Use of intensive care, intracranial pressure monitoring, and external ventricular drainage devises in patients with bacterial meningitis, a cohort study.

BACKGROUND: Bacterial meningitis can cause a life-threatening increase in intracranial pressure (ICP). ICP-targeted treatment including an ICP monitoring device and external ventricular drainage (EVD) may improve outcomes but is also associated with the risk of complications. The frequency of use and complications related to ICP monitoring devices and EVDs among patients with bacterial meningitis remain unknown. We aimed to investigate the use of ICP monitoring devices and EVDs in patients with bacterial meningitis including frequency of increased ICP, drainage of cerebrospinal fluid (CSF), and complications associated with the insertion of ICP monitoring and external ventricular drain (EVD) in patients with bacterial meningitis. METHOD: In a single-center prospective cohort study (2017-2021), we examined the frequency of use and complications of ICP-monitoring devices and EVDs in adult patients with bacterial meningitis. RESULTS: We identified 108 patients with bacterial meningitis admitted during the study period. Of these, 60 were admitted to the intensive care unit (ICU), and 47 received an intracranial device (only ICP monitoring device N = 16; EVD N = 31). An ICP > 20 mmHg was observed in 8 patients at insertion, and in 21 patients (44%) at any time in the ICU. Cerebrospinal fluid (CSF) was drained in 24 cases (51%). Severe complications (intracranial hemorrhage) related to the device occurred in two patients, but one had a relative contraindication to receiving a device. CONCLUSIONS: Approximately half of the patients with bacterial meningitis needed intensive care and 47 had an intracranial device inserted. While some had conservatively correctable ICP, the majority needed CSF drainage. However, two patients experienced serious adverse events related to the device, potentially contributing to death. Our study highlights that the incremental value of ICP measurement and EVD in managing of bacterial meningitis requires further research.

Beneficial effects of exercise, testosterone, vitamin D, calcium and protein in older men-A randomized clinical trial.

BACKGROUND: Due to increasing older populations worldwide, injuries, disabilities and deaths caused by falls among the elderly represent a growing human and societal problem. We aimed to improve health among men of at least 70 years of age with low-normal to low testosterone and mobility problems by using testosterone undecanoate (TU) injections, progressive strength training, and oral supplements of vitamin D, calcium and protein. METHODS: This was a single-centre, randomized, placebo-controlled, double-blind trial with 148 older men with a median age of 77 (73-81) years, testosterone levels at median 8 (5-9) nmol/L (full range from 1.1 to 12.9 nmol/L) and mobility problems, recruited at University Hospital of Copenhagen, Herlev Hospital, Denmark. Participants were randomized into four arms for 20 weeks: (1) TU therapy (n = 37); (2) progressive resistance training with supplements of calcium, vitamin D and protein (n = 36); (3) both interventions combined (n = 36); or (4) no intervention (n = 39). The main outcome measure was the 30-s chair stand test, due to test performance correlating with the risk of serious fall injuries and lower extremity muscle strength. Outcome measurements were performed at baseline and after 20 weeks. RESULTS: After the intervention, the combination group receiving progressive resistance training, TU and supplements achieved a median score of 13 (11-15) compared to the control group at 10 (0-14) in the 30-s chair stand test (P = 0.003). This median improvement of 3.0 was clinically important. Compared to the control group, participants in the combination group also increased quality of life (P < 0.05) and reduced both tiredness (P < 0.05) and leg fat (P < 0.05) and had higher variability in the RR interval (P < 0.01). The group receiving TU reduced gynoid and leg fat compared to the control group (both P < 0.05). Blood tests improved for several variables, especially in the combination group. There was no statistically significant increase in adverse effects from either the supplements or training. CONCLUSIONS: In men ≥70 years old with low-normal to low testosterone and mobility problems, supplements of testosterone, calcium, vitamin D and protein combined with progressive resistance training improved 30-s chair stand test performance, muscle strength and quality of life. Both tiredness and leg fat were reduced, and RR interval variability was increased. Significant adverse effects were not observed.

Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration.

Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration.

N-acetyl aspartate levels early after ischemic stroke accurately reflect long-term brain damage.

Background: Estimation of brain damage following an ischemic stroke is most often performed within the first few days after the insult, where large amounts of oedematous fluid have accumulated. This can potentially hamper correct measurement of infarcted area, since oedema formation poorly reflects infarct size. This study presents a non-invasive, easily applicable and reliable method to accurately predict long-term evolution and late-stage infarction. Objective: We performed a longitudinal analysis of brain infarct evolution after MCAO in mice, in order to determine whether water-compensated N-Acetylaspartate (NAA) levels in the infarct area, measured 24 h after the insult, is a suitable marker for late-stage infarction and thereby prognosis. Methods: Twenty mice were divided into 4 groups and scanned longitudinally at different time-points after MCAO, followed by euthanisation for histology: Group 1) MRI/MRS at day 1 after MCAO (n = 4), Group 2) MRI/MRS at days 1 and 7 after MCAO (n = 5), Group 3) MRI/MRS at days 1, 7, and 14 after MCAO (n = 3), and Group 4) MRI/MRS at days 1, 7, 14, and 28 after MCAO (n = 4). At days 1, 7, 14, and 28, NAA levels were correlated with histological determination of neuronal death based on Nissl and H&E stainings. Results: Twenty-four hours after the insult, NAA levels in the infarcted area decreased by 35 %, but steadily returned to normal after 28 days. In the acute phases, NAA levels strongly correlated with loss of Nissl substance (r2 = -0.874, p = 0.002), whereas NAA levels in later stages reflect glial metabolism and tissue reorganisation. Most importantly, NAA levels 24 h after MCAO was highly correlated with late stage infarction at days 14 and 28 (r2 = 0.73, p = 0.01), in contrast to T2 (r2 = 0.06, p = 0.59). Conclusions: By using a fixed voxel, which is easily positioned in the affected area, it is possible to obtain reliable measures of the extent of neuronal loss at early time points independent of oedema and brain deformation. Importantly, NAA levels 24 h after MCAO accurately reflects late-stage infarction, suggesting that NAA is a useful prognostic biomarker early after an ischemic stroke.

Multidisciplinary interventions increase weekly working hours and quality of life in persons with post-concussion syndrome.

OBJECTIVES: To improve labor market attachment, general health and quality of life in persons suffering from post-concussion syndrome. Labor market attachment often changes after mTBI, and especially in persons suffering from post-concussion syndrome, and constitutes a huge societal burden. METHODS: Eighty-two adults with persistent post-concussion syndrome participated in this single-center and uncontrolled interventional efficacy open-label investigation. The primary endpoint was to increase weekly working hours. Outcome measures ranged from self-reported cognitive symptoms to objective performance testing. Multidisciplinary interventions were used to reduce symptoms of fatigue, stress, pain, oculomotor malfunction, and sensitivity to both sound and light. RESULTS: Workhours improved from median 0 to 6 hours (p = 0.00002). Several significant improvements were observed in quality of life measured by the SF-36. General fatigue measured by the MFI-20 was reduced (p < 0.0001), and symptoms of depression were reduced (p < 0.0001). The COPM results were improved for task completion satisfaction and for ability to perform a task (p < 0.0001). Reading speed, and performances in the Groffman Visual Tracing Test and the King-Devick Test, all improved (p < 0.01). The intervention did not reduce perception of pain intensity (p = 0.11). CONCLUSION: After the intervention, participants increased weekly workhours and improved in many aspects of life - including quality of life, performance in everyday activities, fatigue and depression. Perception of pain intensity was not improved.

Effect of controlled blood pressure increase on cerebral blood flow velocity and oxygenation in patients with subarachnoid haemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid haemorrhage (SAH) might have impaired cerebral autoregulation, that is, CBF - and thereby oxygen delivery - passively increase with an increase in CPP. This physiological study aimed to investigate the cerebral haemodynamic effects of controlled blood pressure increase in the early phase after SAH before any signs of delayed cerebral ischaemia (DCI) occurred. METHODS: The study was carried out within 5 days after ictus. Data were recorded at baseline and after 20 min of noradrenaline infusion to increase mean arterial blood pressure (MAP) by a maximum of 30 mmHg and to an absolute level of no more than 130 mmHg. The primary outcome was the difference in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler (TCD), while differences in intracranial pressure (ICP), brain tissue oxygen tension (PbtO2 ), and microdialysis markers of cerebral oxidative metabolism and cell injury were assessed as exploratory outcomes. Data were analysed using Wilcoxon signed-rank test with correction for multiplicity for the exploratory outcomes using the Benjamini-Hochberg correction. RESULTS: Thirty-six participants underwent the intervention 4 (median, IQR: 3-4.75) days after ictus. MAP was increased from 82 (IQR: 76-85) to 95 (IQR: 88-98) mmHg (p-value: <.001). MCAv remained stable (baseline, median 57, IQR: 46-70 cm/s; controlled blood pressure increase, median: 55, IQR: 48-71 cm/s; p-value: .054), whereas PbtO2 increased significantly (baseline, median: 24, 95%CI: 19-31 mmHg; controlled blood pressure increase, median: 27, 95%CI: 24-33 mmHg; p-value <.001). The remaining exploratory outcomes were unchanged. CONCLUSION: In this study of patients with SAH, MCAv was not significantly affected by a brief course of controlled blood pressure increase; despite this, PbtO2 increased. This suggests that autoregulation might not be impaired in these patients or other mechanisms could mediate the increase in brain oxygenation. Alternatively, a CBF increase did occur that, in turn, increased cerebral oxygenation, but was not detected by TCD. TRIAL REGISTRATION: clinicaltrials.gov (NCT03987139; 14 June 2019).

Astrocytes: integrators of arousal state and sensory context.

The integration of external information with the internal state of the body is central to the survival of virtually every multicellular organism. However, a complete picture of the mechanisms that govern this process is lacking. In this opinion article, we synthesize evidence demonstrating that astrocytes sense the momentary arousal state - through neuromodulator release - as well as the sensory inputs - through local synaptic activity - and respond to them with changes in calcium (Ca2+) signaling. We hypothesize that astrocytes integrate sensory signals with the internal state and that this process is necessary to secure optimal behavior. Finally, we argue that dysfunctional astrocytic Ca2+ signaling could be an underlying factor in disorders characterized by disrupted sensory processing.

Awake Laser Ablation with Continuous Neuropsychological Testing During Treatment of Brain Tumors and Epilepsy.

MR-guided laser interstitial thermal therapy (LITT) is feasible and safe in the awake patient. Awake LITT may be performed with analgesics for head fixation in a head-ring, no sedation during laser ablation, and with continuous neurological testing in patients with brain tumors and epilepsy. In the LITT treatment of lesions near eloquent areas and subcortical fiber tracts, neurological function can potentially be preserved by monitoring the patient during laser ablation.

Versatile treadmill system for measuring locomotion and neural activity in head-fixed mice.

Here, we present a protocol for using a versatile treadmill system to measure locomotion and neural activity at high temporal resolution in head-fixed mice. We first describe the assembly of the treadmill system. We then detail surgical implantation of the headplate on the mouse skull, followed by habituation of mice to locomotion on the treadmill system. The system is compact, movable, and simple to synchronize with other data streams, making it ideal for monitoring brain activity in diverse behavioral frameworks. For complete details on the use and execution of this protocol, please refer to Rasmussen et al. (2019).

Long-term immune cell profiling in stroke patients with or without infections.

PURPOSE: Infections are frequent complications in acute ischemic stroke and may be caused by an altered immune response influencing brain damage. We compared long-term immune responses in stroke patients with or without infections during the recovery period by performing a long-term profiling of clinically relevant inflammatory parameters from stroke onset until day 49. MATERIALS AND METHODS: Thirty-four stroke patients were retrospectively included and divided into two groups depending on infection status. Group 1 had no infections (N = 17) and group 2 had post-admission infection (N = 17). The patients were evaluated carefully for infections and evolution of the peripheral inflammatory response. Neutrophils, monocytes, lymphocytes, total leukocytes and C-reactive protein were evaluated in relation to the occurrence and development of infections. In both patient groups, an acute boost in neutrophils and monocytes were observed whereas the opposite was true for lymphocytes. RESULTS: In Group 1, neutrophils and monocytes approached normal levels after 20-30 days, but remained elevated in Group 2. We found an increase in neutrophils (p = 0.01) and leukocytes (p < 0.01) as well as C-reactive protein (p < 0.01) among infected patients. Lymphocytes remained depressed in Group 2, while Group 1 slowly approached baseline levels. In both groups, CRP levels initially increased with a slow return to baseline levels. From day 0 to 49 after stroke, uninfected patients generally experienced a decline in leukocytes, neutrophils and monocytes (all p < 0.05), while no similar changes happened among infected patients. CONCLUSIONS: Our study provides an overview of general immune cell kinetics after stroke related to infection status. Immune cell numbers were severely disturbed for weeks after the insult, independent of infection status, although infected patients achieved the highest cell counts of neutrophils, leukocytes and for C-reactive protein. The sustained depression of lymphocytes, especially and paradoxically among infected patients, warrants future studies into the mechanisms behind this, with potential for future therapies aimed at restoring normal immunity and thereby improving patient outcome.

[Cerebral manifestationsof tuberculosis].

Almost two billion people are infected with M. Tuberculosis. The most common manifestation of TB is pulmonary; however, severe manifestations of TB can affect the central nervous system. This case report describes a young refugee with onset of sixth nerve palsy and an MRI consistent with a pontine tumor. Stereotactic biopsy showed giant cells and acid-fast rods, Quantiferon test was positive, thus fulfilling the criteria for tuberculoma. The patient immediately began antituberculous treatment and slowly recovered. The purpose of this article was to elucidate the necessity of screening migrants from TB-endemic areas.

Biophysical Modeling of Dopaminergic Denervation Landscapes in the Striatum Reveals New Therapeutic Strategy.

Parkinson's disease (PD) results from a loss of dopaminergic neurons. What triggers the break-down of neuronal signaling, and how this might be compensated, is not understood. The age of onset, progression and symptoms vary between patients, and our understanding of the clinical variability remains incomplete. In this study, we investigate this, by characterizing the dopaminergic landscape in healthy and denervated striatum, using biophysical modeling. Based on currently proposed mechanisms, we model three distinct denervation patterns, and show how this affect the dopaminergic network. Depending on the denervation pattern, we show how local and global differences arise in the activity of striatal neurons. Finally, we use the mathematical formalism to suggest a cellular strategy for maintaining normal dopamine (DA) signaling following neuronal denervation. This strategy is characterized by dual enhancement of both the release and uptake capacity of DA in the remaining neurons. Overall, our results derive a new conceptual framework for the impaired dopaminergic signaling related to PD and offers testable predictions for future research directions.

More than meets the eye: The metabolic state of the body shapes visual sensations.

How body metabolism impacts sensory processing in the brain remains unresolved. In a recent study in Neuron, Padamsey et al. (2021) revealed that when the body is food restricted for several weeks, neurons in the visual cortex reduce their energy consumption at the cost of response selectivity and visual performance.

Vision therapy improves binocular visual dysfunction in patients with mild traumatic brain injury.

OBJECTIVE: To evaluate benefits of binocular vision and ocular motility training in patients with long-term sequelae after mild traumatic brain injury (mTBI). METHODS: Twenty-eight mTBI (concussion) patients from 25 to 61 years of age with oculomotor dysfunction were selected by optometric examination. The vision therapy was designed to improve convergence, pursuit and saccades as well as to increase fusional reserves. The vision therapy was conducted by a neurooptometrist and a speech therapist, and took place weekly for 1 hour during 10 continuous weeks. Between vision training sessions, patients trained at home for 15-20 minutes daily. Before and after vision therapy, patients completed a test battery including the Groffman Visual Tracing Test, King-Devick test (K-D), a reading speed test, Multidimensional Fatigue Inventory (MFI-20) and patient interviews based on a modified version of the Canadian Occupational Performance Measure (COPM). RESULTS: Twenty-seven patients completed the vision therapy. After the therapy, improvements were measured on all test parameters, e.g. Groffman Visual Tracing Test (p < 0.05), K-D-Test (p = 0.01), Reading Speed Test (p < 0.01) and MFI-20 total (p < 0.05). The results for the modified COPM were significantly improved for both performance and satisfaction (0.0001 < p < 0.01). CONCLUSION: Vision therapy improved fixation stability and endurance. Reading speed measured by the numbers of saccades and regressions time consumption per read word increased. There was also an improvement in visual attention, possibly making patients safer in traffic and outdoor activities.

The elusive varicose astrocytes.

The evolutionary pattern of different astrocyte types across animal species remains unresolved. In a recent study, Falcone and colleagues revealed that varicose projection astrocytes, a rare form of astrocyte characterized by long varicosities-containing processes, are exclusively found in hominoid brains while being absent from other primate brains.

EyeLoop: An Open-Source System for High-Speed, Closed-Loop Eye-Tracking.

Eye-trackers are widely used to study nervous system dynamics and neuropathology. Despite this broad utility, eye-tracking remains expensive, hardware-intensive, and proprietary, limiting its use to high-resource facilities. It also does not easily allow for real-time analysis and closed-loop design to link eye movements to neural activity. To address these issues, we developed an open-source eye-tracker - EyeLoop - that uses a highly efficient vectorized pupil detection method to provide uninterrupted tracking and fast online analysis with high accuracy on par with popular eye tracking modules, such as DeepLabCut. This Python-based software easily integrates custom functions using code modules, tracks a multitude of eyes, including in rodents, humans, and non-human primates, and operates at more than 1,000 frames per second on consumer-grade hardware. In this paper, we demonstrate EyeLoop's utility in an open-loop experiment and in biomedical disease identification, two common applications of eye-tracking. With a remarkably low cost and minimum setup steps, EyeLoop makes high-speed eye-tracking widely accessible.

[MR-guided laser interstitial thermal therapy in the treatment of brain tumours and epilepsy].

MR-guided laser interstitial thermal therapy (LITT) is a minimally invasive neurosurgical procedure, which in the last decade has gained significant momentum of the treatment of intracranial tumours and epileptic foci. In brief, LITT utilises the heat from a stereotactically placed laser catheter to selectively ablate a lesion or a structure under real-time MRI guidance, which is summarised and discussed in this review. The first LITT system gained FDA approval in 2007 and was CE-marked in 2018. In December 2020, the first patient with recurrent glioblastoma was treated at the Department of Neurosurgery at Rigshospitalet, Copenhagen.

Tranexamic Acid for Prevention of Hematoma Expansion in Intracerebral Hemorrhage Patients With or Without Spot Sign.

BACKGROUND AND PURPOSE: The computed tomography angiography or contrast-enhanced computed tomography based spot sign has been proposed as a biomarker for identifying on-going hematoma expansion in patients with acute intracerebral hemorrhage. We investigated, if spot-sign positive participants benefit more from tranexamic acid versus placebo as compared to spot-sign negative participants. METHODS: TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status. RESULTS: Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, -12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, -8.4% to 12.8%) for spot-sign negative participants (Pheterogenity=0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants (Pheterogenity=0.88). CONCLUSIONS: Data from the TICH-2 trial do not support that admission spot sign status modifies the treatment effect of tranexamic acid versus placebo in patients with acute intracerebral hemorrhage. The results might have been affected by low statistical power as well as treatment delay. Registration: URL: http://www.controlled-trials.com; Unique identifier: ISRCTN93732214.

Binocular integration of retinal motion information underlies optic flow processing by the cortex.

Locomotion creates various patterns of optic flow on the retina, which provide the observer with information about their movement relative to the environment. However, it is unclear how these optic flow patterns are encoded by the cortex. Here, we use two-photon calcium imaging in awake mice to systematically map monocular and binocular responses to horizontal motion in four areas of the visual cortex. We find that neurons selective to translational or rotational optic flow are abundant in higher visual areas, whereas neurons suppressed by binocular motion are more common in the primary visual cortex. Disruption of retinal direction selectivity in Frmd7 mutant mice reduces the number of translation-selective neurons in the primary visual cortex and translation- and rotation-selective neurons as well as binocular direction-selective neurons in the rostrolateral and anterior visual cortex, blurring the functional distinction between primary and higher visual areas. Thus, optic flow representations in specific areas of the visual cortex rely on binocular integration of motion information from the retina.