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BACKGROUND: Early diagnosis of encephalitis involves identifying signs of neuroinflammation, including cerebrospinal fluid (CSF) pleocytosis. However, absence of CSF pleocytosis in encephalitis has been described, most notably in autoimmune encephalitis. We examined clinical characteristics and outcomes associated with the absence or presence of CSF white blood cell pleocytosis (≥ 5 cells/µL), to inform timely diagnosis and management of encephalitis. METHODS: This retrospective study compares initial CSF profiles in 597 adult patients with all-cause encephalitis. RESULTS: Of the 597 patients, 446 (74.7%) had CSF pleocytosis while 151 (25.3%) did not. CSF pleocytosis occurred more commonly in infectious cases (200/446, 44.8%), along with 59 (13.2%) autoimmune cases, comprised chiefly of anti-NMDAR encephalitis (37/59, 62.7%). Notably, the group without pleocytosis was comprised of similar proportions of infectious (47/151, 31.1%) and autoimmune (38/151, 25.92%; p>0.05) encephalitis. Among those with infectious encephalitis, 47/247 (19%) had absent pleocytosis, including 18/76 (23.7%) with HSV-1 encephalitis. The absence of pleocytosis was associated with a decreased rate of acyclovir administration (47.7% in patients without pleocytosis vs. 71.1% in patients with pleocytosis, p<0.001). Despite pleocytosis being associated with some measures of clinical severity at admission such as a Full Outline of UnResponsiveness (FOUR) score ≤14, it was not associated with mortality or prolonged hospitalization. CONCLUSION: CSF pleocytosis is an important criterion for encephalitis diagnosis, but 25.3% of patients with all-cause encephalitis and 23.7% of those with HSV-1 encephalitis exhibit absence of pleocytosis on initial LP. Acyclovir initiation should not be delayed in the absence of pleocytosis in patients with suspected encephalitis.
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INTRODUCTION: Autoimmune encephalitis (AE) comprises a heterogeneous group of autoantibody-mediated disorders targeting the brain parenchyma. Therapeutic plasma exchange (TPE), one of several first-line therapies for AE, is often initiated when AE is suspected, albeit prior to an established diagnosis. We sought to characterize the role of TPE in the treatment of suspected AE. METHODS: A single-center, retrospective analysis was performed of adults (≥18 years) who underwent at least one TPE procedure for "suspected AE." The following parameters were extracted and evaluated descriptively: clinicopathologic characteristics, treatment course, TPE-related adverse events, outcomes (e.g., modified Rankin scale [mRS]), and diagnosis once investigation was complete. RESULTS: A total of 37 patients (median age 56 years, range 28-77 years, 62.2% male) were evaluated. Autoimmune antibody testing was positive in serum for 43.2% (n = 16) and cerebrospinal fluid for 29.7% (n = 11). Patients underwent a median of five TPE procedures (range 3-16), with 97.3% (n = 36) via a central line and 21.6% (n = 8) requiring at least one unit of plasma as replacement fluid. Fifteen patients (40.5%) experienced at least one TPE-related adverse event. Compared with mRS at admission, the mRS at discharge was improved in 21.6% (n = 8), unchanged in 59.5% (n = 22), or worse in 18.9% (n = 7). Final diagnosis of AE was determined to be definite in 48.6% (n = 18), probable in 8.1% (n = 3) and possible in 27.0% (n = 10). Six (16.2%) patients were ultimately determined to have an alternate etiology. CONCLUSION: Empiric TPE for suspected AE is generally well-tolerated. However, its efficacy remains uncertain in the absence of controlled trials, particularly in the setting of seronegative disease.
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Doenças Autoimunes do Sistema Nervoso , Encefalite , Doença de Hashimoto , Troca Plasmática , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Troca Plasmática/métodos , Estudos Retrospectivos , Plasmaferese , AutoanticorposRESUMO
The patterning and ossification of the mammalian skeleton requires the coordinated actions of both intrinsic bone morphogens and extrinsic neurovascular signals, which function in a temporal and spatial fashion to control mesenchymal progenitor cell (MPC) fate. Here, we show the genetic inhibition of tropomyosin receptor kinase A (TrkA) sensory nerve innervation of the developing cranium results in premature calvarial suture closure, associated with a decrease in suture MPC proliferation and increased mineralization. In vitro, axons from peripheral afferent neurons derived from dorsal root ganglions (DRGs) of wild-type mice induce MPC proliferation in a spatially restricted manner via a soluble factor when cocultured in microfluidic chambers. Comparative spatial transcriptomic analysis of the cranial sutures in vivo confirmed a positive association between sensory axons and proliferative MPCs. SpatialTime analysis across the developing suture revealed regional-specific alterations in bone morphogenetic protein (BMP) and TGF-ß signaling pathway transcripts in response to TrkA inhibition. RNA sequencing of DRG cell bodies, following direct, axonal coculture with MPCs, confirmed the alterations in BMP/TGF-ß signaling pathway transcripts. Among these, the BMP inhibitor follistatin-like 1 (FSTL1) replicated key features of the neural-to-bone influence, including mitogenic and anti-osteogenic effects via the inhibition of BMP/TGF-ß signaling. Taken together, our results demonstrate that sensory nerve-derived signals, including FSTL1, function to coordinate cranial bone patterning by regulating MPC proliferation and differentiation in the suture mesenchyme.
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Proteínas Morfogenéticas Ósseas/metabolismo , Suturas Cranianas/metabolismo , Sistema Nervoso/metabolismo , Transdução de Sinais , Transcriptoma , Fator de Crescimento Transformador beta/metabolismo , Animais , CamundongosRESUMO
BACKGROUND: Timely intensive care unit (ICU) admission for patients with encephalitis is associated with better prognosis. Therefore, our aim was to create a risk score predicting ICU admission in adults with encephalitis, which could aid in optimal management and resource allocation. METHODS: We initially identified variables that would be most predictive of ICU admission among 372 patients with encephalitis from two hospital systems in Houston, Texas (cohort 1), who met the International Encephalitis Consortium (IEC) criteria from 2005 to 2023. Subsequently, we used a binary logistic regression model to create a risk score for ICU admission, which we then validated externally using a separate cohort of patients from two hospitals in Baltimore, Maryland (cohort 2), who met the IEC criteria from 2006 to 2022. RESULTS: Of 634 patients with encephalitis, 255 (40%) were admitted to the ICU, including 45 of 113 (39.8%) patients with an autoimmune cause, 100 of 272 (36.7%) with an infectious cause, and 110 of 249 (44.1%) with an unknown cause (p = 0.225). After conducting a multivariate analysis in cohort 1, we found that the presence of focal neurological signs, new-onset seizure, a Full Outline of Unresponsiveness score ≤ 14, leukocytosis, and a history of chronic kidney disease at admission were associated with an increased risk of ICU admission. The resultant clinical score for predicting ICU admission had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95% confidence interval [CI] 0.72-0.82, p < 0.001). Patients were classified into three risk categories for ICU admission: low risk (score 0, 12.5%), intermediate risk (scores 1-5, 49.5%), and high risk (scores 6-8, 87.5%). External validation in cohort 2 yielded an AUROC of 0.76 (95% CI 0.69-0.83, p < 0.001). CONCLUSIONS: ICU admission is common in patients with encephalitis, regardless of etiology. Our risk score, encompassing neurologic and systemic factors, may aid physicians in decisions regarding intensity of care for adult patients with encephalitis upon hospital admission.
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Encephalitis is a devastating neurologic disease often complicated by prolonged neurologic deficits. Best practices for the management of adult patients include universal testing for a core group of etiologies, including herpes simplex virus (HSV)-1, varicella zoster virus (VZV), enteroviruses, West Nile virus, and anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody encephalitis. Empiric acyclovir therapy should be started at presentation and in selected cases continued until a second HSV-1 polymerase chain reaction test is negative. Acyclovir dose can be increased for VZV encephalitis. Supportive care is necessary for other viral etiologies. Patients in whom no cause for encephalitis is identified represent a particular challenge. Management includes repeat brain magnetic resonance imaging, imaging for occult malignancy, and empiric immunomodulatory treatment for autoimmune conditions. Next-generation sequencing (NGS) or brain biopsy should be considered. The rapid pace of discovery regarding autoimmune encephalitis and the development of advanced molecular tests such as NGS have improved diagnosis and outcomes. Research priorities include development of novel therapeutics.
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Encefalite por Herpes Simples , Encefalite , Herpesvirus Humano 1 , Doenças do Sistema Nervoso , Adulto , Humanos , Aciclovir/uso terapêutico , Herpesvirus Humano 3 , Encefalite/diagnóstico , Encefalite/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/tratamento farmacológicoRESUMO
BACKGROUND: Encephalitis represents a challenging condition to diagnose and treat. To assist physicians in considering autoimmune encephalitis (AE) sooner, we developed and validated a risk score. METHODS: The study was conducted as a retrospective cohort of patients with a diagnosis of definite viral encephalitis (VE) and AE fromââ February 2005 to December 2019. Clinically relevant and statistically significant features between cases of AE and VE were explored in a bivariate logistic regression model and results were used to identify variables for inclusion in the risk score. A multivariable logistic model was used to generate risk score values and predict risk for AE. Results were externally validated. RESULTS: A total of 1310 patients were screened. Of the 279 enrolled, 36 patients met criteria for definite AE and 88 criteria for definite VE. Patients with AE compared with VE were more likely to have a subacute to chronic presentation (odds ratio [OR] = 22.36; 95% confidence interval [CI], 2.05-243.7), Charlson comorbidity index <2 (OR = 6.62; 95% CI, 1.05-41.4), psychiatric and/or memory complaints (OR = 203.0; 95% CI, 7.57-5445), and absence of robust inflammation in the cerebrospinal fluid defined as <50 white blood cells/µL and protein <50 mg/dL (OR = 0.06; 95% CI, .005-0.50). Using these 4 variables, patients were classified into 3 risk categories for AE: low (0-1), intermediate (2-3), and high (4). Results were externally validated and the performance of the score achieved an area under the curve of 0.918 (95% CI, .871-.966). DISCUSSION: This risk score allows clinicians to estimate the probability of AE in patients presenting with encephalitis and may assist with earlier diagnosis and treatment.
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Doenças Autoimunes do Sistema Nervoso , Encefalite Viral , Encefalite , Adulto , Humanos , Estudos Retrospectivos , Encefalite/diagnóstico , Fatores de Risco , Encefalite Viral/diagnósticoRESUMO
PURPOSE OF REVIEW: Recent years have seen a dramatic increase in the identification of autoimmune encephalitis (AE) and the emergence of new causes of infectious encephalitis (IE). However, management of these patients remains challenging, with many requiring care in intensive care units. Here, we describe recent advances in the diagnosis and management of acute encephalitis. RECENT FINDINGS: Advances in the identification of clinical presentations, neuroimaging biomarkers, and electroencephalogram patterns have enabled more rapid diagnosis of encephalitis. Newer modalities such as meningitis/encephalitis multiplex PCR panels, metagenomic next-generation sequencing, and phage display-based assays are being evaluated in an effort to improve detection of autoantibodies and pathogens. Specific advances in the treatment of AE include establishment of a systematic approach to first-line therapies and the development of newer second-line modalities. The role of immunomodulation and its applications in IE are actively being investigated. In the ICU, particular attention to status epilepticus, cerebral edema, and dysautonomia may improve outcomes. SUMMARY: Substantial diagnostic delays still occur, with many cases left without an identified etiology. Antiviral therapies remain scarce, and optimal treatment regimens for AE still need to be clarified. Nevertheless, our understanding of diagnostic and therapeutic approaches to encephalitis is rapidly evolving.
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Encefalite , Doença de Hashimoto , Humanos , Encefalite/diagnóstico , Encefalite/terapia , Unidades de Terapia Intensiva , AutoanticorposRESUMO
OBJECTIVES: Anti-leucine glioma-inactivated protein 1 (anti-LGI1) autoimmune encephalitis (AE) presents as subacute memory loss, behavioral changes, and seizures. Diagnosis and treatment delays can result in long term sequelae, including cognitive impairment. 18F-FDG PET/CT may be more sensitive than MRI in patients with AE. Our objective was to determine if anti-LGI1 is associated with a distinct pattern of FDG uptake and whether this pattern persists following treatment. METHODS: Nineteen18F-FDG PET/CT brain scans (13 pre-treatment, 6 convalescent phase) for 13 patients with anti-LGI1 were studied using NeuroQ™ and CortexID™. The sensitivity of the PET images was compared to MRI. The Z scores of 47 brain regions between the pre-treatment and next available follow-up images during convalescence were compared. RESULTS: All 18F-FDG PET/CT scans demonstrated abnormal FDG uptake, while only 6 (42.9%) pre-treatment brain MRIs were abnormal. The pre-treatment scans demonstrated hypermetabolism in the bilateral medial temporal cortices, basal ganglia, brain stem, and cerebellum and hypometabolism in bilateral medial and mid frontal, cingulate, and parietotemporal cortices. Overall, the brain uptake during convalescence showed improvement of the Z scores towards 0 or normalization of previous hypometabolic activity in medial frontal cortex, inferior frontal cortex, Broca's region, parietotemporal cortex, and posterior cingulate cortex and previous hypermetabolic activity in medial temporal cortices, caudate, midbrain, pons and cerebellum. CONCLUSIONS: Brain FDG uptake was more commonly abnormal than MRI in the pre-treatment phase of anti-LGI1, and patterns of dysmetabolism differed in the pre-treatment and convalescent phases. These findings may expedite the diagnosis, treatment, and monitoring of anti-LGI1 patients.
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Doenças Autoimunes do Sistema Nervoso , Glioma , Humanos , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Leucina , Convalescença , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis patients have been reported to exhibit visual dysfunction without retinal thinning. The objective of our study was to examine the involvement of the visual pathway structure and function in anti-NMDAR encephalitis by assessing postrecovery visual function and retinal structure, and acute-phase occipital cortex function. METHODS: In this cross-sectional study, patients diagnosed with anti-NMDAR encephalitis per consensus criteria underwent postrecovery visual acuity (VA) testing and optical coherence tomography (OCT) with automated retinal layer segmentation. Clinical data and acute-phase brain 18F-fluorodeoxyglucose (FDG) PET/CT (performed within 90 days of symptom onset, assessed qualitatively and semi-quantitatively) were retrospectively analyzed. VA and OCT measures were compared between anti-NMDAR and age, sex, and race-matched healthy controls (HC). When available, FDG-PET/CT metabolism patterns were analyzed for correlations with VA, and OCT measures. RESULTS: A total of 16 anti-NMDAR (32 eyes) and 32 HC (64 eyes) were included in the study. Anti-NMDAR exhibited lower low-contrast VA (2.5% contrast: -4.4 letters [95% CI; -8.5 to -0.3]; P = 0.04, 1.25% contrast: -6.8 letters [95%CI; -12 to -1.7]; P = 0.01) compared with HC, but no differences were found on OCT-derived retinal layer thicknesses. Acute-phase FDG-PET/CT medial occipital cortex metabolism did not correlate with follow-up low-contrast VA or ganglion cell/inner plexiform layer thickness (GCIPL) (n = 7, 2.5% contrast: r = -0.31; P = 0.50, 1.25% contrast: r = -0.34; P = 0.45, GCIPL: r = -0.04; P = 0.94). CONCLUSIONS: Although the visual system seems to be involved in anti-NMDAR encephalitis, no retinal structural or occipital cortex functional abnormalities seem to be responsible for the visual dysfunction. When detected acutely, occipital lobe hypometabolism in anti-NMDAR encephalitis does not seem to associate with subsequent retrograde trans-synaptic degenerative phenomena, potentially reflecting reversible neuronal/synaptic dysfunction in the acute phase of the illness rather than neuronal degeneration.
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Encefalite Antirreceptor de N-Metil-D-Aspartato , Células Ganglionares da Retina , Humanos , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia de Coerência Óptica/métodos , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Estudos Retrospectivos , Vias Visuais/diagnóstico por imagem , Estudos Transversais , Fibras Nervosas , Acuidade VisualRESUMO
BACKGROUND: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. METHODS: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. RESULTS: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. CONCLUSIONS: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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Doenças Autoimunes , COVID-19 , Doenças Autoimunes/epidemiologia , Teste para COVID-19 , Humanos , Pandemias , Fatores de Risco , SARS-CoV-2RESUMO
Wallerian degeneration (WD) is a conserved axonal self-destruction program implicated in several neurological diseases. WD is driven by the degradation of the NAD+ synthesizing enzyme NMNAT2, the buildup of its substrate NMN, and the activation of the NAD+ degrading SARM1, eventually leading to axonal fragmentation. The regulation and amenability of these events to therapeutic interventions remain unclear. Here we explored pharmacological strategies that modulate NMN and NAD+ metabolism, namely the inhibition of the NMN-synthesizing enzyme NAMPT, activation of the nicotinic acid riboside (NaR) salvage pathway and inhibition of the NMNAT2-degrading DLK MAPK pathway in an axotomy model in vitro. Results show that NAMPT and DLK inhibition cause a significant but time-dependent delay of WD. These time-dependent effects are related to NMNAT2 degradation and changes in NMN and NAD+ levels. Supplementation of NAMPT inhibition with NaR has an enhanced effect that does not depend on timing of intervention and leads to robust protection up to 4 days. Additional DLK inhibition extends this even further to 6 days. Metabolite analyses reveal complex effects indicating that NAMPT and MAPK inhibition act by reducing NMN levels, ameliorating NAD+ loss and suppressing SARM1 activity. Finally, the axonal NAD+/NMN ratio is highly predictive of cADPR levels, extending previous cell-free evidence on the allosteric regulation of SARM1. Our findings establish a window of axon protection extending several hours following injury. Moreover, we show prolonged protection by mixed treatments combining MAPK and NAMPT inhibition that proceed via complex effects on NAD+ metabolism and inhibition of SARM1.
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Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida-Nucleotídeo Adenililtransferase , Degeneração Walleriana , Animais , Proteínas do Domínio Armadillo/metabolismo , Axônios/patologia , Proteínas do Citoesqueleto/metabolismo , Humanos , Mamíferos/metabolismo , NAD/metabolismo , Degeneração Neural/patologia , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Inibidores de Proteínas Quinases , Degeneração Walleriana/metabolismoRESUMO
Varicella-zoster virus (VZV) maintains lifelong latency in neurons following initial infection and can subsequently be reactivated to result in herpes zoster or severe neurological manifestations such as encephalitis. Mechanisms of VZV neuropathogenesis have been challenging to study due to the strict human tropism of the virus. Although neuronal entry mediators of other herpesviruses, including herpes simplex virus, have been identified, little is known regarding how VZV enters neurons. Here, we utilize a human stem cell-based neuronal model to characterize cellular factors that mediate entry. Through transcriptional profiling of infected cells, we identify the cell adhesion molecule nectin-1 as a candidate mediator of VZV entry. Nectin-1 is highly expressed in the cell bodies and axons of neurons. Either knockdown of endogenous nectin-1 or incubation with soluble forms of nectin-1 produced in mammalian cells results in a marked decrease in infectivity of neurons. Notably, while addition of soluble nectin-1 during viral infection inhibits infectivity, addition after infection has no effect on infectivity. Ectopic expression of human nectin-1 in a cell line resistant to productive VZV infection confers susceptibility to infection. In summary, we have identified nectin-1 as a neuronal entry mediator of VZV. IMPORTANCE Varicella-zoster virus (VZV) causes chickenpox, gains access to neurons during primary infection where it resides lifelong, and can later be reactivated. Reactivation is associated with shingles and postherpetic neuralgia, as well as with severe neurologic complications, including vasculitis and encephalitis. Although the varicella vaccine substantially decreases morbidity and mortality associated with primary infection, the vaccine cannot prevent the development of neuronal latency, and vaccinated populations are still at risk for reactivation. Furthermore, immunocompromised individuals are at higher risk for VZV reactivation and associated complications. Little is known regarding how VZV enters neurons. Here, we identify nectin-1 as an entry mediator of VZV in human neurons. Identification of nectin-1 as a neuronal VZV entry mediator could lead to improved treatments and preventative measures to reduce VZV related morbidity and mortality.
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Herpesvirus Humano 3 , Nectinas/imunologia , Infecção pelo Vírus da Varicela-Zoster/virologia , Herpesvirus Humano 3/imunologia , Herpesvirus Humano 3/fisiologia , Humanos , Células-Tronco Neurais , Internalização do VírusRESUMO
The severe acute respiratory syndrome coronavirus 2 or coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the correlation with this viral illness and increased risk of stroke. Although it is too early in the pandemic to know the strength of the association between COVID-19 and stroke, it is an opportune time to review the relationship between acute viral illnesses and stroke. Here, we summarize pathophysiological principles and available literature to guide understanding of how viruses may contribute to ischemic stroke. After a review of inflammatory mechanisms, we summarize relevant pathophysiological principles of vasculopathy, hypercoagulability, and hemodynamic instability. We will end by discussing mechanisms by which several well-known viruses may cause stroke in an effort to inform our understanding of the relationship between COVID-19 and stroke.
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Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , COVID-19/complicações , COVID-19/epidemiologia , AVC Isquêmico/complicações , AVC Isquêmico/fisiopatologia , Doença Aguda , Coagulação Sanguínea , Isquemia Encefálica/virologia , Hemodinâmica , Herpesvirus Humano 3 , Humanos , Inflamação/fisiopatologia , AVC Isquêmico/virologia , Pandemias , Placa Aterosclerótica/fisiopatologia , Risco , Trombofilia/fisiopatologia , Trombose/fisiopatologia , Doenças Vasculares/fisiopatologia , Viroses/fisiopatologiaRESUMO
PURPOSE OF REVIEW: The COVID-19 pandemic has cast increased attention on emerging infections. Clinicians and public health experts should be aware of emerging infectious causes of encephalitis, mechanisms by which they are transmitted, and clinical manifestations of disease. RECENT FINDINGS: A number of arthropod-borne viral infections -- transmitted chiefly by mosquitoes and ticks -- have emerged in recent years to cause outbreaks of encephalitis. Examples include Powassan virus in North America, Chikungunya virus in Central and South America, and tick-borne encephalitis virus in Europe. Many of these viruses exhibit complex life cycles and can infect multiple host animals in addition to humans. Factors thought to influence emergence of these diseases, including changes in climate and land use, are also believed to underlie the emergence of the rickettsial bacterium Orientia tsutsugamushi, now recognized as a major causative agent of acute encephalitis syndrome in South Asia. In addition, the COVID-19 pandemic has highlighted the role of bats as carriers of viruses. Recent studies have begun to uncover mechanisms by which the immune systems of bats are poised to allow for viral tolerance. Several bat-borne infections, including Nipah virus and Ebola virus, have resulted in recent outbreaks of encephalitis. SUMMARY: Infectious causes of encephalitis continue to emerge worldwide, in part because of climate change and human impacts on the environment. Expansion of surveillance measures will be critical in rapid diagnosis and limiting of outbreaks in the future.
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COVID-19/complicações , Encefalite por Arbovirus/transmissão , Encefalite/etiologia , Viroses/complicações , Animais , Humanos , Pandemias , Vigilância em Saúde Pública , Viroses/transmissãoRESUMO
The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.
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The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.
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Corticosteroides/uso terapêutico , Doenças Autoimunes/diagnóstico , Encefalite/diagnóstico , Imunoglobulinas Intravenosas/uso terapêutico , Plasmaferese , Doenças Autoimunes/terapia , Encefalite/terapia , Humanos , Resultado do TratamentoRESUMO
Encephalitis is a condition of inflammation of the brain parenchyma, occurs as a result of infectious or autoimmune causes, and can lead to encephalopathy, seizures, focal neurological deficits, neurological disability, and death. Viral causes account for the largest proportion, but in the last decade there has been growing recognition of anti-neuronal antibody syndromes. This Seminar focuses on the diagnosis and management of acute encephalitis in adults. Although viral and autoimmune causes are highlighted because of their prominent roles in encephalitis, other infectious pathogens are also considered. The role of cerebrospinal fluid studies, MRI, and novel diagnostic modalities (eg, next-generation sequencing) are discussed. Management approaches, including treatment of acute neurological complications and the use of immune suppressive and modulatory drugs for cases of suspected or confirmed autoimmune cause, are covered. Additionally, we discuss the remaining challenges in the diagnosis, management, and prognosis of encephalitis.
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Encefalite/diagnóstico , Encefalite/terapia , Hospedeiro Imunocomprometido , Convulsões , Doença Aguda , Adulto , Encéfalo , HumanosRESUMO
Sensory nerves emanating from the dorsal root extensively innervate the surfaces of mammalian bone, a privileged location for the regulation of biomechanical signaling. Here, we show that NGF-TrkA signaling in skeletal sensory nerves is an early response to mechanical loading of bone and is required to achieve maximal load-induced bone formation. First, the elimination of TrkA signaling in mice harboring mutant TrkAF592A alleles was found to greatly attenuate load-induced bone formation induced by axial forelimb compression. Next, both in vivo mechanical loading and in vitro mechanical stretch were shown to induce the profound up-regulation of NGF in osteoblasts within 1 h of loading. Furthermore, inhibition of TrkA signaling following axial forelimb compression was observed to reduce measures of Wnt/ß-catenin activity in osteocytes in the loaded bone. Finally, the administration of exogenous NGF to wild-type mice was found to significantly increase load-induced bone formation and Wnt/ß-catenin activity in osteocytes. In summary, these findings demonstrate that communication between osteoblasts and sensory nerves through NGF-TrkA signaling is essential for load-induced bone formation in mice.
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Músculo Esquelético/metabolismo , Fator de Crescimento Neural/metabolismo , Osteogênese/fisiologia , Receptor trkA/metabolismo , Células Receptoras Sensoriais/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Camundongos , Camundongos Mutantes , Fator de Crescimento Neural/genética , Osteoblastos/metabolismo , Receptor trkA/genética , Suporte de Carga/fisiologiaRESUMO
Measurements of the mechanical response of biological cells are critical for understanding injury and disease, for developing diagnostic tools, and for computational models in mechanobiology. Although it is well known that cells are sensitive to the topography of their microenvironment, the current paradigm in mechanical testing of adherent cells is mostly limited to specimens grown on flat two-dimensional substrates. In this study, we introduce a technique in which cellular indentation via optical trapping is performed on cells at a high spatial resolution to obtain their regional mechanical properties while they exist in a more favorable three-dimensional microenvironment. We combine our approach with nonlinear contact mechanics theory to consider the effects of a large deformation. This allows us to probe length scales that are relevant for obtaining overall cell stiffness values. The experimental results herein provide the hyperelastic material properties at both high (â¼100 s-1) and low (â¼1-10 s-1) strain rates of murine central nervous system glial cells. The limitations due to possible misalignment of the indenter in the three-dimensional space are examined using a computational model.
Assuntos
Microambiente Celular , Animais , Fenômenos Biomecânicos , Células Cultivadas , Camundongos , Pinças Ópticas , Estresse Mecânico , Alicerces Teciduais/químicaRESUMO
PURPOSE OF REVIEW: Autoimmune encephalitis is increasingly recognized and must be distinguished from infectious forms of encephalitis. Moreover, physicians should be aware of infectious triggers of autoimmune encephalitis and of infectious complications associated with treatment. RECENT FINDINGS: Recent epidemiological studies suggest that the incidence of autoimmune encephalitis may rival that of infectious encephalitis. Although distinguishing autoimmune from infectious forms of encephalitis on clinical grounds can be challenging, recently proposed diagnostic criteria can provide some assistance. There has been an explosion in our knowledge of autoimmune encephalitis associated with antibodies to neuronal cell surface antigens, and two of the most common forms, anti-NMDA receptor encephalitis and anti-LGI1 encephalitis, are typically associated with distinctive clinical features. Although tumors have long been known to trigger autoimmune encephalitis, it has been recently recognized that herpes simplex encephalitis may trigger the generation of antineuronal autoantibodies resulting in an autoimmune neurologic relapse. Both first and second-line therapies for autoimmune encephalitis are associated with infectious complications, whereas emerging treatments, including anakinra and tocilizumab, may also result in increased susceptibility to certain infections. SUMMARY: The diagnosis and management of autoimmune encephalitis is complex, and awareness of diagnostic criteria and modalities, typical clinical syndromes, infectious triggers of disease, and infectious complications of therapies is critical in optimizing care for affected patients.