local decrease in oxygen availability causing the formation of hypoxic areas affecting the photoreceptor (PR) cells. Here, we addressed the underlying pathological mechanisms of PR degeneration by focusing on energy metabolism during chronic activation of hypoxia-inducible factors (HIFs) in rod PR. Methods We used two-photon laser scanning microscopy (TPLSM) of genetically encoded biosensors delivered by adeno-associated viruses (AAV) to determine lactate and glucose dynamics in PR and inner retinal cells. Retinal layer-specific proteomics, in situ enzymatic assays and immunofluorescence studies were used to analyse mitochondrial metabolism in rod PRs during chronic HIF activation. Results PRs exhibited remarkably higher glycolytic flux through the hexokinases than neurons of the inner retina. Chronic HIF activation in rods did not cause overt change in glucose dynamics but an increase in lactate production nonetheless. Furthermore, dysregulation of the oxidative phosphorylation pathway (OXPHOS) and tricarboxylic acid (TCA) cycle in rods with an activated hypoxic response decelerated cellular anabolism causing shortening of rod photoreceptor outer segments (OS) before onset of cell degeneration. Interestingly, rods with deficient OXPHOS but an intact TCA cycle did not exhibit these early signs of anabolic dysregulation and showed a slower course of degeneration. Conclusion Together, these data indicate an exceeding high glycolytic flux in rods and highlight the importance of mitochondrial metabolism and especially of the TCA cycle for PR survival in conditions of increased HIF activity., Molecular Neurodegeneration, 18 (1)

Objective To assess if a new dual-energy computed tomography (DECT) technique enables an improved visualization of ischemic brain tissue after mechanical thrombectomy in acute stroke patients. Material and Methods The DECT head scans with a new sequential technique (TwinSpiral DECT) were performed in 41 patients with ischemic stroke after endovascular thrombectomy and were retrospectively included. Standard mixed and virtual non-contrast (VNC) images were reconstructed. Infarct visibility and image noise were assessed qualitatively by two readers using a 4-point Likert scale. Quantitative Hounsfield units (HU) were used to assess density differences of ischemic brain tissue versus healthy tissue on the non-affected contralateral hemisphere. Results Infarct visibility was significantly better in VNC compared to mixed images for both readers R1 (VNC: median 1 (range 1–3), mixed: median 2 (range 1–4), p p p p p Conclusion TwinSpiral DECT allows an improved qualitative and quantitative visualization of ischemic brain tissue in ischemic stroke patients after endovascular treatment.

Purpose Patients with Moyamoya Angiopathy (MMA) require hemodynamic assessment to evaluate the risk of stroke. Hemodynamic evaluation by use of breath-hold-triggered fMRI (bh-fMRI) was proposed as a readily available alternative to the diagnostic standard [15O]water PET. Recent studies suggest voxel-wise hemodynamic delay correction in hypercapnia-triggered fMRI. The aim of this study was to evaluate the effect of delay correction of bh-fMRI in patients with MMA and to compare the results with [15O]water PET. Methods bh-fMRI data sets of 22 patients with MMA were evaluated without and with voxel-wise delay correction within different shift ranges and compared to the corresponding [15O]water PET data sets. The effects were evaluated combined and in subgroups of data sets with most severely impaired CVR (apparent steal phenomenon), data sets with territorial time delay, and data sets with neither steal phenomenon nor delay between vascular territories. Results The study revealed a high mean cross-correlation (r = 0.79, p 15O]water PET. The correlation was strongly dependent on the choice of the shift range. Overall, no shift range revealed a significantly improved correlation between bh-fMRI and [15O]water PET compared to the correlation without delay correction. Delay correction within shift ranges with positive high high cutoff revealed a lower agreement between bh-fMRI and PET overall and in all subgroups. Conclusion Voxel-wise delay correction, in particular with shift ranges with high cutoff, should be used critically as it can lead to false-negative results in regions with impaired CVR and a lower correlation to the diagnostic standard [15O]water PET.

BackgroundFollowing spinal cord injury (SCI), disease processes spread gradually along the spinal cord forming a spatial gradient with most pronounced changes located at the lesion site. However, the dynamics of this gradient in sub-acute SCI patients is not established.ObjectiveThis study tracks the spatiotemporal dynamics of remote anterograde and retrograde spinal tract degeneration in the upper cervical cord following SCI over two years utilizing quantitative MRI.MethodsTwenty-three acute SCI patients (11 paraplegics, 12 tetraplegics) and 21 healthy controls were scanned with a T1-weighted sequence for volumetry and a FLASH sequence for myelin-sensitive magnetization transfer saturation (MTsat) map of the upper cervical cord. We estimated myelin content from MTsat maps within the corticospinal tracts (CST) and dorsal columns (DC) and measured spinal cord atrophy by means of left-right width (LRW) and anterior-posterior width (APW) on the T1-weighted images across cervical levels C1-C3. MTsat in the CST and LRW were considered proxies for retrograde degeneration, while MTsat in the DC and APW provided evidence for anterograde degeneration, respectively. Using regression models, we compared the temporal and spatial trajectories of these MRI readouts between tetraplegics, paraplegics, and controls over a 2-year period and assessed their associations with clinical improvement.ResultsLinear rates and absolute differences in myelin-sensitive MTsat indicated retrograde and anterograde neurodegeneration in the CST and DC, respectively. Changes in MTsat within the CST (change per cervical level: -0.247 p.u./level, p=0.034) and LRW (change per level: -0.323 mm/level, p=0.024) progressively developed over time with a strong gradient towards lower cervical segments specifically in tetraplegics. Within the DC, MTsat was already decreased at all cervical levels at baseline and linear rates in APW were similar across all cervical levels showing no spatial gradient in para- and tetraplegics. The relative improvement in light touch score was correlated with MTsat within the DC at baseline (1.5 months) (rs=0.575, p=0.014).ConclusionRostral and remote to the injury, the CST and DC showed ongoing structural changes, indicative of myelin reductions and atrophy within 2 years after SCI. While anterograde degeneration in the DC was already detectable uniformly at C1-C3 early following SCI, retrograde degeneration in the CST developed over time revealing specific spatial and temporal neurodegenerative gradients. Disentangling and quantifying such dynamic pathological processes may provide biomarkers for regenerative and remyelinating therapies, where antero- and retrograde spinal pathways become specifically affected.

Although phenobarbital (PB) is commonly used as a first-line antiseizure medication (ASM) for neonatal seizures, in 2015 we chose to replace it with levetiracetam (LEV), a third-generation ASM. Here, we compared the safety and efficacy of LEV and PB as first-line ASM, considering the years before and after modifying our treatment protocol.We conducted a retrospective cohort study of 108 neonates with electroencephalography (EEG)-confirmed seizures treated with first-line LEV or PB in 2012 to 2020.First-line ASM was LEV in 33 (31%) and PB in 75 (69%) neonates. The etiology included acute symptomatic seizures in 69% of cases (30% hypoxic-ischemic encephalopathy, 32% structural vascular, 6% infectious, otherwise metabolic) and neonatal epilepsy in 22% (5% structural due to brain malformation, 17% genetic). Forty-two of 108 (39%) neonates reached seizure freedom following first-line therapy. Treatment response did not vary by first-line ASM among all neonates, those with acute symptomatic seizures, or those with neonatal-onset epilepsy. Treatment response was lowest for neonates with a higher seizure frequency, particularly for those with status epilepticus versus rare seizures (P 0.001), irrespective of gestational age, etiology, or EEG findings. Adverse events were noted in 22 neonates treated with PB and in only one treated with LEV (P 0.001).Our study suggests a potential noninferiority and a more acceptable safety profile for LEV, which may thus be a reasonable option as first-line ASM for neonatal seizures in place of PB. Treatment should be initiated as early as possible since higher seizure frequencies predispose to less favorable responses.

Stimulus induced repetitive periodic or ictal discharges (SIRPIDs) are a commonly observed EEG pattern in critically ill patients. However, the epileptic significance of SIRPIDs remain unclear. We identified and reviewed 55 cases with SIRPIDs according to the ACNS criteria. SIRPIDs occurred after standardized painful stimuli during a standard 20-minute EEG. These cases were investigated regarding their relation to non-convulsive status epilepticus (NCSE) according to Salzburg Consensus Criteria and in-hospital mortality. In 37/55 patients (67.3%), SIRPIDs were associated with NCSE. In most patients (26/37 cases, 70.3%) with concurrent status epilepticus, SIRPIDs occurred after status epilepticus (on average 4.8 days later), but in 3/37 patients (8.1%) they were observed before a later status epilepticus. In four cases (4/37 cases, 10.8%), SIRPIDs appeared both before and after an episode of NCSE and in other four cases the two patterns coexisted in the same EEG. In 50% of the patients, status epilepticus was refractory, super-refractory or the patient died before its resolution. The overall mortality in the cohort was high at 58.2%. These findings corroborate the hypothesis that SIRPIDs might represent a state with increased epileptogenic potential, commonly co-occurring with NCSE. Furthermore, SIRPIDs are associated with therapy-refractory course of status epilepticus and high mortality.

Background The five-repetition sit-to-stand test (5R-STS) has recently been validated as an objective measure of functional impairment in patients with lumbar degenerative disease (LDD). Knowledge of factors influencing 5R-STS performance is useful to correct for confounders, create personalized adjusted test times, and potentially identify prognostic subgroups. We evaluate factors predicting the 5R-STS performance in patients with LDD. Methods Patients with LDD requiring surgery were included. Each participant performed the 5R-STS and completed a questionnaire that included their age, gender, weight, height, body mass index (BMI), smoking status, education level, employment type, ability to work, analgesic drug usage, history of previous spinal surgery, and EQ5D depression and anxiety domain. Surgical indication and index level of the spinal pathology were also recorded. Predictors of 5R-STS were identified through multivariable linear regression. Results The cohort consisted of 240 patients, 47.9% being female (mean age, 47.7 ± 13.6 years). In the final multivariable model incorporating confounders, height (regression coefficient (RC), 0.08; 95% confidence interval (CI), 0.003/0.16, p = 0.042) and being an active smoker (RC, 2.44; 95%CI, 0.56/4.32, p = 0.012) were significant predictors of worse 5R-STS performance. Full ability to work (RC, − 2.39; 95%CI, − 4.39/ − 0.39, p = 0.020) was associated with a better 5R-STS performance. Age, height, surgical indication, index level of pathology, history of previous spine surgery, history of pain, analgesic drug use, employment type, and severity of anxiety and depression symptoms demonstrated confounding effect on the 5R-STS time. Conclusions Greater height, being an active smoker, and inability to work are significant predictors of worse 5R-STS performance in patients with LDD. Trial registration ClinicalTrials.gov Identifier: NCT03303300 and NCT03321357.

To improve risk stratification in extracranial internal carotid artery disease (CAD), patients who would benefit maximally from revascularization must be identified. In cardiology, the fractional flow reserve (FFR) has become a reference standard for evaluating the functional severity of coronary artery stenosis, and noninvasive surrogates thereof relying on computational fluid dynamics (CFD) have been developed. Here, we present a CFD-based workflow using digital twins of patients’ carotid bifurcations derived from computed tomography angiography for the noninvasive functional assessment of CAD. We reconstructed patient-specific digital twins of 37 carotid bifurcations. We implemented a CFD model using common carotid artery peak systolic velocity (PSV) acquired with Doppler ultrasound (DUS) as inlet boundary condition and a two-element Windkessel model as oulet boundary condition. The agreement between CFD and DUS on the PSV in the internal carotid artery (ICA) was then compared. The relative error for the agreement between DUS and CFD was 9% ± 20% and the intraclass correlation coefficient was 0.88. Furthermore, hyperemic simulations in a physiological range were feasible and unmasked markedly different pressure drops along two ICA stenoses with similar degree of narrowing under comparable ICA blood flow. Hereby, we lay the foundation for prospective studies on noninvasive CFD-based derivation of metrics similar to the FFR for the assessment of CAD., NeuroImage: Clinical, 38, ISSN:2213-1582

Brain Stimulation, 16 (2), ISSN:1935-861X, ISSN:1876-4754

STUDY DESIGN Prospective, multicenter, longitudinal cohort study. OBJECTIVES To describe female-male differences in first-line urological management during spinal cord injury (SCI) rehabilitation. SETTING Inpatient specialized post-acute SCI rehabilitation in Switzerland. METHODS Data on bladder storage medication (antimuscarinic and beta-3 agonist) use, suprapubic catheter placement, demographic and SCI characteristics was collected within 40 days of SCI and at rehabilitation discharge from May 2013-September 2021. Prevalence and indicators of bladder storage medication and suprapubic catheter use at discharge were investigated with sex-stratified descriptive and logistic regression analyses. RESULTS In 748 patients (219 females, 29%), bladder storage medication use at discharge had a prevalence of 24% (95% CI: 18-29%) for females and 30% (95% CI: 26-34%) for males and was indicated by cervical AIS grade A, B, C and traumatic SCI in both sexes. Thoracic AIS grade A, B, C SCI (males), and lumbar/sacral AIS grade A, B, C SCI (females) predicted higher odds of bladder storage medication use (SCI characteristic*sex interaction, p 60 in both sexes. Females with thoracic grade A, B, C SCI tended to have higher odds of suprapubic catheter use (SCI characteristic*sex interaction, p = 0.013). CONCLUSIONS We identified sex differences in urological management especially in persons with AIS grade C or higher sub-cervical SCI. There is scope for well-powered, female-specific research in SCI in order to understand the underlying mechanisms and support patient-tailored management.

Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I–VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I–VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification.

EEG has been the primary diagnostic tool in clinical epilepsy for nearly a century. Its review is performed using qualitative clinical methods that have changed little over time. However, the intersection of higher resolution digital EEG and analytical tools developed in the last decade invites a re-exploration of relevant methodology. In addition to the established spatial and temporal markers of spikes and high frequency oscillations, novel markers involving advanced post-processing and active probing of the interictal EEG are gaining ground. This review provides an overview of the EEG-based passive and active markers of cortical excitability in epilepsy and of the techniques developed to facilitate their identification. Several different emerging tools are discussed in the context of specific EEG applications and the barriers we must overcome to translate these tools into clinical practice.

Item does not contain fulltext STUDY DESIGN: Consensus study. OBJECTIVES: The purpose of this study is to define a standardized (network) outcomes set for traumatic spinal cord injury (t-SCI), covering the patient journey from acute to chronic rehabilitation phase, including patient-relevant outcomes, adequate measurement instruments, as well as case-mix and risk factors. SETTING: Acute Spinal Cord Injury (ASCI) Unit Nijmegen, the Netherlands. METHODS: A modified Delphi method was performed, including a multidisciplinary panel of 19 health-care professionals with experience in t-SCI management. Formal consensus was reached after two web-based surveys, a face-to-face meeting, and a final confirmation round (threshold consensus: 70%). RESULTS: In the first two Delphi rounds, 18/19 invited panelists (94.7%) responded and 10 panelists participated in the final meeting. The prefinal set was confirmed by all panelists. The standard set encompasses the three-tiered outcome hierarchy and consists of patient-reported and clinician-reported outcome domains and measurement instruments. Consensus was reached to include survival, degree of health or recovery, time to recovery, and return to normal activities, disutility of care or treatment process, sustainability of health and nature of recurrences, and long-term consequences of therapy. A measurement schedule was defined as well as for proposed casemix and risk factors, including demographics, clinical status, and treatment process. CONCLUSION: A standard set of network outcomes is developed that could be implemented in hospitals and rehabilitation centers involved in the treatment of t-SCI. Using this standard set, comparison of the quality of care is possible and prognostic prediction of outcomes of treatment is feasible, so that each patient receives the right care at the right time in the right place. 01 september 2022

Background Myelosuppression is the major toxicity encountered during temozolomide chemoradiotherapy for newly diagnosed glioblastoma. Methods We assessed the association of myelosuppression (neutropenia, thrombocytopenia, anemia, and lymphopenia) during temozolomide chemoradiotherapy alone or in combination with experimental agents with progression-free survival (PFS) or overall survival (OS) in 2073 patients with newly diagnosed glioblastoma enrolled into five clinical trials: CENTRIC, CORE, EORTC 26082, AVAglio, and EORTC 26981. A landmark Cox model was used. For each primary association analysis, a significance level of 1.7% was used. Results Lower neutrophil counts at baseline were associated with better PFS (P = .011) and OS (P < .001), independently of steroid intake. Females experienced uniformly more myelotoxicity than males. Lymphopenia during concomitant chemoradiotherapy was associated with OS (P = .009): low-grade (1-2) lymphopenia might be associated with superior OS (HR 0.78, 98.3% CI 0.58–1.06), whereas high-grade (3-4) lymphopenia might be associated with inferior OS (HR 1.08, 98.3% CI 0.75–1.54). There were no associations of altered hematological parameters during concomitant chemoradiotherapy with PFS. During maintenance chemoradiotherapy, no significant association was found between any parameter of myelosuppression and PFS or OS, although exploratory analysis at 5% significance level indicated that either mild-to-moderate (HR 0.76, 95% CI 0.62–0.93) or high-grade lymphopenia (HR 0.65, 95% CI 0.46–0.92) was associated with superior OS (P = .013), but not PFS. Conclusions The association of higher neutrophil counts at baseline with inferior PFS and OS requires further prospective evaluation. The link of therapy-induced lymphopenia to better outcome may guide the design for immunotherapy trials in newly diagnosed glioblastoma.

Background and ObjectivesEyelid myoclonia (EM) with absences (EMA) is a generalized epilepsy syndrome with a prognosis and clinical characteristics that are still partially undefined. We investigated electroclinical endophenotypes and long-term seizure outcome in a large cohort of patients with EMA.MethodsIn this multicenter retrospective study, patients with EMA with ≥5 years of follow-up were included. We investigated prognostic patterns and sustained terminal remission (STR), along with their prognostic factors. Moreover, a 2-step cluster analysis was used to investigate the presence of distinct EMA endophenotypes.ResultsWe included 172 patients with a median age at onset of 7 years (interquartile range [IQR] 5–10 years) and a median follow-up duration of 14 years (IQR 8.25–23.75 years). Sixty-six patients (38.4%) displayed a nonremission pattern, whereas remission and relapse patterns were encountered in 56 (32.6%) and 50 (29.1%) participants. Early epilepsy onset, history of febrile seizures (FS), and EM status epilepticus significantly predicted a nonremission pattern according to multinomial logistic regression analysis. STR was achieved by 68 (39.5%) patients with a mean latency of 14.05 years (SD ±12.47 years). Early epilepsy onset, psychiatric comorbid conditions, and a history of FS and generalized tonic-clonic seizures were associated with a lower probability of achieving STR according to a Cox regression proportional hazards model. Antiseizure medication (ASM) withdrawal was attempted in 62 of 172 patients, and seizures recurred in 74.2%. Cluster analysis revealed 2 distinct clusters with 86 patients each. Cluster 2, which we defined as EMA-plus, was characterized by an earlier age at epilepsy onset, higher rate of intellectual disability, EM status epilepticus, generalized paroxysmal fast activity, self-induced seizures, FS, and poor ASM response, whereas cluster 1, the EMA-only cluster, was characterized by a higher rate of seizure remission and more favorable neuropsychiatric outcome.DiscussionEarly epilepsy onset was the most relevant prognostic factor for poor treatment response. A long latency between epilepsy onset and ASM response was observed, suggesting the effect of age-related brain changes in EMA remission. Last, our cluster analysis showed a clear-cut distinction of patients with EMA into an EMA-plus insidious subphenotype and an EMA-only benign cluster that strongly differed in terms of remission rates and cognitive outcomes.

High frequency oscillations (HFO) in scalp EEG are a new and promising epilepsy biomarker. However, considerable fluctuations of HFO rates have been observed through sleep stages and cycles. Here, we aimed to identify the optimal timing within sleep and the minimal data length for sensitive and reproducible HFO detection.We selected 16 whole-night scalp EEG recordings of paediatric patients with a focal structural epilepsy. We used an automated clinically validated HFO detector to determine HFO rates (80-250 Hz). We evaluated the reproducibility of HFO detection across intervals.HFO rates were higher in N3 than in N2 and REM (rapid eye movement) sleep and highest in the first sleep cycle, decreasing with time in sleep. In N3 sleep, the median reliability of HFO detection increased from 67% (interquartile range: iqr 57) to 78% (iqr 59) to 100% (iqr 70%) for 5-, 10-, and 15-min data intervals, improving significantly (p = 0.004, z = 2.9) from 5 to 10 min but not from 10 to 15 min.We identified the first N3 sleep stage as the most sensitive time window for HFO rate detection. At least 10 min N3 data intervals are required and sufficient for reliable measurements of HFO rates.Our study provides a robust and reliable framework for scalp HFO detection that may facilitate their implementation as an EEG biomarker in paediatric epilepsy.

Here we review the paradigm-change from one-size-fits-all psychiatry to more personalized-psychiatry, where we distinguish between 'precision psychiatry' and 'stratified psychiatry'. Using examples in Depression and ADHD we argue that stratified psychiatry, using biomarkers to facilitate patients to best 'on-label' treatments, is a more realistic future for implementing biomarkers in clinical practice.

To test the robustness and signal-to-noise ratio of pain-related evoked potentials following intra-epidermal electrical stimulation (IES) compared to contact heat stimulation in healthy controls, and to explore the feasibility and potential added value of IES in the diagnosis of spinal disorders.Pain-related evoked potentials induced by IES (custom-made, non-invasive, concentric triple pin electrode with steel pins protruding 1 mm from the anode, triangularly separated by 7-10 mm respectively) and contact heat stimulation were compared in 30 healthy subjects. Stimuli were applied to four different body sites. Two IES intensities, i.e., high (individually adapted to contact heat painfulness) and low (1.5 times pain threshold), were used. Additionally, a 40-year-old patient with unilateral dissociated sensory loss due to a multi-segmental syringohydromyelia was assessed comparing IES and contact heat stimulation.Both IES and contact heat stimulation led to robust pain-related evoked potentials recorded in all healthy subjects. Low intensity IES evoked potentials (14.1-38.0 µV) had similar amplitudes as contact heat evoked potentials (11.8-32.3 µV), while pain ratings on the numeric rating scale were lower for IES (0.8-2.5, compared to 1.5-3.9 for contact heat stimulation). High intensity IES led to evoked potentials with higher signal-to-noise ratio than low intensity IES and contact heat stimulation. The patient case showed impaired pain-related evoked potentials in segments with hypoalgesia for both IES modes. IES evoked potentials were preserved, with delayed latencies, while contact heat evoked potentials were abolished.IES evoked robust pain-related cortical potentials, while being less painful in healthy controls. The improved signal-to-noise ratio supports the use of IES for objective segmental testing of nociceptive processing. This was highlighted in a spinal syndrome case, where IES as well as contact heat stimulation reliably detected impaired segmental nociception.

BACKGROUND CONTEXT Early postoperative MR images are frequently necessary after spine surgery. The appearance of commonly used adjunct hemostatic agents and dural sealants in MR images has not been systematically evaluated. PURPOSE The purpose of this experimental study was to systematically analyze and describe the characteristics of the most commonly applied hemostatic agents and dural sealants in spine surgery on early postoperative MR images. STUDY DESIGN Cadaver Study METHODS Four commonly applied dural sealants (Duraseal, Bioglue, Tachosil, Tisseel) and five commonly used hemostatic agents (Surgiflo, Bonewax, , Spongostan, Gelfoam, Avitene) were investigated. The experimental setting involved a human cadaver where a standard left-sided laminotomy was performed on nine levels of the thoracolumbar spine, and the materials were separately applied and mixed with fresh blood or water for hemostatic and dural sealants, respectively. The cadaver model was scanned at a 3 Tesla MRI and the imaging findings for all materials were compared to the surrounding tissue and systematically reported. RESULTS All investigated dural sealants and hemostatic agents were distinguishable from the surrounding tissue on MR images with different appearances on the MR sequences. A detailed atlas for the identification of the materials in postoperative spine MRI was established. CONCLUSION Commonly used hemostatic agents and dural sealants can be successfully identified on early postoperative spine MRI. CLINICAL SIGNIFICANCE Knowledge about MRI appearances of commonly used adjunct surgical materials helps in interpretation of postoperative imaging and supports clinical decision making.

Affective disorders are frequent comorbidities of temporal lobe epilepsy (TLE). The endogenous opioid system has been implicated in both epilepsy and affective disorders, and may play a significant role in their bidirectional relationship. In this cross-sectional study, we investigated the association between μ-opioid receptor binding and affective disorders in patients with TLE.Nine patients with TLE and depression/anxiety underwentWe observed widely reduced CFN binding potential (BP) in bilateral frontal lobes and striata in patients with TLE compared to healthy controls. In the TLE group, more severe anxiety and negative affect were associated with decreased CFN BP in the posterior cingulate gyrus.In patients with TLE, interictally reduced binding in the opioid system was associated with higher levels of anxiety and negative affect. We speculate that seizure-related agonist-driven desensitization and downregulation of opioid receptors could be a potential underlying pathomechanism.

Many studies in patients with brain tumors evaluating innovative PET tracers have been published in recent years, and the initial results are promising. Here, the Response Assessment in Neuro-Oncology (RANO) PET working group provides an overview of the literature on novel investigational PET tracers for brain tumor patients. Furthermore, newer indications of more established PET tracers for the evaluation of glucose metabolism, amino acid transport, hypoxia, cell proliferation, and others are also discussed. Based on the preliminary findings, these novel investigational PET tracers should be further evaluated considering their promising potential. In particular, novel PET probes for imaging of translocator protein and somatostatin receptor overexpression as well as for immune system reactions appear to be of additional clinical value for tumor delineation and therapy monitoring. Progress in developing these radiotracers may contribute to improving brain tumor diagnostics and advancing clinical translational research.