Pathophysiology of Acute Infectious Encephalitis PDF

Pathophysiology of acute infectious encephalitis Thomas de Broucker, MD Service de Neurologie Hôpital Delafontaine Saint-Denis, France  OBJECTIVE …understand the pathophysiology of acute infectious encephalitis… What makes the brain vulnerable t...

Pathophysiology of acute infectious encephalitis Thomas de Broucker, MD Service de Neurologie Hôpital Delafontaine Saint-Denis, France  OBJECTIVE …understand the pathophysiology of acute infectious encephalitis… What makes the brain vulnerable to a foreign organism aggression ? What makes a microorganism able to infect the CNS (brain & meninges) ? What makes a microorganism target specific structures or cell types of the CNS ? What are the CNS lesions due to acute encephalitis ? Micro-organism + Brain Immune system CNS manifestations 1. The brain, its accessories and the immune system  The CNS cells (1/2) Neurons – Specialized cells in specialized areas Neuroglial cells – Astrocytes participate To the maintenance & structure of the brain To the neuromediator homeostasis To the blood-brain barrier (BBB) To the innate host’s immune response To the wound healing (astroglial scar) – Oligodendroglial cells : myelin sheath – Ependymal cells : ventricular lining – Microglial cells Resident antigen-presenting cells Participate to the innate and adaptative immune responses  The CNS cells (2/2) Nonglial cells – Cerebrovascular endothelial cells (CVE) – Perivascular and plexus choroid endothelial cells – Macrophages and dendritic cells – Leptomeningeal cells Blood-derived leukocytes trafficking cells – Lymphocytes Vessels and Blood-Brain Barrier Capillary level  The BBB at the postcapillary level Inner vascular basement membrane Outer vascular basement membrane Glia limitans basement membrane fused gliovascular membrane The CSF flow From the choroïd plexuses… Lateral, 3rd, 4th ventricles Posterior fossa cisterns Basal cisterns of the skull Pericerebral subarachnoïd spaces Paccioni granulations … to the brain venous sinuses How the brain defends itself The immune system of the brain  Immunology of the CNS : the brain is an immunologically specialized organ Foreign organisms have a limited access to the brain Immune response must be less noisy than in other organs : – Brain poor ability to support swelling – Limitation of neuronal destruction APC have a limited surface expression of MHC => reduction of the immune response There are no resident adaptative immune cells into the CNS The steps of the CNS innate immune response (once a microorganism succeed to invade) 1. Recognition of pathogens-associated molecular patterns by the Toll-like Receptors (TLRs) of microglial cells and astrocytes – Single and double stranded viral RNA – Bacterial lipopolysaccharides, etc. 2. Activation of the TLR-wearing cells, leading to : – Production of NO and IFN alpha and beta – Expression of MHC on microglia, perivascular macrophages and astrocytes – Cytokines & chemokines production by microglia and astrocytes 3. Activation of cerebrovascular endothelial cells  Cytokines and chemokines Cytokines : proinflammatory signals (IL-1, IL-6, TNF- alpha) sent to target cells (ie CVE cells) Chemokines : target migratory cells – Mononuclear phagocytes, T lymphocytes – CCL2 (MCP-1), CCL3 (MIP-beta), CCL5 (RANTES), CXCL10 (IP10) CVE cells products – Intercellular adhesion molecules Entry of systemic – Vascular cell adhesion molecules immune system cells – Matrix metalloproteinases  1 2 Ag detection cytokines + chemokines Matrix metalloproteases + APC increase of the BBB permeability parenchymal migration + cell rolling, adhesion, migration  The adaptative immune system CNS invasion by immunocompetent cells in response to cytokines and chemokines stimulation In order of appearance : NK cells Antigen-specific CD8+ and CD4+ T cells B cells Monocytes and macrophages Meningeal & parenchymatous inflammation Objective : clearance of the foreign microorganism Micro-organism infection + Immune system Brain lesions  Primary lesions due to infection vary depending on - the particular/cellular tropism of the microorganism - the magnitude of the inflammatory response Destructive phagedenic process = abscess Neuronal dysfunction / death Oligodendrocyte dysfunction / destruction Astrocyte transformation / destruction / gliosis Ependymal necrosis Infiltration of inflammatory cells Infectious granuloma Vasculitis  CNS lesions due to secondary insults Brain edema and compression of healthy structures (herniation) and microvasculature Hydrodynamic-induced damage (hydrocephalus) Infarction (arterial or venous) Hypoxic anoxic damage – Convulsive status – Intracranial hypertension – Systemic cardiac/pulmonary deficiency CNS lesions clinical manifestations of encephalitis headache, seizures, focal deficits (motor, sensory, cognitive), consciousness decrease, etc. 2. The micro-organisms Bacteria Viruses Fungi Parasites The neurotropism of micro-organisms All the foreign micro-organisms do not invade the CNS The different routes of neuroinvasion – Directly (vicinity) – By the blood stream Blood choroid plexuses CSF brain Blood meninges CSF brain Blood brain – By neuronal axonal & trans-synaptic pathway Neurotropism and different cell tropisms are organism specific  Different target cells of the CNS Neurons : polioencephalitis/myelitis – neuronal death & neuronophagia Cortex Basal ganglia Πολιός = grey Motor neurons λευκός = white Glial cells : leukoencephalitis – Oligodendrocytes demyelination – Astrocytes BBB dysfunction, astrogliosis – Ependymocytes ventriculitis – Microglia microglial nodules All types of CNS cells : panencephalitis  Other targets into the CNS Choroïd plexus Meninges and CSF – Leptomeninges Pia mater Arachnoïd – Pachymeninges (dura mater) Vessels – Vasculitis Some examples of encephalitis pathophysiology Viruses – Herpes simplex 1 panencephalitis – Varicella Zoster Virus encephalitis – Enterovirus and arbovirus polioencephalitis – HIV – Rabies Bacteria – Mycobacterium tuberculosis – Listeria monocytogenes Parasites – Malaria Fungi – Cryptococcosis – Aspergillosis  Neurotropic Viruses Schweighardt & Atwood. J Neurovirol;7:187-195 Virus entry strategies. J Cell Biol.2011;195:1071-1082  HSV-1 Route of entry – Reactivation of latent infection Trigeminal ganglion Other sites of latent CNS virus (olfactory bulb, pons, medulla) – Direct neuroinvasion (olfactory sensory cells) – Hematogenous spread during viraemia (prodromal phase) Cell infection involves – Viral glycoproteins (gB, gC, gD, gH, GL) – Neuronal surface molecules (heparan sulfate, HVEM, nectin 1 & 2) neuron After cell entry HSV is a DNA virus : – nuclear invasion – DNA replication – DNA expression & protein production Host cell lysis Virus spread & mutiple cell type infection (panencephalitis) MHC expression and immune system recruitment Massive inflammatory response Œdema and Necrosis Detersion  HSV1 meningoencephalitis an acute necrotizing panencephalitis Early phase Full-blown infection sequelae  HSV encephalitis and auto-immunity Anti-NMDAR antibodies are observed in the blood, CSF or both during the acute-subacute phase of the encephalitis in 30% of the cases, but not during EV and VZV encephalitis 44 cases IgG, IgA and IgM Variable kinetics No clinical difference between Ab+ and Ab- groups Prüss et al. Ann Neurol.2012;72:903-911 Relapses are frequently linked to the occurrence of anti-NMDAR Ab – Mainly described in children – Could account for half of the cases Hacohen et al. Mov Dis.2013;20:90-96  ‘Herpes virus encephalitis is a trigger of autoimmunity’ Armangue et al. Ann Neurol 2014;75:317–323 4 children (+1 adult) having a HSVE relapse (delay 7-41 days) 34 retrospective cases of HSVE tested after 1week – 3 : anti NMDAR positive, all relapsing – 10 : other unknown neuronal surface antibody Mechanism of antibody production : Molecular mimicry ? Antibody production secondary to neuronal lysis and antigen release ? VZV meningoencephalitis pathophysiology Context : VZV primary infection or reactivation Meningeal inflammation Brain swelling Parenchymal VZV infection - Present in varicella encephalitis - Uncertain in VZV reactivation encephalitis Focal vasculitis of different vessel sizes with endothelial and smooth muscle in vessel walls infection Role of immunocompromission Elderlies Lymphoma & cancer Immunosuppressant drugs AIDS  VZV vasculopathies Zoster ophtalmicus & Multifocal (AIDS) contralateral hemiplegia Demyelinating meningoencephalitis A I D VZ reactivation & infection of : S Astrocytes Oligodendrocytes Ependymocytes Endothelial cells Ventriculitis  Enterovirus polioencephalitis RNA viruses – Enterovirus (70,71) – Poliovirus (1, 2, 3) – Cocksackie (A4, A7, B3) – Echovirus (2, 9, 30) Poliovirus Inflammation, microglial nodules, neuronophagia Cocksakie  Multiple routes of CNS invasion (after fecal-oral transmission) BBB crossing during viremia BBB crossing by EV-infected immune cells : (Trojan horse) Neuronal centripetal spreading from damaged muscle nerve terminals Specific CNS neurotropism (neuronal, glial & meningeal) – Poliovirus binds to cell receptor CD155 of : All neurons including ganglionic sensory cells ; astrocytes & oligodendrocytes pyramidal tract and spinal cord anterior horn Polio virus – EV 71 (cell receptor SCARB2) : Neurons & astrocytes Basal ganglia and pyramidal systems, reticular formation – Coxsackie (cell receptor CAR) : Neuronal progenitor cells and neurons CD155 Choroid plexus, neurogenic regions, hippocampus, cortex Role of humoral immunity defect in Echovirus encephalitis  Meningo Polio Encephalo Myelitis due to Enterovirus GM involved WM spared Exemple of Arbovirus encephalitis : Japanese encephalitis – Mosquito sting N – Hematogenous invasion E U R – Infection of O Meningeal, & Neuronal Endothelial cells N E U – Polio-encephalitis R Brain & cerebellar cortex, O basal ganglia, N O substantia nigra, T thalamus, R hippocampus, P pons, medulla oblongata I S spinal cord anterior horn JEV M  HIV Route of entry early contamination of CNS : primary encephalitis resting virus during AIDS : Trojan horse (mononuclear phagocytes) + direct invasion CNS cells targets = microglial cells & astrocytes During the primary infection During full-blown AIDS During controlled systemic but not CNS HIV infection Different forms of neuropathology : Leukoencephalitis Poliodystrophy due to host & viral toxic factors IRIS (CD8 massive infiltration)  Rabies Infection through a skin/muscle wound (dog bite) Neurotropism – Slow rate replication in muscle fibers – Entry through nicotinic receptor of motor endplate – Sensory/autonomic skin innervation (?) Retrograde axonal transport to the spinal cord Cell to cell and transsynaptic ascending spreading Brain neuronal infection (caudal-rostral polio-encephalitis) Centrifugal dissemination from the brain to the innervated organs (skin, salivary glands, myocardium,…) Furious rabies Paralytic rabies Lancet Neurol 2013; 12: 498–513 Bacteria  Mycobacterium tuberculosis Low-level bacteriemia infection of microvessels endothelial cells caseating vascular focus (Rich focus) Meningeal or parenchymatous location Release of MT and dissemination meningitis, encephalitis, tuberculoma, abscess  Tuberculous meningoencephalitis – Dense gelatinous inflammatory exsudate Most florid in the basal cisterns (as a result of the flow pattern of CSF) Prepontine and around the spinal cord Surrounding nerves and arteries (vasculitis) Impairment of CSF flow meningeal exudate of macrophages, lymphocytes, plasma cells, and fibrin  Listeria monocytogenes Route to brain/meningeal infection – Haematogenous spread from gut meningitis – Neuronal spread : rhombencephalitis Haematogenous dissemination neuronal infection (cranial nerves) cell-cell and axonal CNS spreading oral mucosa trigeminal nerve brainstem Role of immunosuppression in the initial phase of infection Parasites  Cerebral malaria – Plasmodium falciparum infection causing a global CNS dysfunction – Sequestration of parasitized red blood cells in the brain microvasculature : engorgement of small vessels – Deposition of Ag-Ab complexes, endothelial damage and platelet aggregation : edema, capillary necrosis, perivascular haemorrhages Haemorrhage centered by a necrotic blood vessel Dürck granuloma – Cell-mediated immune inflammatory response : parenchymal and meningeal inflammation  Fungi Route of infection – Inhalation, skin wound or gut translocation – Brain invasion : haematogenous route or direct from infected sinus air or bone Immunocompromission is frequent – Cryptococcus neoformans, Candida sp., Histoplasma capsulatum, Blastomyces dermatidis, Aspergillus sp. Lesions : basal meningitis, parenchymal granulomas and abscesses, vascular infiltration / obstruction  LESIONS Yeast Branching hyphae Pseudo hyphae Leptomeningitis Large vessels Microvasculature obstruction obstruction Blastomyces Aspergillosis Candida sp. Candida Cladosporium Coccidioides Fusarium Cryptococcus Mucormycosis Histoplasma Allescheria boydii Paracoccidioides Sporotrichum Torulopsis Aspergillus fumigatus Exserohilum rostratum  conclusion As many microorganisms, as many pathophysiologies of the encephalitis