REM and NREM Sleep Parasomnia in Anti-NMDA Receptor Encephalitis.

OBJECTIVES: Encephalitis with anti-N-methyl-d-aspartate receptor antibodies (anti-NMDARe) is a rare disorder characterized by cognitive impairment, psychosis, seizures, and abnormal movements. Abnormal behaviors during REM sleep have not been described in anti-NMDARe. METHODS: Patients were monitored by video-polysomnography on a first night followed by multiple sleep latency tests and 18 hours of bed rest. RESULTS: Two patients with anti-NMDARe developed during the acute and postacute phase parasomnias including REM sleep behavior disorder and continuous finalistic quiet gesturing during a mixed N2/R sleep. The parasomnia disorder was improved by gabapentin and clonazepam. DISCUSSION: Video-polysomnography avoids misdiagnosing these parasomnia behaviors for seizure or movement disorders and allows adequate treatment.

FX06 to rescue SARS-CoV-2-induced acute respiratory distress syndrome: a randomized clinical trial.

BACKGROUND: Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS. METHODS: This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering-from day 1 to day 7-of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi). RESULTS: Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median [IQR] 15.6 mL/kg [13.5; 18.5]), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, - 1.9 [- 3.3; - 0.5] vs. - 0.8 [- 5.5; - 1.1] mL/kg; estimated effect - 0.8 [- 3.1; + 2.4], p = 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO2/FiO2 ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%), p = 0.009). CONCLUSIONS: In this unique-dosing-regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens. Trial registration NCT04618042. Registered 5 November 2020.

Clinical features, etiologies, and outcomes in adult patients with meningoencephalitis requiring intensive care (EURECA): an international prospective multicenter cohort study.

PURPOSE: We aimed to characterize the outcomes of patients with severe meningoencephalitis requiring intensive care. METHODS: We conducted a prospective multicenter international cohort study (2017-2020) in 68 centers across 7 countries. Eligible patients were adults admitted to the intensive care unit (ICU) with meningoencephalitis, defined by an acute onset of encephalopathy (Glasgow coma scale (GCS) score [Formula: see text] 13), a cerebrospinal fluid pleocytosis [Formula: see text] 5 cells/mm3, and at least two of the following criteria: fever, seizures, focal neurological deficit, abnormal neuroimaging, and/or electroencephalogram. The primary endpoint was poor functional outcome at 3 months, defined by a score of three to six on the modified Rankin scale. Multivariable analyses stratified on centers investigated ICU admission variables associated with the primary endpoint. RESULTS: Among 599 patients enrolled, 589 (98.3%) completed the 3-month follow-up and were included. Overall, 591 etiologies were identified in those patients which were categorized into five groups: acute bacterial meningitis (n = 247, 41.9%); infectious encephalitis of viral, subacute bacterial, or fungal/parasitic origin (n = 140, 23.7%); autoimmune encephalitis (n = 38, 6.4%); neoplastic/toxic encephalitis (n = 11, 1.9%); and encephalitis of unknown origin (n = 155, 26.2%). Overall, 298 patients (50.5%, 95% CI 46.6-54.6%) had a poor functional outcome, including 152 deaths (25.8%). Variables independently associated with a poor functional outcome were age > 60 years (OR 1.75, 95% CI 1.22-2.51), immunodepression (OR 1.98, 95% CI 1.27-3.08), time between hospital and ICU admission > 1 day (OR 2.02, 95% CI 1.44-2.99), a motor component on the GCS [Formula: see text] 3 (OR 2.23, 95% CI 1.49-3.45), hemiparesis/hemiplegia (OR 2.48, 95% CI 1.47-4.18), respiratory failure (OR 1.76, 95% CI 1.05-2.94), and cardiovascular failure (OR 1.72, 95% CI 1.07-2.75). In contrast, administration of a third-generation cephalosporin (OR 0.54, 95% CI 0.37-0.78) and acyclovir (OR 0.55, 95% CI 0.38-0.80) on ICU admission were protective. CONCLUSION: Meningoencephalitis is a severe neurologic syndrome associated with high mortality and disability rates at 3 months. Actionable factors for which improvement could be made include time from hospital to ICU admission, early antimicrobial therapy, and detection of respiratory and cardiovascular complications at admission.

Outcomes of Patients With Active Cancer and COVID-19 in the Intensive-Care Unit: A Multicenter Ambispective Study.

Background: Several studies report an increased susceptibility to SARS-CoV-2 infection in cancer patients. However, data in the intensive care unit (ICU) are scarce. Research Question: We aimed to investigate the association between active cancer and mortality among patients requiring organ support in the ICU. Study Design and Methods: In this ambispective study encompassing 17 hospitals in France, we included all adult active cancer patients with SARS-CoV-2 infection requiring organ support and admitted in ICU. For each cancer patient, we included 3 non cancer patients as controls. Patients were matched at the same ratio using the inverse probability weighting approach based on a propensity score assessing the probability of cancer at admission. Mortality at day 60 after ICU admission was compared between cancer patients and non-cancer patients using primary logistic regression analysis and secondary multivariable analyses. Results: Between March 12, 2020 and March 8, 2021, 2608 patients were admitted with SARS-CoV-2 infection in our study, accounting for 2.8% of the total population of patients with SARS-CoV-2 admitted in all French ICUs within the same period. Among them, 105 (n=4%) presented with cancer (51 patients had hematological malignancy and 54 patients had solid tumors). 409 of 420 patients were included in the propensity score matching process, of whom 307 patients in the non-cancer group and 102 patients in the cancer group. 145 patients (35%) died in the ICU at day 60, 59 (56%) with cancer and 86 (27%) without cancer. In the primary logistic regression analysis, the odds ratio for death associated to cancer was 2.3 (95%CI 1.24 - 4.28, p=0.0082) higher for cancer patients than for a non-cancer patient at ICU admission. Exploratory multivariable analyses showed that solid tumor (OR: 2.344 (0.87-6.31), p=0.062) and hematological malignancies (OR: 4.144 (1.24-13.83), p=0.062) were independently associated with mortality. Interpretation: Patients with cancer and requiring ICU admission for SARS-CoV-2 infection had an increased mortality, hematological malignancy harboring the higher risk in comparison to solid tumors.

Brain Biopsy for Neurological Diseases of Unknown Etiology in Critically Ill Patients: Feasibility, Safety, and Diagnostic Yield.

OBJECTIVES: Brain biopsy is a useful surgical procedure in the management of patients with suspected neoplastic lesions. Its role in neurologic diseases of unknown etiology remains controversial, especially in ICU patients. This study was undertaken to determine the feasibility, safety, and the diagnostic yield of brain biopsy in critically ill patients with neurologic diseases of unknown etiology. We also aimed to compare these endpoints to those of non-ICU patients who underwent a brain biopsy in the same clinical context. DESIGN: Monocenter, retrospective, observational cohort study. SETTING: A French tertiary center. PATIENTS: All adult patients with neurologic diseases of unknown etiology under mechanical ventilation undergoing in-ICU brain biopsy between January 2008 and October 2020 were compared with a cohort of non-ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 2,207 brain-biopsied patients during the study period, 234 biopsies were performed for neurologic diseases of unknown etiology, including 29 who were mechanically ventilated and 205 who were not ICU patients. Specific histological diagnosis and final diagnosis rates were 62.1% and 75.9%, respectively, leading to therapeutic management modification in 62.1% of cases. Meningitis on prebiopsy cerebrospinal fluid analysis was the sole predictor of obtaining a final diagnosis (2.3 [1.4-3.8]; p = 0.02). ICU patients who experienced therapeutic management modification after the biopsy had longer survival (p = 0.03). The grade 1 to 4 (mild to severe) complication rates were: 24.1%, 3.5%, 0%, and 6.9%, respectively. Biopsy-related mortality was significantly higher in ICU patients compared with non-ICU patients (6.9% vs 0%; p = 0.02). Hematological malignancy was associated with biopsy-related mortality (1.5 [1.01-2.6]; p = 0.04). CONCLUSIONS: Brain biopsy in critically ill patients with neurologic disease of unknown etiology is associated with high diagnostic yield, therapeutic modifications and postbiopsy survival advantage. Safety profile seems acceptable in most patients. The benefit/risk ratio of brain biopsy in this population should be carefully weighted.

Endothelial cell biomarkers in critically ill COVID-19 patients with encephalitis.

COVID-19 is associated with encephalitis in critically ill patients and endothelial dysfunction seems to contribute to this life-threatening complication. Our objective was to determine the hallmark of endothelial activation in COVID-19-related encephalitis. In an observational study in intensive care unit (ICU), we compared vascular biomarkers of critically ill COVID-19 patients with or without encephalitis. To be classified in the encephalitis group, patients had to have new onset of central neurologic symptom, and pathological findings on either brain magnetic resonance imaging (MRI) and/or electroencephalogram (EEG). Among the 32 critically ill COVID-19 consecutive patients, 21 were categorized in the control group and 11 in the encephalitis group. Encephalitis patients had a longer ICU stay than control patients (median length [25th-75th percentile] of 52 [16-79] vs. 20.5 [11-44] days, respectively, p = 0.04). Nine-month overall follow-up mortality reached 21% (7/32 patients), with mortality rates in the encephalitis group and the control group of 27% and 19%, respectively. Encephalitis was associated with significant higher release of soluble endothelial activation markers (sE-selectin, tumor necrosis factor-α (TNF-α), interleukin 6, placental growth factor, and thrombomodulin), but these increases were correlated with TNF-α plasmatic levels. The hypoxia-inducible protein angiopoietin-like 4 (ANGPTL4) was at significantly higher levels in encephalitis patients compared to control patients (p = 0.0099), and in contrary to the other increased factors, was not correlated with TNF-α levels (r = 0.2832, p = 0.1163). Our findings suggest that COVID-19-related encephalitis is a cytokine-associated acute brain dysfunction. ANGPTL4 was the only elevated marker found in encephalitis patients, which was not correlated with systemic inflammation, suggesting that ANGPTL4 might be a relevant factor to predict encephalitis in critically ill COVID-19 patients.

Therapeutic plasma exchange in a critically ill Covid-19 patient.

Here we describe the effect of therapeutic plasma exchange with 5% albumin as sole replacement solution for the management of Covid-19. A 74-year-old man was admitted for severe Covid-19 acute respiratory distress syndrome. Based on the growing body of evidence that cytokine release syndrome, and especially interleukin-6, plays a key role in critically ill Covid-19 patients, we decided to implement therapeutic plasma exchange as a rescue therapy. The patient's clinical status rapidly improved, and biological records showed convincing results of decrease in interleukin-6 and inflammatory parameters under treatment. This case presents a proof-of-concept for the use of therapeutic plasma exchange with 5% albumin as sole replacement solution in a critically ill Covid-19 patient with cytokine release syndrome. This could constitute a major benefit in terms of security compared to long-lasting immunosuppressive monoclonal antibodies, or to therapeutic plasma exchange with plasma as replacement fluid. Hence, we think that a further evaluation of risk-benefit balance of this therapy in severe cases of Covid-19 should rapidly be undertaken.

Prone positioning monitored by electrical impedance tomography in patients with severe acute respiratory distress syndrome on veno-venous ECMO.

BACKGROUND: Prone positioning (PP) during veno-venous ECMO is feasible, but its physiological effects have never been thoroughly evaluated. Our objectives were to describe, through electrical impedance tomography (EIT), the impact of PP on global and regional ventilation, and optimal PEEP level. METHODS: A monocentric study conducted on ECMO-supported severe ARDS patients, ventilated in pressure-controlled mode, with 14-cmH2O driving pressure and EIT-based "optimal PEEP". Before, during and after a 16-h PP session, EIT-based distribution and variation of tidal impedance, VTdorsal/VTglobal ratio, end-expiratory lung impedance (EELI) and static compliance were collected. Subgroup analyses were performed in patients who increased their static compliance by ≥ 3 mL/cmH2O after 16 h of PP. RESULTS: For all patients (n = 21), tidal volume and EELI were redistributed from ventral to dorsal regions during PP. EIT-based optimal PEEP was significantly lower in PP than in supine position. Median (IQR) optimal PEEP decreased from 14 (12-16) to 10 (8-14) cmH2O. Thirteen (62%) patients increased their static compliance by ≥ 3 mL/cmH2O after PP on ECMO. This subgroup had higher body mass index, more frequent viral pneumonia, shorter ECMO duration, and lower baseline VTdorsal/VTglobal ratio than patients with compliance ≤ 3 mL/cmH2O (P < 0.01). CONCLUSION: Although baseline tidal volume distribution on EIT may predict static compliance improvement after PP on ECMO, our results support physiological benefits of PP in all ECMO patients, by modifying lung mechanics and potentially reducing VILI. Further studies, including a randomized-controlled trial, are now warranted to confirm potential PP benefits during ECMO.

Mechanical thrombectomy in acute ischemic stroke patients under venoarterial extracorporeal membrane oxygenation.

BACKGROUND: Use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) in adult patients to treat refractory cardiogenic shock has increased in recent years, and ischemic stroke is the most frequent VA-ECMO-induced cerebrovascular complication. No adult case of mechanical thrombectomy (MT) has been reported. METHODS: Retrospective observational study of hospital medical records of patients who received circulatory support with VA-ECMO with acute ischemic stroke treated with MT, from 2006 to 2018. RESULTS: Two adult patients on VA-ECMO with acute ischemic stroke treated with MT were found. Both cases were successfully treated. CONCLUSION: These cases illustrate the feasibility of performing MT in adult patients on ECMO.

Targeting Type IV pili as an antivirulence strategy against invasive meningococcal disease.

Bacterial virulence factors are attractive targets for the development of therapeutics. Type IV pili, which are associated with a remarkable array of properties including motility, the interaction between bacteria and attachment to biotic and abiotic surfaces, represent particularly appealing virulence factor targets. Type IV pili are present in numerous bacterial species and are critical for their pathogenesis. In this study, we report that trifluoperazine and related phenothiazines block functions associated with Type IV pili in different bacterial pathogens, by affecting piliation within minutes. Using Neisseria meningitidis as a paradigm of Gram-negative bacterial pathogens that require Type IV pili for pathogenesis, we show that piliation is sensitive to altered activity of the Na+ pumping NADH-ubiquinone oxidoreductase (Na+-NQR) complex and that these compounds probably altered the establishment of the sodium gradient. In vivo, these compounds exert a strong protective effect. They reduce meningococcal colonization of the human vessels and prevent subsequent vascular dysfunctions, intravascular coagulation and overwhelming inflammation, the hallmarks of invasive meningococcal infections. Finally, they reduce lethality. This work provides a proof of concept that compounds with activity against bacterial Type IV pili could beneficially participate in the treatment of infections caused by Type IV pilus-expressing bacteria.

Transvenous Renal Biopsy of Critically Ill Patients: Safety and Diagnostic Yield.

OBJECTIVES: Transvenous renal biopsy is an alternative way to obtain kidney samples from patients with bleeding risk factors (e.g., antiplatelet therapy and anticoagulation or coagulation disorders). This study was undertaken to determine the safety and diagnostic yield of transvenous renal biopsy of critically ill patients. DESIGN: Monocenter, retrospective, observational cohort study. SETTING: A 26-bed French tertiary ICU. PATIENTS: All patients undergoing in-ICU transvenous renal biopsy between January 2002 and February 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty patients (male/female sex ratio, 0.95; mean ± SD age, 47.3 ± 18.3 yr) were included. A histologic diagnosis was obtained for 77 patients (96.3%), with acute tubular necrosis being the most frequent: 23 (29.9%). A potentially treatable cause was found for 47 patients (58.7%). The numbers of patients with 0, 1, 2, or 3 factors (i.e., antiplatelet therapy, thrombopenia [< 150 G/L], and preventive or curative anticoagulation) at the time of the biopsy were, respectively: seven (8.8%), 37 (46.2%), 31 (38.7%), and five (6.3%). Four (5%) and two (2.5%) patients, respectively, had renal hematoma and macroscopic hematuria; none required any specific treatment. Six patients (7.5%) died in-ICU, and 90-day mortality was 8 of 80 (10%). No death was related to transvenous renal biopsy, and median biopsy-to-death interval was 38 days (interquartile range, 19.7-86 d). CONCLUSIONS: Based on this cohort of ICU patients with acute kidney injury, transvenous renal biopsy was safe and obtained a high diagnostic yield for these selected critically ill patients, even in the presence of multiple bleeding risk factors.

[Neuro-Langerhans cell histiocytosis]. / Neurohistiocytose langerhansienne.

Langerhans cell histiocytosis (LCH) is a rare multisystemic disease. LCH is characterized by proliferation of myeloid progenitors with altered differentiation program and similar phenotypic features to epidermal dendritic cells termed Langerhans cell. LCH cells express CD1a+ and langerin and exhibit BRAF V600E mutation in ∼50% of cases. Neurological involvement or neuro-LCH is observed in 5 to 10% of cases. Three subtypes of neuro-LCH are individualized. The tumor type, accounting for 45% of neuro-LCH, affect mainly young adults. Tumor neuro-LCH is characterized by space occupying lesion(s) with contrast enhancement on MRI. Clinical symptoms are due to tumor brain location(s). Pathological examination of tumor neuro-LCH lesions reveals typical features of LCH. Treatment relies on surgical resection with/without chemotherapy. Degenerative neuro-LCH, accounting for 45% of cases, is usually revealed, mostly in children, by: (i) a cerebellar syndrome, (ii) a pyramidal syndrome, (iii) a pseubulbar palsy, and/or (iv) cognitive disorders. On MRI, several signs may coexist: (i) cortex atrophy, (ii) white matter T2 hyperintensities, and (iii) deep gray matter T1 hyperintensities. Pathological analysis of degenerative neuro-LCH lesions have been rarely performed and have never detected CD1a+ histiocytes but unspecific lesions (i.e. gliosis, neuronal loss and/or demyelination). Treatment of degenerative neuro-LCH patients is poorly standardized and poorly efficient. Functional rehabilitation and socio-educational care of these young patients are crucial. The mixed subtype of neuro-LCH combines clinico-radio-pathological characteristics of the first two first forms in the same patient, and represents 10% of neuro-HL. Neuro-HL, therefore, includes three very distinct entities with epidemiological, clinical, radiological and histological specific features requiring specific medical management.

Dural Arteriovenous Fistula Mimicking a Brainstem Glioma.

BACKGROUND: Brainstem intracranial dural arteriovenous fistulas are extremely rare and can mimic a glioma at the time of presentation. CASE: We report a patient with an infiltrating brainstem lesion that finally revealed an intracranial dural arteriovenous fistula, with full neurological improvement after embolization. CONCLUSION: A careful radiological study looking for dilated vessels around the brainstem is necessary in the workup of an infiltrating brainstem lesion, in order to rule out intracranial dural arteriovenous fistula.

The cognitive spectrum in neurodegenerative Langerhans cell histiocytosis.

Clinical spectrum of cognitive troubles complicating neurodegenerative Langerhans cell histiocytosis (ND-LCH) is poorly known. The aim of this study is to evaluate cognitive functions in ND-LCH. The cognitive functions of a series of eight adult patients (7 males and 1 female; mean age 26 years IQ 25-75; range 20-33) suffering from clinical and/or radiological ND-LCH were evaluated using the following tests: (1) forward/backward digit and spatial span tasks of the WAIS-R scale and the Corsi block task, (2) the French version of the free and cued selective reminding test, (3) verbal fluency tests, (4) the Frontal Assessment Battery (FAB), (5) backward measurement of the verbal and visuospatial memories of the WAIS-R scale, (6) the Rey complex figure test, (7) the trail making tests A and B, (8) digit symbol and symbol search of the WAIS-IV scale, and (9) the Stroop test. Episodic (i.e. autobiographical or personal) memory free recall, categorical verbal fluency, phonological verbal fluency, visuospatial processing skills, attention, speed of processing, and sensitivity to interference were impaired in ND-LCH patients. In contrast, verbal and visuospatial short-term memories (i.e. immediate memories or forward span tasks) were preserved in all patients. Adult ND-LCH patients suffer from a severe but dissociated dysexecutive syndrome, mostly affecting executive strategies and relatively sparing short-term memory. Our study supports the need of assessing executive functions using comprehensive cognitive evaluation in ND-LCH patients for early diagnosis.

Granulomatous angiitis of the CNS revealing a Hodgkin lymphoma.

Apart from the iatrogenic effects of treatment, neurologic complications of Hodgkin lymphoma (HL) can be divided into direct (meningeal or intracranial/spinal localization) and indirect (paraneoplastic/immune complications).(1) Here, we present a patient with granulomatous angiitis of the CNS (GANS) associated with HL that dramatically improved after the treatment of the angiitis by cyclophosphamide, methylprednisolone, and specific chemotherapy.