Microglial Nodules Research Articles

Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.

COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38–97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20–30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

Pathophysiology and Spectrum of Neuro-COVID

Some neurological manifestations may not be specific for COVID-19 and due to other causes but that COVID-19 must be considered as a differential of all acute neurological conditions. The following neuropathological abnormalities were found: acute microscopic thrombotic ischemic infarcts; microscopic haemorrhagic infarcts; petechial haemorrhage; focal perivascular parenchymal Tcell infiltrates; diffuse perivascular parenchymal T-cell infiltrates; leptomeningeal inflammation; interstitial brainstem inflammation with neuronal loss; capillary endothelium expression of ACE2 receptors; microglial nodules; and hypoxicischemia changes and neuronal loss.

Neuropathology of COVID-19 (neuro-COVID): clinicopathological update.

Coronavirus disease 2019 (COVID-19) is emerging as the greatest public health crisis in the early 21stcentury. Its causative agent, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is an enveloped single stranded positive-sense ribonucleic acid virus that enters cells via the angiotensin converting enzyme 2 receptor or several other receptors. While COVID-19 primarily affects the respiratory system, other organs including the brain can be involved. In Western clinical studies, relatively mild neurological dysfunction such as anosmia and dysgeusia is frequent (~70-84%) while severe neurologic disorders such as stroke (~1-6%) and meningoencephalitis are less common. It is unclear how much SARS-CoV-2 infection contributes to the incidence of stroke given co-morbidities in the affected patient population. Rarely, clinically-defined cases of acute disseminated encephalomyelitis, Guillain-Barré syndrome and acute necrotizing encephalopathy have been reported in COVID-19 patients. Common neuropathological findings in the 184 patients reviewed include microglial activation (42.9%) with microglial nodules in a subset (33.3%), lymphoid inflammation (37.5%), acute hypoxic-ischemic changes (29.9%), astrogliosis (27.7%), acute/subacute brain infarcts (21.2%), spontaneous hemorrhage (15.8%), and microthrombi (15.2%). In our institutional cases, we also note occasional anterior pituitary infarcts. COVID-19 coagulopathy, sepsis, and acute respiratory distress likely contribute to a number of these findings. When present, central nervous system lymphoid inflammation is often minimal to mild, is detected best by immunohistochemistry and, in one study, indistinguishable from control sepsis cases. Some cases evince microglial nodules or neuronophagy, strongly supporting viral meningoencephalitis, with a proclivity for involvement of the medulla oblongata. The virus is detectable by reverse transcriptase polymerase chain reaction, immunohistochemistry, or electron microscopy in human cerebrum, cerebellum, cranial nerves, olfactory bulb, as well as in the olfactory epithelium; neurons and endothelium can also be infected. Review of the extant cases has limitations including selection bias and limited clinical information in some cases. Much remains to be learned about the effects of direct viral infection of brain cells and whether SARS-CoV-2 persists long-term contributing to chronic symptomatology.

Deep Spatial Profiling of COVID-19 Brains Reveals Neuroinflammation by Compartmentalized Local Immune Cell Interactions and Targets for Intervention

COVID-19 can cause acute and chronic neurological symptoms. The underlying pathophysiological mechanisms, the involved immune cells, their spatial distribution, cellular interactions and the role of virus tropism remain largely unclear. Here, we deeply interrogated the brain stem and olfactory bulb in COVID-19 patients with imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional single-cell level. We observed significant immune activation in the CNS and identified distinct phenotypes of T cells and microglial clusters, their presence in specific anatomical regions and context-specific cellular interactions. Microglial nodules and perivascular immune cell clusters constitute key sites of the local immune response, with viral antigen present in ACE2-expressing cells in the perivascular compartment. Disease-associated neuroinflammation is associated with astrogliosis and severe axonal damage as a structural basis for the neurologic deficits. Finally, we identify compartment- and cluster-specific immune checkpoints that can be targeted for future therapeutic interventions.Funding: This project was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, GermanResearch Foundation) (SFB 992, SFB1160, SFB/TRR167, SFB/TRR179, German Excellency strategyCIBSS - EXC-2189– Project ID390939984) and special research funds from the Ministry for Science, Research and Art of Baden-Wuerttemberg dedicated to “COVID-19 research” and “Neuroinflammation”.B.B. was further supported by DFG grant BE-5496/5-1 and M.P. was further supported by the Sobek Foundation, the Ernst-Jung Foundation, the Reinhart-Koselleck-Grant and Gottfried Wilhelm Leibniz-Prize.H.E.M. was supported by DFG ME-3644/5-1.Ethical Approval: The analyses were performed with the approval of the Institutional Review Boards (Ethic Committee of the Albert-Ludwigs-University, Freiburg: 322/20, 10008/09; Ethics Committee of the Hamburg Chamber of Physicians: WF-051/20, PV7311). The study was performed in agreement with the principles expressed in the Declaration of Helsinki (2013).Conflict of Interest: None to declare.

Neuronophagia and microglial nodules in a SARS-CoV-2 patient with cerebellar hemorrhage

We document the neuropathologic findings of a 73-year old man who died from acute cerebellar hemorrhage in the context of relatively mild SARS-CoV2 infection. The patient developed sudden onset of headache, nausea, and vomiting, immediately followed by loss of consciousness on the day of admission. Emergency medical services found him severely hypoxemic at home, and the patient suffered a cardiac arrest during transport to the emergency department. The emergency team achieved return of spontaneous circulation after over 17 min of resuscitation. A chest radiograph revealed hazy bilateral opacities; and real-time-PCR for SARS-CoV-2 on the nasopharyngeal swab was positive. Computed tomography of the head showed a large right cerebellar hemorrhage, with tonsillar herniation and intraventricular hemorrhage. One day after presentation, he was transitioned to comfort care and died shortly after palliative extubation. Autopsy performed 3 h after death showed cerebellar hemorrhage and acute infarcts in the dorsal pons and medulla. Remarkably, there were microglial nodules and neuronophagia bilaterally in the inferior olives and multifocally in the cerebellar dentate nuclei. This constellation of findings has not been reported thus far in the context of SARS-CoV-2 infection.

Impairment in neurocognitive function following experimental neonatal guinea pig cytomegalovirus infection.

BACKGROUND:Cytomegalovirus (CMV) is a leading infectious cause of neurologic deficits, both in the settings of congenital and perinatal infection, but few animal models exist to study neurodevelopmental outcomes. This study examined the impact of neonatal guinea pig CMV (GPCMV) infection on spatial learning and memory in a Morris water maze (MWM) model.METHODS:Newborn pups were challenged intraperitoneally (ip) with a pathogenic red fluorescent protein (RFP)-tagged GPCMV, or sham-inoculated. On days 15–19 post-infection (pi), pups were tested in the MWM. Viral loads were measured in blood and tissue by quantitative PCR (qPCR), and brain samples collected at necropsy were examined by histology and immunohistochemistry.RESULTS:Viremia (DNAemia) was detected at day 3 pi in 7/8 challenged animals. End-organ dissemination was observed, by qPCR, in lung, liver, and spleen. CD4+ and CD8+ T-cell infiltrates were present in brains of challenged animals, particularly in periventricular and hippocampal regions. Reactive gliosis and microglial nodules were observed. Statistically significant spatial learning and memory deficits were observed by MWM, particularly for total maze distance travelled (p<0.0001).CONCLUSION:Neonatal GPCMV infection in guinea pigs results in cognitive defects demonstrable by the MWM. This neonatal guinea pig challenge model can be exploited for studying antiviral interventions.

CD4+ T cell expression of the IL-10 receptor is necessary for facial motoneuron survival after axotomy

BackgroundAfter peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA).MethodsImmunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the facial motor nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets.ResultsCD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro.ConclusionsThese findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA.

How frequent is double pathology in Rasmussen encephalitis?

Rasmussen encephalitis (RE) is an uncommon, medically refractory cause of seizures that usually presents in childhood or adolescence resulting in unilateral hemispheric atrophy in most cases. The purported immune-mediated cause of the disease is supported by the characteristic histopathologic features of diffuse perivascular and intraparenchymal T-cell-predominant infiltrates, microglial activation with microglial nodules, and neuronophagia. A small number of reports have emerged, however, suggesting that double pathology (such as focal cortical dysplasia (FCD) or hippocampal sclerosis) may be present. We asked how often double pathology could be demonstrated in RE. A 15-year retrospective review of all RE cases seen at our pediatric tertiary care hospital yielded 11 patients, many of which had some degree of double pathology. The most diagnostically incontrovertible examples showed leptomeningeal neuronal heterotopia (n = 1) or leptomeningeal melanocytic nevus (n=1). Another coexistent feature was neuronal gigantism unassociated with hemimegaloencephaly, particularly prominent in layer II (n=2). Three additional cases showed dysmorphic neurons in the hippocampus (n=2) and dentate granule cell layer dispersion/bilamination (n=1). Finally, 2 cases had exaggerated radial arrangement of neurons FCD type Ia-like changes) (n=2), a condition known to have interobserver discordance. In summary, 7/11 of our RE cases showed prominent additional pathologies, 6 of which demonstrated disproportionately more severe inflammation, neuronophagia, or microglial activation in regions of double pathology. Our collection of cases shows that a majority of RE cases show double pathology. Although some of these cases can be reactive, the presence of maldevelopment in a subset raises the possibility of a causal relationship with RE. .

Immunofluorescence and histopathological studies in cattle brain for diagnosis of rabies

The present study was conducted with an aim to detect the rabies viral antigen in the brains of naturally infected cattle by immunofluorescence and identify the histopathological alterations of infected brain. For this purpose, a total of 29 brain samples were collected from rabies suspected cows, presented for post-mortem confirmation of rabies in the Department of Veterinary Pathology, GADVASU, Ludhiana. Gross examination of the collected brains showed the presence of severe congestions in both meningeal and cerebral blood vessels, as well, hemorrhage and edema in cerebrum and cerebellum. The immunofluorescence study revealed the presence of the rabies viral antigen, Negri bodies and the characteristic bullet shape of the viral particles. Histopathological examination revealed the presence of intra cytoplasmic inclusion bodies (Negri bodies) in the Purkinje cells of cerebellum, marked neuronal necrosis with satellitosis and neuronophagia, perivascular cuffing (PVC) with mononuclear cells (MNCs) infiltration and gliosis. On the basis of histopathology and fluorescent antibody test (FAT) rabies was confirmed in 17 (58.62%) and 20 (68.96%) cases respectively. Quantitative assessments of histomorphological alterations were moderate to severe congestion in 90% (18/20), hemorrhages in 45% (09/20), gliosis in 85% (17/20), microglial nodules in 65% (13/20), satellitosis in 85% (17/20), neuronal degeneration, neuronal necrosis in 80% (16/20) and perivascular cuffing (PVC) with mononuclear cells (MNCs) infiltration in 95% (19/20) cases respectively. PVC was most prominent (95% cases) followed by gliosis and satellitosis. Neuronophagia was reported in 90% (18/20) cases. Meningitis and edema was present in 25% (05/20) and 35% (07/20). The results of the present study indicated that rabies infection of cows could be easily diagnosed in the laboratory by immunofluorescence and histopathology. Special attention should be given to stray dogs and outdoor rearing of cows.

P: 45 Increased Iba-1 Expression in an Autopsied Brain Samples of ALF &amp; Chronic Liver Disease Patients With Hepatic Encepahlopathy

BACKGROUND: Systemic inflammation both in acute liver failure (ALF) and patients with cirrhosis and hepatic encephalopathy (HE) leads to microglial activation and an increase in oxidative stress. Iba-1 has been found to be a highly specific marker expressed in microglial cells in animal models. We studied Iba-1 expression in the brains of patients with ALF and CLF with hepatic encephalopathy and the control patients without any neurological disease. METHODS: Autopsied frontal cortex samples were obtained from 5 patients with ALF due to viral hepatitis (HEV, HBV flare) or toxic liver injury (ATT induced) or mushroom poisoning. 7 patients with cirrhosis and HE and 7 controls were obtained. Expression of Iba-1 mRNA was investigated by real-time PCR using appropriate molecular probes and protein expression was assessed using immunohistochemistry using commercially available polyclonal antibodies and measure the intensity with the help of H-score. RESULTS: Iba-1 immunostaining highlights the microglial cells in the grey matter of the brain in ALF patients (H-score = 2000) as compared to the patients with cirrhosis and HE (H-score = 450) and to controls (H-score = 300). ALF grey matter specifically highlights the microglial nodule, and faint cytoplasmic hue is also noted in the neurons. Gene expression studies show the increased fold change in Iba-1 in ALF (fold change = 4.08, P = 0.11) and in patients with cirrhosis and HE (fold change = 1.1, P = 0.84) patients when compared with controls, though not statistically significant. CONCLUSIONS: These results demonstrated the increased microglial activation as well as the number of microglial cells in the ALF patients that can contribute to neuroinflammation.

Brain Infection by Hepatitis E Virus Probably via Damage of the Blood-Brain Barrier Due to Alterations of Tight Junction Proteins.

Extrahepatic injury, particularly neurologic dysfunctions such as Guillain-Barré syndrome, neurologic amyotrophy, and encephalitis/meningoencephalitis/myositis were associated with HEV infection, which was supported by both clinical and laboratory studies. Thus, it is crucial to figure out how the virus invades into the central nervous system (CNS). In this study, CNS lesions were determined in rabbits and Mongolian gerbils inoculated with genotype 4 HEV. Junctional proteins were detected in HEV infected primary human brain microvascular cells (HBMVCs). Viral encephalitis associated perivascular cuffs of lymphocytes and microglial nodules were observed in HEV infected rabbits. Both positive- and negative-strand of HEV RNA was detected in brain and spinal cord in rabbits intraperitoneally infected with HEV at 28 dpi (days postinoculation), but not in rabbits gavaged with HEV. HEV ORF2 protein was further examined in both brain and spinal cord sections of infected rabbits, with positive signals located mainly in neural cells and perivascular areas. Ultrastructural study showed thickened and reduplicated basement membranes of capillary endothelium in HEV RNA positive brain tissues. In vitro study showed loss of tight junction proteins including Claudin5, Occludin, and ZO-1 (zonula occludens-1) in HBMVCs inoculated with HEV for 48 h. These findings indicated that disruption of the blood-brain barrier (BBB) might be potential mechanisms of HEV invasion into the CNS. It provides new insights to further study HEV associated neurologic disorders and will be helpful for seeking potential therapeutics for HEV infection in the future.

Microglial nodules provide the environment for pathogenic T cells in human encephalitis

Microglia nodule formation is a common feature in inflammatory brain diseases mediated by T lymphocytes such as viral and paraneoplastic encephalitis, multiple sclerosis, and Rasmussen encephalitis (RE). However, its role has not been fully understood yet. We hypothesized that, in RE, microglial nodules provide an environment for the initiation of the later dominating T-cell cytotoxicity. In RE stage 0, small primary microglia nodules could be identified in the absence of T cells. These primary nodules showed inflammasome activation and endosomal Toll-like receptor upregulation. In stage 1, T cells migrate into the parenchyma and intermingle with microglial cells, thereby forming secondary nodules in which neurons are destroyed. Whole-genome transcriptome analysis at this point showed upregulation of several inflammatory pathways including interferon signaling and major histocompatibility complex-I signaling. Inflammatory profiles, like the ones observed in RE, could be induced upon TLR3 stimulation in neonatal microglial cell cultures. Taken together, our results point towards activation of endosomal TLRs, resulting in increased interferon signaling, inflammasome activation, and chemokine upregulation as early steps in RE pathogenesis. This activity sets the scene for subsequent infiltration of T cells and destruction of neurons. Similar to RE, this microglial microenvironment might be a crucial step in other T-cell-mediated inflammatory brain diseases.

In situ immune response and mechanisms of cell damage in central nervous system of fatal cases microcephaly by Zika virus

Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2 cytokines, other cytokines such as Th1, Th17, Treg, Th9, and Th22 are involved to a lesser extent, but are still likely to participate in the immunopathogenic mechanisms of neural disease in fatal cases of microcephaly caused by ZIKV.

Alterações histopatológicas da encefalite de Rasmussen

Os autores estudam oito casos de encefalite de Rasmussen sob o ponto de vista das alterações histopatológicas correlacionadas com os achados da neuroimagem. Cinco desses casos encontravam-se em uma fase tardia da doença (fase IV), com grande atrofia dos giros cerebrais, acentuada espongiose cortical, com perda de nenrônios e intensa gliose reacional, com a presença de raros nódulos microgliais e discreto infiltrado inflamatório perivascular. Nos demais três casos, havia discreta espongiose, com perda nítida de neurônios e gliose reacional. Havia maior número de nódulos microgliais e infiltração inflamatória linfomononuclear perivascular evidente. Esses casos encontravam-se em uma fase remota da doença {fase 111). Os casos estudados no presente trabalho se encontravam em fase mais avançada da doença, com intensa atrofia de giros cerebrais. Isto se explica pelo fato de o diagnóstico ser suspeitado clinicamente quando o paciente já apresenta hemiatrofia cerebral e a decorrente sintomatologia.

Persistence of parenchymal and perivascular T-cells in treatment-refractory anti-N-methyl-D-aspartate receptor encephalitis

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease mediated by IgG1 or IgG3 antibodies to the GluN1 subunit of the NMDAR, resulting in downregulation of NMDARs. Early diagnosis, prompt reduction of anti-NMDAR antibodies, and removal of associated ovarian tumors when identified are important drivers of prognosis. Immunohistochemical studies were carried out to evaluate B cell, plasma cell, and T-cell infiltrates in the brain of a 3-year-old patient with anti-NMDAR encephalitis who failed to show improvement after plasma exchange and Rituximab treatment. Complement activation was evaluated by C4d staining. Plasma cells and B-cells were rarely detected in the brain. In contrast, persistent intraparenchymal infiltrates and perivascular CD3+ T cells and evidence of complement activation were detected. Activated microglia and microglial nodules were also detected in the frontal lobes and the basal ganglia. The role of T cells and complement activation should be investigated in patients who do not respond to plasma exchange and Rituximab treatment.

Congenital Toxoplasmosis: The Unknown Disease Burden of Pregnant Women in Southeast Asia

AbstractCongenital toxoplasmosis (CT) is caused by Toxoplasma gondii which is an Apicomplexa parasite that requires a cat for its sexual cycle and a wide array of warm-blooded animals, including man for its asexual cycle. CT develops due to vertical transmission of the parasite from an infected mother to the child. It is in this manner when the unborn child becomes susceptible to infection. The literature review revealed that 26.0% of infants born from T. gondii infected mother are subclinically infected at birth and 10.0% are either mildly or severely clinically affected, while 3.0% of neonates die. Predominant manifestation of CT is encephalomyelitis, initiated by formation of microglial nodules in the brain. However, the most remarkable classical triad signs of toxoplasmosis are hydrocephalus or microcephalus, intracranial calcification, and retinochoroiditis. Hence, this review focused on the risks of the child from developing CT, the role of the pregnant women on the transmission of the parasite, and the risks of acquiring the parasite by the expectant mothers from Southeast Asia vis-à-vis transmitting the same to the unborn child. Likewise, this review also included the methods used for the diagnosis of CT and its importance in early detection and management of the disease by assessing practical means of controlling the incidence and preventing further transmission of the parasite.

Zika virus induces inflammasome activation in the glial cell line U87-MG

In the last years, neurological complications related to Zika virus (ZIKV) infection have emerged as an important threat to public health worldwide. ZIKV infection has been associated to neurological disorders such as congenital microcephaly in newborns and Guillain-Barré syndrome, myelopathy and encephalitis in adults. ZIKV is characterized by neurotropism and neurovirulence. Several studies have identified microglial nodules, gliosis, neuronal and glial cells degeneration and necrosis in the brain of ZIKV infected infants, suggesting that ZIKV could play a role in these neurological disorders through neuroinflammation and microglial activation.Little information is available about neuroinflammation and ZIKV-related neurological disorders. Therefore, we investigated if ZIKV is able to infect a glial cell line (U87-MG) and how the glial cell line responds to this infection in terms of inflammation (IL-1β, NLRP-3 and CASP-1), oxidative stress (SOD2 and HemeOX) and cell death.We observed a significant increase of ZIKV load in both cells and supernatants after 72 h, compared to 48 h of infection. We found that ZIKV infection induces an increase of IL-1β, NLRP-3 and CASP-1 genes expression. Significant increase of IL-1β and unchanged pro-IL-1β protein levels have also been detected. Moreover, we observed SOD2 and HemeOX increased gene expression mainly after 72 h post ZIKV infection. Subsequently, we found a decrease of U87-MG cell viability, after both 48 h and 72 h of ZIKV infection.Our results show that U87-MG cells are susceptible to ZIKV infection. ZIKV is able to successfully replicate in infected cells causing oxidative stress, NLRP3 inflammasome activation and subsequent release of mature IL-1β; this process culminates in cell death. Thus, considering the central role of neuroinflammation in neurological disorders, it is important to comprehend every aspect of this mechanism in order to better understand the pathogenesis of ZIKV infection and to identify possible strategies to fight the virus by rescuing cell death.

PATHOLOGY IN CHRONIC ENCEPHALITIS OPIUM ADDICTION IN THE DIFFERENTIAL DIAGNOSIS RATIO WITH OTHER FOCAL BRAIN LESIONS

The analysis of morphological studies of the brain in 33 cases of acute poisoning with opiates in 20 cases of stroke at a young age with a fatal outcome. In the first group drug encephalitis was detected in 23.0% of the observed cases. Studies suggest that, along with morphological signs of encephalopathy (ischemia neuronal proliferation of ependymal cells of the ventricles of the brain, perivascular and pericellular edema, etc.) take place with the formation of neuronophagia microglial nodules at the site of nerve cells lysed. There was a special kind of encephalitis in chronic addiction — ventriculitis histologically manifested plethora subependimarnyh vessels ependymal destruction, infiltration of the ventricular wall and the vascular plexus polymorphonuclear leukocytes. In forensic practice there is a need to differentiate drugs ventriculitis with secondary changes in the ventricles of the brain, which are often accompanied by encephalopathy. When forensic histological examination identified some morphological differences opium encephalitis and focal brain lesions, including vascular origin. Also found that in chronic opiate poisoning characterized by morphological changes in the brain that are not a manifestation of sepsis and associated with primary infection of the brain and can be attached to the drug encephalopathy. Particular attention is paid to specific features, informative for determining the pathological changes of the internal elastic membrane of brain vessels. Identify options tanatogenesis encephalitis drugs, including bacterial, viral and fungal etiology, cerebrovascular disease, and demyelinating diseases.

Asymptomatic diffuse “encephalitic” cerebral toxoplasmosis in a woman with systemic lupus erythematosus

Classic cerebral toxoplasmosis typically presents with neurologic symptoms such as seizures and mental status changes and histological examination shows focal lesions with necrosis. However, in the diffuse “encephalitic” form, patients are asymptomatic with diffuse, inflammatory, non-necrotic lesions. Asymptomatic diffuse “encephalitic” toxoplasmosis has been reported only in four acquired immunodeficiency syndrome patients and one human immunodeficiency virus (HIV) negative patient with chronic lymphocytic leukemia. We present a 36-year-old HIV-negative woman with systemic lupus erythematosus and lupus nephritis who was on immunosuppression for 9years after cadaveric renal transplant and died from pulmonary hemorrhage and cytomegalovirus pneumonia. Brain autopsy findings revealed multifocal microglial nodules containing Toxoplasma bradyzoites and associated astrogliosis. These nodules were prominent in the cerebellum, midbrain and medulla and also present in the cortex and thalamus. No coagulative necrosis, necrotizing abscesses, or other opportunistic infections were present. The patient had previously exhibited no neurologic symptoms and there was no clinical suspicion for toxoplasmosis. To the best of our knowledge, this is the first case of diffuse, non-necrotizing, “encephalitic” cerebral toxoplasmosis reported in a lupus patient and also the first reported female case.