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Coronavirus disease 2019 (COVID‐19) has become a pandemic disease globally. Although COVID-19 directly invades lungs, it also involves the nervous system. Therefore, patients with nervous system involvement as the presenting symptoms in the early stage of infection may easily be misdiagnosed and their treatment delayed. They become silent contagious sources or ‘virus spreaders’. In order to help neurologists to better understand the occurrence, development and prognosis, we have developed this consensus of prevention and management of COVID‐19. It can also assist other healthcare providers to be familiar with and recognise COVID-19 in their evaluation of patients in the clinic and hospital environment.

The gut microbiota constitutes a complex community of microorganisms (including bacteria, viruses, fungi, and protozoa) within the intestinal tract. Over the years, an increasing number of studies have highlighted the bidirectional communication between the gut microbiota and the central nervous system (CNS), a relationship commonly referred to as the “microbiota–gut–brain axis”. In particular, the crosstalk between the gut microbiota and the brain has been associated with the pathogenesis and progression of various CNS disorders. Phages, or bacteriophages, viruses that specifically infect bacteria, constitute the most abundant viral component within the gut microbiota. However, despite their abundance and significance in the gut microbial community, studies exploring the relationship between phages and the CNS remain surprisingly limited. This review examines the biological interplay between gut-resident phages and the CNS. Furthermore, we discuss the current literature linking phages to CNS-related pathologies.

The central nervous system has been proposed as a sanctuary site where HIV can escape antiretroviral control and develop drug resistance. HIV-1 RNA can be at higher levels in CSF than plasma, termed CSF/plasma discordance. We aimed to examine whether discordance in CSF is associated with low level viraemia (LLV) in blood. In this MRC-funded multicentre study, we prospectively recruited patients with LLV, defined as one or more episode of unexplained plasma HIV-1 RNA within 12 months, and undertook CSF examination. Separately, we prospectively collected CSF from patients undergoing lumbar puncture for a clinical indication. Patients with durable suppression of viraemia and no evidence of CNS infection were identified as controls from this group. Factors associated with CSF/plasma HIV-1 discordance overall were examined. One hundred fifty-three patients were recruited across 13 sites; 40 with LLV and 113 undergoing clinical lumbar puncture. Seven of the 40 (18 %) patients with LLV had CSF/plasma discordance, which was significantly more than 0/43 (0 %) with durable suppression in blood from the clinical group ( p  = 0.005). Resistance associated mutations were shown in six CSF samples from discordant patients with LLV (one had insufficient sample for testing), which affected antiretroviral therapy at sampling in five. Overall discordance was present in 20/153 (13 %) and was associated with nadir CD4 but not antiretroviral concentrations in plasma or CSF. CSF/plasma discordance is observed in patients with LLV and is associated with antiretroviral resistance associated mutations in CSF. The implications for clinical practice require further investigation.

Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

Abstract From the earliest days of the coronavirus disease 2019 (COVID-19) pandemic, there have been reports of significant neurological and psychological symptoms following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. This narrative review is designed to examine the potential psychoneuroendocrine pathogenic mechanisms by which SARS-CoV-2 elicits psychiatric sequelae as well as to posit potential pharmacologic strategies to address and reverse these pathologies. Following a brief overview of neurological and psychological sequelae from previous viral pandemics, we address mechanisms by which SARS-CoV-2 could enter or otherwise elicit changes in the CNS. We then examine the hypothesis that COVID-19–induced psychiatric disorders result from challenges to the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal stress axis and monoamine synthesis, physiological mechanisms that are only further enhanced by the pandemic-induced social environment of fear, isolation, and socioeconomic pressure. Finally, we evaluate several FDA-approved therapeutics in the context of COVID-19–induced psychoneuroendocrine disorders.

Coronavirus disease-2019 (COVID‐19) has become a global pandemic. COVID-19 runs its course in two phases, the initial incubation phase and later clinical symptomatic phase. Patients in the initial incubation phase often have insidious clinical symptoms, but they are still highly contagious. At the later clinical symptomatic phase, the immune system is fully activated and the disease may enter the severe infection stage in this phase. Although many patients are known for their respiratory symptoms, they had neurological symptoms in their first 1–2 days of clinical symptomatic phase, and ischaemic stroke occurred 2 weeks after the onset of the clinical symptomatic phase. The key is to prevent a patient from progressing to this severe infection from mild infection. We are sharing our experience on prevention and management of COVID-19.

Neonates with HSV and CNS involvement or skin, eye, and mouth disease were treated with IV acyclovir for 2 to 3 weeks, then acyclovir suppressive therapy or placebo for 6 months. Infants receiving acyclovir suppressive therapy had better neurodevelopmental outcomes. The outcomes of neonatal herpes simplex virus (HSV) disease are dependent on the extent of the disease. 1 Approximately 30% of babies with disseminated disease die, but only 20% of survivors have neurologic sequelae. 2 In contrast, only 6% of babies with central nervous system (CNS) disease die, but approximately 70% have permanent neurologic impairment. 2 Skin, eye, and mouth disease is not associated with death, and neurologic impairment is rare with this manifestation of neonatal herpes. 3 HSV establishes latency in sensory ganglia, with periodic reactivation and recurrence of localized disease. 4 , 5 Whether the virus subclinically reactivates in the brain after neonatal HSV . . .

HIV can infect the brain and impair central nervous system (CNS) function. Combination antiretroviral therapy (cART) has not eradicated CNS complications. HIV-associated neurocognitive disorders (HAND) remain common despite cART, although attenuated in severity. This may result from a combination of factors including inadequate treatment of HIV reservoirs such as circulating monocytes and glia, decreased effectiveness of cART in CNS, concurrent illnesses, stimulant use, and factors associated with prescribed drugs, including antiretrovirals. This review highlights recent investigations of HIV-related CNS injury with emphasis on cART-era neuropathological mechanisms in the context of both US and international settings.

In 1998, an outbreak of acute encephalitis with high mortality rates among pig handlers in Malaysia led to the discovery of a novel paramyxovirus named Nipah virus. A multidisciplinary investigation that included epidemiology, microbiology, molecular biology, and pathology was pivotal in the discovery of this new human infection. Clinical and autopsy findings were derived from a series of 32 fatal human cases of Nipah virus infection. Diagnosis was established in all cases by a combination of immunohistochemistry (IHC) and serology. Routine histological stains, IHC, and electron microscopy were used to examine autopsy tissues. The main histopathological findings included a systemic vasculitis with extensive thrombosis and parenchymal necrosis, particularly in the central nervous system. Endothelial cell damage, necrosis, and syncytial giant cell formation were seen in affected vessels. Characteristic viral inclusions were seen by light and electron microscopy. IHC analysis showed widespread presence of Nipah virus antigens in endothelial and smooth muscle cells of blood vessels. Abundant viral antigens were also seen in various parenchymal cells, particularly in neurons. Infection of endothelial cells and neurons as well as vasculitis and thrombosis seem to be critical to the pathogenesis of this new human disease.

Key Points Specialized endothelial cells in the central nervous system (CNS) limit cellular and ionic movement into the brain parenchyma and act as a critical component of the blood–cerebral spinal fluid and blood–brain barriers. In certain anatomical locations, macrophages, microglia and astrocytes are juxtaposed to CNS blood vessels, and this positions these cells to present foreign antigens and/or provide additional barrier support. Innate immune cells such as macrophages and dendritic cells are also found in the meninges and choroid plexus, enabling surveillance of fluid spaces. Viruses use several different strategies to bypass protective barriers and access the CNS. These strategies include haematological entry mechanisms, such as direct infection of vascular endothelium or travelling in immune cells across CNS barriers through a 'Trojan horse' mechanism. Viruses can also access peripheral nerves that reside outside the protective CNS barriers. Immune responses to neurotropic viruses can promote viral clearance or latency, but sometimes give rise to pathology and disease. HIV persists in CNS myeloid cells (macrophages and microglia), giving rise to chronic innate and adaptive immune responses. This pro-inflammatory milieu can eventually cause neuronal damage and dementia. By contrast, herpes simplex virus latency in sensory ganglion neurons is maintained without injury, in part by innate cytokines and virus-specific T cells. Two-photon laser scanning microscopy (TPLSM) is a microscopic technique that can be used to monitor the dynamics of immune responses to neurotropic viruses in real time. When conducting TPLSM experiments, the tissue preparation must be carefully considered because certain preparations can give rise to injury responses that confound data interpretation. Craniotomies and acute brain slices induce considerable tissue damage, whereas skull thinning opens a window for TPLSM imaging without brain injury. Intravital TPLSM imaging of innate immune sentinels, such as dendritic cells, macrophages and microglia, can provide novel insights into their function within the normal and inflamed brain. Studies have revealed that microglia, for example, are highly dynamic under steady-state conditions and rapidly redirect their cellular processes to engulf debris following tissue injury. Intravital imaging of CNS-infiltrating leukocytes during fatal viral meningitis has revealed that recruitment of myelomonocytic cells by virus-specific cytotoxic lymphocytes causes severe vascular injury and the rapid onset of convulsive seizures. Future imaging studies of CNS inflammatory responses following viral infection are required to determine how the immune system operates during states of viral clearance, latency and persistence. This Review describes the anatomical features of the central nervous system (CNS) barriers and focuses on the way in which the immune system responds to neurotropic viruses that establish latent or persistent infections in the CNS. It also discusses imaging technologies that can be used to understand viral entry and antiviral immune responses in the CNS. Viral infections are a major cause of human disease. Although most viruses replicate in peripheral tissues, some have developed unique strategies to move into the nervous system, where they establish acute or persistent infections. Viral infections in the central nervous system (CNS) can alter homeostasis, induce neurological dysfunction and result in serious, potentially life-threatening inflammatory diseases. This Review focuses on the strategies used by neurotropic viruses to cross the barrier systems of the CNS and on how the immune system detects and responds to viral infections in the CNS. A special emphasis is placed on immune surveillance of persistent and latent viral infections and on recent insights gained from imaging both protective and pathogenic antiviral immune responses.