Viral Infections of the CNS PDF

Viral Infections of the Central Nervous System Dr Allison Imrie  Overview In this lecture, central nervous system (CNS) viral infections that cause important morbidity and mortality will be discussed. By the end of this lecture, you should know the main viruses causing encephal...

Viral Infections of the Central Nervous System Dr Allison Imrie  Overview In this lecture, central nervous system (CNS) viral infections that cause important morbidity and mortality will be discussed. By the end of this lecture, you should know the main viruses causing encephalitis, meningitis, myelitis and paralysis; including enteroviruses, HSV, rabies virus, arboviruses and HIV The Central Nervous System CNS viral infections - Aseptic meningitis Most represent uncommon complications of common systemic infections meningitis, encephalitis, myelitis and paralysis Aseptic meningitis (not caused by pyogenic bacteria) Inflammation of meninges increased mononuclear cell count (mononuclear pleocytosis); normal CSF contain 0-5 MNC per µl Viral infection is the most common cause of aseptic meningitis enterovirus are the most common cause Typical CSF findings in various types of meningitis There are non-infectious causes of aseptic meningitis, however the term is almost synonymous with viral meningitis Clinical features most commonly include a triad of fever, meningism and vomiting. CNS viral infections - Encephalitis Encephalitis: infection (inflammation) of the brain Myelitis: inflammation of the spinal cord; when both brain and spinal cord are involved, condition is called encephalomyelitis Encephalitis with meningitis is called meningoencephalitis Symptoms: headache, fever, confusion, drowsiness; more advanced disease includes convulsions, seizures, hallucinations, memory loss and coma; can be fatal Viral encephalitis may be direct effect of acute infection or a complication of latent disease Most diagnosed viral encephalitis is caused by enterovirus; HSV; rabies virus and arboviruses Top: HIV-infected macrophages forming multinucleated giant cells. Bottom: HSV encephalitis with perivascular mononuclear cells and brain necrosis. Viral Encephalitis CNS viral infections – AFP/AFM Acute flaccid paralysis: acute onset of flaccid paralysis in one or more limbs May be caused by anterior horn cell infection with wild or vaccine polio virus, or other viruses e.g. Enterovirus 71 A child with AFM affecting the proximal muscles in his right upper extremity. Note the muscular atrophy in his supraspinatus fossa, deltoid and biceps. Anterior horn of spinal cord contains bodies of motor neurons, which p brain deci ion based on sensory information into action. Damage to anterior horn cells affects muscle movements Viruses and severity of disease Enteroviruses Non-enveloped, (+) ssRNA genome Picornaviridae at least 72 serotypes 5 main groups: Poliovirus: paralytic poliomyelitis, aseptic meningitis, febrile illness Coxsackie group A: aseptic meningitis Coxsackie group B: aseptic meningitis and encephalitis Echovirus: aseptic meningitis Enterovirus: meningitis Transmission occur via hand-to-mouth contact Similar to poliovirus in epidemiological and infec Enterovirus infections of CNS Transmission occur via hand-to-mouth contact (saliva, nasal mucous or sputum of infected person) Similar to poliovirus in epidemiological and infectious characteristics but less virulent Responsible for respiratory infections, conjunctivitis and hand-foot- mouth disease (HFMD) Rare cases of coxsackievirus and echovirus paralysis, aseptic meningitis and encephalitis Enterovirus 71 Usually causes mild disease in adults and children Outbreaks of EV71 are associated with severe disease meningitis and encephalitis especially in young children (under 5 years) Reported in Asia for many years and occasionally in Australia  Earliest known representation of limb atrophy presumed due to Poliovirus and Poliomyelitis poliomyelitis. Egypt, 1403–1365 BC Non-enveloped, (+) ssRNA linear genome 3 serotypes (1-3), each with slightly different capsid protein; types 2 and 3 are eradicated Transmitted by faecal-oral route, or via contaminated food or water - resistant to acid, bile and detergents can survive stomach acids when ingested Multiplies in intestine, enters circulatory system, then CNS Poliomyelitis (polio) acute enteroviral infection of the spinal cord that can cause neuromuscular paralysis 1 in 200 infections leads to irreversible paralysis; 5-10% of paralysed persons die when breathing muscles become immobilised Paralytic disease occurs mostly in adolescents Poliovirus and Poliomyelitis Poliovirus infect mucosal cells in oropharynx and intestine, multiply in number and shed in throat and faeces, some leak into blood Most infections are short-term with mild viraemia non-specific symptoms including fever, headache, nausea, sore throat and myalgia If viraemia persists, virus spreads to spinal cord and brain If nervous tissue is infected but not destroyed - Muscle pain and spasms, meningeal inflammation and vague Predicted age distribution of polio hypersensitivity survivors in the USA in 2016 Invasion of motor neurons causes flaccid paralysis Decades later post-polio syndrome (PPS) progressive muscle deterioration; occurs in 25-50% of patients infected with polioviruses in childhood 25-40% of polio survivors have PPS in the USA CNS viral infections – AFP/AFM Most of the patients with AFM (more than 90%) had a mild respiratory illness or fever consistent with a viral infection before they developed AFM. Most AFM cases are children (over 90%). The large number of AFM cases identified in 2014 coincided with a national outbreak of severe respiratory illness caused by EV-D68. Arboviruses Top: Percentage of viral pathogens Flaviviridae in viral encephalitis cases with Japanese encephalitis confirmed aetiology. St. Lois encephalitis Bottom: Percentage of viral West Nile pathogens in viral meningitis Togaviridae cases with confirmed aetiology. BMC Infect Dis. 2017 Jul 14;17(1):494 Eastern equine encephalitis Western equine encephalitis Bunyaviridae La Crosse encephalitis Anterior and posterior horn neurons have been destroyed by WNV Worldwide distribution of major arboviral encephalitis  The transmission cycle of Japanese encephalitis virus The transmission cycle of Japanese encephalitis virus. The virus is transmitted naturally between aquatic birds by Culex mosquitoes; during the rainy season, when there is an increase in the number of mosquitoes, the virus “overflows” into pigs and other domestic animals and then into humans, who do not transmit the virus further (dead-end hosts). https://www.nature.com/articles/nrneurol.2018.30  Origin and genotype spread of JEV in Southeast Asia https://journals.asm.org/doi/10.1128/jvi.77.5.3091-3098.2003 https://www.nature.com/articles/nrneurol.2018.30  Overview of of Japanese encephalitis pathogenesis Spread of JEV to the CNS can be prevented by neutralizing antibody, which alone is sufficient to prevent encephalitis The mechanism by which JEV enters into the brain remains elusive The observations of peripheral replication and viraemia in animal models, along with the distribution of lesions in the brain strongly suggest that JEV enters the CNS from the blood. JEV antigen is detected in the vascular endothelium- unclear if this reflects actual replication Trojan horse' mechanism of CNS entry via an infected leukocyte is possible Marked inflammation in brain: T cells, monocytes, macrophages https://www.nature.com/articles/nrneurol.2018.30  Japanese encephalitis: Clinical Signs Acute encephalitis Headache, high fever, stiff neck, stupor May progress to paralysis, seizures, convulsions, coma and death Neuropsychiatric sequelae 45-70% of survivors In utero infection is possible Abortion of foetus About 1 in 25 – 1:1000 infected people develop symptomatic disease  Sequelae of Japanese encephalitis Flexion deformities are apparent in this child 2 months after Poliomyelitis-like acute flaccid paralysis. the initial illness This child has marked weakness and wasting a year after the initial presentation. About 30% of hospitalized patients with JE die About half of survivors have severe neurologic sequelae About half of those classed with ‘good recovery’ have subtle neurologic sequelae such as learning difficulties, behavioural problems, subtle neurologic signs Post Mortem Lesions Pan-encephalitis Infected neurons throughout CNS Occasional microscopic necrotic foci Herpes simplex virus Enveloped, ds DNA genome - Herpesviridae Acute gingivostomatitis, herpes labialis, herpetic whitlow, ocular herpes, genital herpes, neonatal herpes, meningitis and encephalitis Herpes simplex encephalitis is responsible for about 10% of all encephalitis cases About 30% of cases result from initial infection with HSV, majority of cases are caused but reactivation of an earlier infection HSV encephalitis can present as neonatal HSVE (mortality rate >25%); or as focal disease following HSV reactivation (mortality 70% in absence of treatment) Varicella Zoster Virus (VZV) Enveloped, ds DNA genome - Herpesviridae Varicella (chickenpox) following primary infection self-limiting disease of children; morbidity and mortality in other age groups and immunocompromised Herpes zoster (shingles) following reactivation of VZV in sensory nerve ganglia - most often in the elderly or immunocompromised Encephalitis in immunocompromised patients Rabies Enveloped, (-) ssRNA, bullet-shaped virus Rhabdoviridae (Lyssavirus) Rabies (Latin for madness) has been known for >2500 years Spread by bite from infected animal; salivary contamination of mucous membranes; aerosols Virus replicates first in muscle, moves along peripheral nerves to CNS via retrograde flow in axons -typically via sensory and motor nerves at the initial site of infection Once virus enters the nerves it is not accessible to the host immune defences Infection cycle completed when virus replicates in the salivary glands Rabies Incubation of several weeks to up to 2 years - short in children and for bites to the head or neck Clinical phases: Prodromal phase fever, nausea, vomiting, headache, fatigue; some patients experience pain, burning, tingling sensations at site of wound Furious phase agitation, disorientations, seizures, twitching, hydrophobia Dumb phase paralysed, disoriented and stupor Progression to coma phase, resulting in death ~ 100% Vaccine (recombinant antigen, human anti-sera or Mab) can be given post-exposure protection, if given before symptoms arise Negri bodies are the classic histopathologic feature of rabies. They are sharply delineated, eosinophilic inclusions found in some neuronal cells HIV and the Nervous System HIV enters the nervous system early, at the time of initial infection, and may immediately ca e mp om or ma ca e mp om an ime d ring he per on life ime HIV easily crosses the blood-brain barrier Primary HIV disease can lead to: AIDS Dementia Complex (brain) Vacuolar Myelopathy (spinal cord) Peripheral Neuropathy (nerve) Meningitis (acute or chronic) Sustained viral replication and high viral load is associated with brain tissue inflammation, permanent cell death and HIV-associated neurocognitive disorders  HIV enters brain early in infection Peripheral blood variants of HIV-1 infect immune cells that spread to brain via blood However: In some patients HIV-1 variants in CSF are not found in blood – CNS is a compartmentalized viral reservoir HIV-associated Neurocognitive Disorders HAND HIV-associated neurocognitive disorders Neuropathogenic mechanisms that contribute to HIV-associated neurocognitive disorders HIV-infected macrophages and microglial cells release neurotoxic viral proteins that trigger astrocyte activation, which results in increased glutamate release and reduced glutamate uptake. Elevated extracellular glutamate levels cause neuronal bioenergetic disturbances that lead to aberrant synapto-dendritic pruning and neuronal injury. Moreover, systemic inflammation and microbial translocation products lead to microglial activation and increased production of chemokines and cytokines that contribute to neuronal injury. Nat Rev Neurol. 2016 Apr;12(4):234-48 General immunosuppression caused by HIV can lead to opportunistic infections Medical treatments for HIV-dementia complex Many types of HAART do not easily cross into the brain in laboratory studies However, HIV-infected individuals may show increased permeability of the BBB HAART usually reduces viral load both in the periphery and in the CNS Reduction of viral load in the CNS is associated with reduced cognitive symptoms (improvement of cognitive functions) Patients with stable viral load do not show increased risk for cognitive decline, even after 5 years of monitoring HIV Anti-Retroviral Therapy: Transmission is reduced to almost zero when VL is undetectable for >6 months