Cause Of Fatal Encephalitis Research Articles

Pathogenesis and outcome of VA1 astrovirus infection in the human brain are defined by disruption of neural functions and imbalanced host immune responses.

Astroviruses (AstVs) can cause of severe infection of the central nervous system (CNS) in immunocompromised individuals. Here, we identified a human AstV of the VA1 genotype, HAstV-NIH, as the cause of fatal encephalitis in an immunocompromised adult. We investigated the cells targeted by AstV, neurophysiological changes, and host responses by analyzing gene expression, protein expression, and cellular morphology in brain tissue from three cases of AstV neurologic disease (AstV-ND). We demonstrate that neurons are the principal cells targeted by AstV in the brain and that the cerebellum and brainstem have the highest burden of infection. Detection of VA1 AstV in interconnected brain structures such as thalamus, deep cerebellar nuclei, Purkinje cells, and pontine nuclei indicates that AstV may spread between connected neurons transsynaptically. We found transcriptional dysregulation of neural functions and disruption of both excitatory and inhibitory synaptic innervation of infected neurons. Importantly, transcriptional dysregulation of neural functions occurred in fatal cases, but not in a patient that survived AstV-ND. We show that the innate, but not adaptive immune response was transcriptionally driving host defense in the brain of immunocompromised patients with AstV-ND. Both transcriptome and molecular pathology studies showed that most of the cellular changes were associated with CNS-intrinsic cells involved in phagocytosis and injury repair (microglia, perivascular/parenchymal border macrophages, and astrocytes), but not CNS-extrinsic cells (T and B cells), suggesting an imbalance of innate and adaptive immune responses to AstV infection in the brain as a result of the underlying immunodeficiencies. These results show that VA1 AstV infection of the brain in immunocompromised humans is associated with imbalanced host defense responses, disruption of neuronal somatodendritic compartments and synapses and increased phagocytic cellular activity. Improved understanding of the response to viral infections of the human CNS may provide clues for how to manipulate these processes to improve outcomes.

New World camelids are sentinels for the presence of Borna disease virus.

Borna disease (BD), a frequently fatal neurologic disorder caused by Borna disease virus 1 (BoDV-1), has been observed for decades in horses, sheep, and other mammals in certain regions of Europe. The bicoloured white-toothed shrew (Crocidura leucodon) was identified as a persistently infected species involved in virus transmission. Recently, BoDV-1 attracted attention as a cause of fatal encephalitis in humans. Here, we report investigations on BoDV-1-infected llamas from a farm in a BD endemic area of Switzerland, and alpacas from holdings in a region of Germany where BD was last seen in the 1960s but not thereafter. All New World camelids showed apathy and abnormal behaviour, necessitating euthanasia. Histologically, severe non-suppurative meningoencephalitis with neuronal Joest-Degen inclusion bodies was observed. BoDV-1 was confirmed by immunohistology, RT-qPCR, and sequencing in selected animals. Analysis of the llama herd over 20years showed that losses due to clinically suspected BD increased within the last decade. BoDV-1 whole-genome sequences from one Swiss llama and one German alpaca and-for comparison-from one Swiss horse and one German shrew were established. They represent the first published whole-genome sequences of BoDV-1 clusters 1B and 3, respectively. Our analysis suggests that New World camelids may have a role as a sentinel species for BoDV-1 infection, even when symptomatic cases are lacking in other animal species.

Nipah virus in India: past, present and future

Nipah virus (NiV) is one of the emerging highly pathogenic virus. Like Ebola and Zika viruses, NiV too is threatening the integrity of the mankind. The family Paramyxoviruses has been traditionally associated with a group of viruses with narrow host range and typically causes outbreaks with low mortality rates. But with the emergence of highly pathogenic Hendra virus and closely related NiV, they have evolved as a cause of fatal encephalitis across broad range of vertebrate species including humans. The natural reservoir of NiV is Pteropus bat, which is apparently distributed all over the South East Asia. The bat population from North East to North West states in India have NiV antibodies which mean there is active NiV infection among Indian bats. As NiV is associated with high morbidity and mortality they pose a risk from natural outbreaks, laboratory accidents or deliberate misuse. The development of effective prevention and treatment strategies is very crucial. Preparedness, surveillance, constant vigil needs to be carried out continuously in the country. The present outbreak in India after nearly eleven years with a high case fatality rate indicate that there is a total lack of health care systems preparedness and surveillance strategy. The anthropogenic and environmental changes occurring due to rapid urbanization and massive deforestation has made India now even more vulnerable for such recurrent outbreaks. This review highlights the changing trend of the NiV outbreaks in the past and the current outbreak in India.

Rabies: the most common cause of fatal encephalitis in India

Rabies, a rapidly progressing encephalitis, is a substantial public health problem in India, responsible for more than 20 000 deaths every year. Although steps are being taken to contain the disease, India still carries over 35% of the global burden of rabies, due to inadequate post-exposure prophylaxis. Will India be able to control rabies? Sanjeet Bagcchi investigates.

Therapeutic implications of new insights into the critical role of VP16 in initiating the earliest stages of HSV reactivation from latency.

Reactivation of herpes simplex virus (HSV) is a leading cause of fatal encephalitis in the USA and recurrent herpetic keratitis is a major infectious cause of blindness. There is no effective vaccine and no cure for HSV latency. While current antiviral drugs reduce viral replication, none prevent the initiation of reactivation in the nervous system and, thus, chronic inflammatory damage proceeds. The discovery that HSV VP16 is necessary for the exit from latency represents the first potential target for preventing the chronic inflammatory insult associated with HSV reactivation. Blocking VP16 transactivation would reduce the spread of the virus in the population and, importantly, presumably reduce or prevent the pathological long term chronic inflammation in the nervous system.

Nondominant Hemisphere Encephalitis in Patient with Signs of Viral Meningitis, New York, USA

To the Editor: Herpes simplex virus (HSV) is the most common cause of sporadic fatal encephalitis across the globe and for all ages. HSV is the etiologic agent of 10%–20% of the 20,000 cases of encephalitis per year in the United States (1); >50% of untreated cases are fatal. Of the 2 types of HSV, HSV-1 and HSV-2, HSV-1 most commonly affects persons 20–40 years of age, whereas HSV-2 commonly affects neonates. This rapidly progressive disease is a common cause of fatal encephalitis in the United States. Signs and symptoms include fever and headache for a few days, followed by confusion, focal deficits, seizures or hemiparesis, hallucinations, and altered levels of consciousness (2). One third of all HSV encephalitis cases afflict children and adolescents. Lumbar puncture typically shows lymphocytic pleocytosis, increased erythrocytes, and elevated protein (2); glucose level is typically within normal limits. Serologic assays often show prior infection. Brain imaging frequently indicates unilateral frontal or temporal lobe abnormalities with edema or hematoma (3,4). The involvement of the nondominant brain hemisphere is associated with atypical signs and symptoms (5). Diagnosis is usually made by using PCR to examine viral DNA in cerebrospinal fluid (CSF) (6). This method of finding DNA in CSF is highly sensitive (98%) and specific (94%–100%). Without therapy, 70% of patients die; with therapy, 20%–30% die (6). Illness includes behavioral sequelae. A 43-year-old female immigrant from China was admitted to Flushing Hospital Medical Center in Flushing, New York, with complaints of headache, fever, and vomiting, which she had experienced for ≈1 week. She had no photophobia, confusion, or rash; neurologic examination found no abnormalities. CSF contained 81 leukocytes with 82% lymphocytes, 3 erythrocytes, protein at 194 mg/dL, and glucose at 67 mg/dL. CSF was positive for HSV-1 viral DNA by PCR. A computed tomography (CT) scan of the head showed unilateral temporal lobe edema. Intravenous acyclovir 10 mg/kg every 8 hours was administered. HIV test was negative. On day 5, a repeat CT scan showed worsening edema and hemorrhage, despite clinical improvement (Figure). CSF contained 490 leukocytes with 99% lymphocytes and protein at 336 mg/dL. After continued treatment with parenteral acyclovir, the patient’s symptoms resolved. On day 12, the patient was discharged after a final CT scan showed resolution of hemorrhage and edema and CSF contained decreased leukocytes and protein. Figure Computed tomography scan showing hemorrhage in edematous part of brain of patient with herpes simplex virus encephalitis, day 5 of hospitalization. Although this patient had classic signs of meningitis without encephalitis, the CT scan of the head showed cerebral involvement. These factors can be explained by the location of cerebral inflammation in the nondominant lobe of the brain, thereby masking signs of encephalitis. The classic teaching that viral meningitis may not need treatment may miss the occasional viral encephalitis if brain imaging and CSF PCR are not performed. Failure to perform these tests may lead to illness and death from HSV encephalitis if this disease is not considered as a possible diagnosis.

Fatal Case of Deer Tick Virus Encephalitis

Deer tick virus is related to Powassan virus, a tickborne encephalitis virus. A 62-year-old man presented with a meningoencephalitis syndrome and eventually died. Analyses of tissue samples obtained during surgery and at autopsy revealed a widespread necrotizing meningoencephalitis. Nucleic acid was extracted from formalin-fixed tissue, and the presence of deer tick virus was verified on a flavivirus-specific polymerase-chain-reaction (PCR) assay, followed by sequence confirmation. Immunohistochemical analysis with antisera specific for deer tick virus identified numerous immunoreactive neurons, with prominent involvement of large neurons in the brain stem, cerebellum, basal ganglia, thalamus, and spinal cord. This case demonstrates that deer tick virus can be a cause of fatal encephalitis.

A Comparative Study of Pathogenicity and Antigenicity of Four Strains of Herpes Simplex

Summary Comparative studies of pathogenicity and antigenicity were made of four strains of herpes simplex in order to investigate some of the differences which may exist between strains of a single viral species. Mice, rabbits, guinea pigs, white rats, hamsters, cotton rats and chick embryos were observed after inoculation of mouse brain emulsions by various routes. Although herpes simplex is a pantropic virus, differences between strains are accentuated by certain tests. Thus, death of the majority of animals following corneal infection of the rabbit or intranasal inoculation of the cotton rat can be used to indicate strains with prominent neurotropic tendencies, while marked local reactions after intradermal injection of the guinea pig are indicative of dermatotropism. These distinctions probably hold only for the particular species of animals and routes tested, as the strain which was most dermatotropic in our laboratory, “O”, was the cause of fatal encephalitis in a human being. It is not known whether these differences in potentiality of herpes strains are of epidemiologic significance. The development of neutralizing antibodies in rabbits after corneal and intra-abdominal inoculations was studied. Significant levels of antibody were present by three weeks and peak titers were attained by six weeks. The serologic relationships were investigated by testing the corneal reactivity of immunized rabbits to homologous and heterologous strains and by cross neutralization tests in mice and chick embryos. The chick embryo tests were found to be the most sensitive and satisfactory for this purpose.