Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

BACKGROUND: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).

Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products.

To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [< 30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥ 30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p = 0.362). No differences were identified in transfusions 6 h prior (p = 0.087) or 12 h after (p = 0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p = 0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.

Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients.

BACKGROUND: Acute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety. METHODS: The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy. RESULTS: The panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy. CONCLUSION: The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema.

Evaluation of a New Catheter for Simultaneous Intracranial Pressure Monitoring and Cerebral Spinal Fluid Drainage: A Pilot Study.

OBJECTIVES: Intracranial pressure (ICP) monitoring is a common practice when treating intracranial pathology with risk of elevated ICP. External ventricular drain (EVD) insertion is a standard approach for both monitoring ICP and draining cerebrospinal fluid (CSF). However, the conventional EVD cannot serve these two purposes simultaneously because it cannot accurately measure ICP and its pulsatile waveform while the EVD is open to CSF drainage. A new Integra® Camino® FLEX Ventricular Catheter (Integra Lifesciences, County Offaly, Ireland) with a double-lumen construction has been recently introduced into the market, and it can monitor ICP waveforms even during CSF drainage. The aim of this study was to evaluate and validate this new FLEX catheter for ICP monitoring in a neurological intensive care unit. METHODS: Six patients with 34 EVD open/close episodes were retrospectively analyzed. Continuous ICP was detected in two ways: through the FLEX sensor at the tip (ICPf) and through a fluid-coupled manometer within the FLEX catheter, functioning as a conventional EVD (ICPe). The morphologies of ICPf and ICPe pulses were extracted using Morphological Clustering and Analysis of ICP algorithm, an algorithm that has been validated in previous publications. The mean ICP and waveform shapes of ICP pulses detected through the two systems were compared. Bland-Altman plots were used to assess the agreement of the two systems. RESULTS: A significant linear relationship existed between mean ICPf and mean ICPe, which can be described as: mICPf = 0.81 × mICPe + 1.67 (r = 0.79). The Bland-Altman plot revealed that no significant difference existed between the two ICPs (average of [ICPe-ICPf] was - 1.69 mmHg, 95% limits of agreement: - 7.94 to 4.56 mmHg). The amplitudes of the landmarks of ICP pulse waveforms from the two systems showed strong, linear relationship (r ranging from 0.89 to 0.94). CONCLUSIONS: This study compared a new FLEX ventricular catheter with conventional fluid-coupled manometer for ICP waveform monitoring. Strong concordance in ICP value and waveform morphology between the two systems indicates that this catheter can be used for reliability for both clinical and research applications.

Cerebral Vascular Changes During Acute Intracranial Pressure Drop.

OBJECTIVE: This study applied a new external ventricular catheter, which allows intracranial pressure (ICP) monitoring and cerebral spinal fluid (CSF) drainage simultaneously, to study cerebral vascular responses during acute CSF drainage. METHODS: Six patients with 34 external ventricular drain (EVD) opening sessions were retrospectively analyzed. A published algorithm was used to extract morphological features of ICP recordings, and a template-matching algorithm was applied to calculate the likelihood of cerebral vasodilation index (VDI) and cerebral vasoconstriction index (VCI) based on the changes of ICP waveforms during CSF drainage. Power change (∆P) of ICP B-waves after EVD opening was also calculated. Cerebral autoregulation (CA) was assessed through phase difference between arterial blood pressure (ABP) and ICP using a previously published wavelet-based algorithm. RESULTS: The result showed that acute CSF drainage reduced mean ICP (P = 0.016) increased VCI (P = 0.02) and reduced ICP B-wave power (P = 0.016) significantly. VCI reacted to ICP changes negatively when ICP was between 10 and 25 mmHg, and VCI remained unchanged when ICP was outside the 10-25 mmHg range. VCI negatively (r = - 0.44) and VDI positively (r = 0.82) correlated with ∆P of ICP B-waves, indicating that stronger vasoconstriction resulted in bigger power drop in ICP B-waves. Better CA prior to EVD opening triggered bigger drop in the power of ICP B-waves (r = - 0.612). CONCLUSIONS: This study demonstrates that acute CSF drainage reduces mean ICP, and results in vasoconstriction which can be detected through an index, VCI. Cerebral vessels actively respond to ICP changes or cerebral perfusion pressure (CPP) changes in a certain range; beyond which, the vessels are insensitive to the changes in ICP and CPP.

Diagnostic Approach to Health Care- and Device-Associated Central Nervous System Infections.

Health care- and device-associated central nervous system (CNS) infections have a distinct epidemiology, pathophysiology, and microbiology that require a unique diagnostic approach. Most clinical signs, symptoms, and tests used to diagnose community-acquired CNS infections are insensitive and nonspecific in neurosurgical patients due to postsurgical changes, invasive devices, prior antimicrobial exposure, and underlying CNS disease. The lack of a standardized definition of infection or diagnostic pathway has added to this challenge. In this review, we summarize the epidemiology, microbiology, and clinical presentation of these infections, discuss the issues with existing microbiologic tests, and give an overview of the current diagnostic approach.

Treatment options for posttraumatic epilepsy.

PURPOSE OF REVIEW: Posttraumatic seizures (PTS) and posttraumatic epilepsy (PTE) are common and debilitating consequences of traumatic brain injury (TBI). Early PTS result in secondary brain injury by raising intracranial pressure and worsening cerebral edema and metabolic crisis. PTE is a localization-related epilepsy strongly associated with TBI severity, but risk factors for PTE and epileptogenesis are incompletely understood and are active areas of research. Medical management of PTS in adults and children is reviewed. Surgical options for posttraumatic drug-resistant epilepsy are also discussed. RECENT FINDINGS: Continuous electroencephalography is indicated for children and adults with TBI and coma because of the high incidence of nonconvulsive seizures, periodic discharges, and associated secondary brain injury in this population. Neuroinflammation is a central component of secondary brain injury and appears to play a key role in epileptogenesis. Levetiracetam is increasingly used for seizure prophylaxis in adults and children, but variability remains. SUMMARY: PTS occur commonly after TBI and are associated with secondary brain injury and worse outcomes in adults and children. Current medical and surgical management options for PTS and PTE are reviewed.

Functional interferometric diffusing wave spectroscopy of the human brain.

Cerebral blood flow (CBF) is essential for brain function, and CBF-related signals can inform us about brain activity. Yet currently, high-end medical instrumentation is needed to perform a CBF measurement in adult humans. Here, we describe functional interferometric diffusing wave spectroscopy (fiDWS), which introduces and collects near-infrared light via the scalp, using inexpensive detector arrays to rapidly monitor coherent light fluctuations that encode brain blood flow index (BFI), a surrogate for CBF. Compared to other functional optical approaches, fiDWS measures BFI faster and deeper while also providing continuous wave absorption signals. Achieving clear pulsatile BFI waveforms at source-collector separations of 3.5 cm, we confirm that optical BFI, not absorption, shows a graded hypercapnic response consistent with human cerebrovascular physiology, and that BFI has a better contrast-to-noise ratio than absorption during brain activation. By providing high-throughput measurements of optical BFI at low cost, fiDWS will expand access to CBF.

Distribution and volume analysis of early hemorrhagic contusions by MRI after traumatic brain injury: a preliminary report of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx).

Traumatic brain injury (TBI) can produce heterogeneous injury patterns including a variety of hemorrhagic and non-hemorrhagic lesions. The impact of lesion size, location, and interaction between total number and location of contusions may influence the occurrence of seizures after TBI. We report our methodologic approach to this question in this preliminary report of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx). We describe lesion identification and segmentation of hemorrhagic contusions by early posttraumatic magnetic resonance imaging (MRI). We describe the preliminary methods of manual lesion segmentation in an initial cohort of 32 TBI patients from the EpiBioS4Rx cohort and the preliminary association of hemorrhagic contusion and edema location and volume to seizure incidence.

Continuous Electroencephalographic Training for Neuroscience Intensive Care Unit Nurses: A Feasibility Study.

BACKGROUND: Use of continuous electroencephalographic (cEEG) monitoring has more than doubled at our institution for the last 4 years. Although intensive care unit cEEG is reviewed remotely by board-certified epileptologists every 4 to 6 hours, there are inherent delays between occurrence, recognition, and treatment of epileptiform activity. Neuroscience intensive care unit (NSICU) nurses are uniquely positioned to monitor cEEG in real time yet do not receive formal training. The purpose of this study was to evaluate the effectiveness of an education program to teach nurses to monitor cEEG, identify a burst suppression pattern, and measure the duration of suppression. METHODS: We performed a retrospective analysis of pretest and posttest data. All NSICU nurses (40) were invited to complete the pretest (PT-0), with 25 participating. Learning style/preference, demographics, comfort with cEEG, and knowledge of EEG fundamentals were assessed. A convenience cohort of NSICU nurses (13) were selected to undergo EEG training. Posttests evaluating EEG fundamental knowledge were completed immediately after training (PT-1), at 3 months (PT-3), and at 6 months (PT-6). The cohort also completed a burst suppression module after the training, which assessed ability to quantify the duration of suppression. RESULTS: Mean cohort test scores significantly improved after the training (P < .001). All nurses showed improvement in test scores, and 76.9% passed PT-1 (a score of 80% or higher). Reported mean comfort level with EEG also significantly improved after the training (P = .001). There was no significant difference between mean cohort scores between PT-1, PT-3, and PT-6 (all 88.6%; P = 1.000). Mean cohort score from the bust suppression module was 73%, with test scores ranging from 31% to 93%. CONCLUSIONS: NSICU nurses can be taught fundamentals of cEEG, to identify a burst suppression pattern, and to quantify the duration of suppression. Further research is needed to determine whether this knowledge can be translated into clinical competency and affect patient care.

Analysis of high-frequency PbtO2 measures in traumatic brain injury: insights into the treatment threshold.

OBJECTIVEBrain tissue hypoxia is common after traumatic brain injury (TBI). Technology now exists that can detect brain hypoxia and guide corrective therapy. Current guidelines for the management of severe TBI recommend maintaining partial pressure of brain tissue oxygen (PbtO2) > 15-20 mm Hg; however, uncertainty persists as to the optimal treatment threshold. The object of this study was to better inform the relationship between PbtO2 values and outcome for patients with TBI.METHODSPbtO2 measurements were prospectively and automatically collected every minute from consecutive patients admitted to the San Francisco General Hospital neurological ICU during a 6-year period. Mean PbtO2 values in TBI patients as well as the proportion of PbtO2 values below each of 75 thresholds between 0 mm Hg and 75 mm Hg over various epochs up to 30 days from the time of admission were analyzed. Patient outcomes were determined using the Glasgow Outcome Scale. The authors explored putative treatment thresholds by generating 675 separate receiver operating characteristic curves and 675 generalized linear models to examine each 1-mm Hg threshold for various epochs.RESULTSA total of 1,380,841 PbtO2 values were recorded in 190 TBI patients. A high proportion of PbtO2 measures were below 20 mm Hg irrespective of the examined epoch. Time below treatment thresholds was more strongly associated with outcome than mean PbtO2. A treatment window was suggested: a threshold of 19 mm Hg most robustly distinguished patients by outcome, especially from days 3-5; however, benefit was suggested from maintaining values at least as high as 33 mm Hg.CONCLUSIONSThis analysis of high-frequency physiological data substantially informs the relationship between PbtO2 values and outcome. The results suggest a therapeutic window for PbtO2 in TBI patients along with minimum and preferred PbtO2 treatment thresholds, which may be examined in future studies. Traditional treatment thresholds that have the strongest association with outcome may not be optimal.

Seizures and the Role of Anticonvulsants After Traumatic Brain Injury.

Posttraumatic seizures are a common complication of traumatic brain injury. Posttraumatic epilepsy accounts for 20% of symptomatic epilepsy in the general population and 5% of all epilepsy. Early posttraumatic seizures occur in more than 20% of patients in the intensive care unit and are associated with secondary brain injury and worse patient outcomes. Most posttraumatic seizures are nonconvulsive and therefore continuous electroencephalography monitoring should be the standard of care for patients with moderate or severe brain injury. The literature shows that posttraumatic seizures result in secondary brain injury caused by increased intracranial pressure, cerebral edema and metabolic crisis.