CNS Viral Infections

• CNS infections can be caused by viruses and lead to inflammation of the CNS, including meningitis, encephalitis and myelitis.
• Viruses mainly cause acute meningitis and encephalitis.

How CNS Infection Occurs

• Entry to the CNS happens through the hematogenous route from inoculation at another site.
• This happens via the respiratory epithelium from aerosols or droplets. An example of this is meningococci.
• Entry to the CNS can happen from animal bites, rabies virus, or bug bites, such as West Nile virus.
• Entry to the CNS can happen transplacentally like in cytomegalovirus, rubella or Zika virus.
• From blood to CNS happens via the choroid plexus or infection of CNS endothelial cells.
• Entry to the CNS can happen through direct inoculation through trauma or surgery.

How Virions Reach the CNS

• Neurotropism is when virions enter the CNS.
• Poliovirus affects motor neurons of the spinal cord and medulla.
• Mumps virus affects ependymal cells lining the ventricles in the fetal brain.
• Rabies virus enters the distal terminals of peripheral nerves and travels inside nerve axons via axoplasmic transport to reach nerve cell bodies in sensory ganglia and the spinal cord.
• Some viruses and infectious agents can penetrate the body through olfactory nerve endings via direct contact with the external environment.
• Nasal infections with rabies virus and some arboviruses under conditions such as caves filled with infected bats.
• After chickenpox, which comes from primary infection with varicella-zoster virus (VZV), the virus spreads through the skin through sensory nerves to become latent in neurons in sensory ganglia.
• Reactivation results in spread of virus through sensory nerves to produce zoster, also known as shingles.
• HSV spreads through the nerves from sites of primary infection like oropharyngeal like HSV-1 or genital mucosa primarily HSV-2 to infect trigeminal or sacral ganglia.
• The virus becomes latent in sensory neurons and reactivation results in spread of virus along sensory nerves to mucosal surfaces, producing recurrent herpes labialis (cold sores) or herpes genitalis.

Epidemiology

• Arboviruses that spread by vectors like mosquitoes and ticks are more commonly seen in summer.
• Enterovirus infections usually peak in late summer and fall.
• Pathogens such as HSV, the common cause of sporadic viral encephalitis in adults have no specific seasonal variation and happen equally.
• Some arboviruses are named after their initial area of isolation, such as California encephalitis virus, St. Louis encephalitis virus, West Nile virus, and Zika virus.
• Modern distribution is much larger than initial.
• Zika virus was named after a forest in Uganda, and spread to South and Central America as well as the Caribbean.
• West Nile virus was 1st isolated from the West Nile Valley in Uganda and is now widely distributed throughout North America.

Common Viral CNS Infection Etiologies:

• Enteroviruses: Coxsackievirus A and B, Echovirus & Enterovirus
• Arboviruses: Eastern and Western equine encephalitis virus, LaCrosse encephalitis virus, St. Louis encephalitis virus
• Herpes Simplex Virus (HSV)
• Varicella-zoster virus (VZV)

Less Common Viral CNS Infection Etiologies:

• JC Virus causes Progressive Multifocal Leukoencephalopathy (PML)
• Rabies virus
• Lymphocytic choriomeningitis virus(LCMV)
• Polio virus was previously a cause of infantile paralysis and is now preventable with a vaccine.
• sIgA is a potent aspect of the immune response.

Acute Viral Meningitis

• Viruses are a leading cause of aseptic meningitis
• Symptoms include fever, rash, headache, nuchal rigidity, photophobia, and an increased number of lymphocytes in CSF or lymphocytic pleocytosis.

Bacterial Vs. Viral Meningitis

• Bacterial meningitis presentations are focal or global, while viral meningitis presentations are mostly focal.
• In bacterial meningitis, CSF opening pressure, PMNs, and Protein are elevated while Glucose is decreased. Viral meningitis has a normal or elevated opening pressure and glucose, with lymphocytes and normal protein elevated.
• Bacterial meningitis has high mortality and morbidity versus the low mortality and morbidity with viral meningitis.
• Bacterial meningitis treatment is immediate abx therapy, as viral meningitis can be treated with supportive therapy.
• Empirical antimicrobial treatment is initiated in infants, even if viral is suspected.

CSF Analysis for Bacterial Vs. Viral Meningitis

• Leukocytes are >1,000 in acute bacterial meningitis vs. 10-1,000 (usually <300) in acute viral meningitis
• % Neutrophils is >50 in acute bacterial meningitis as well as may predominate in first 24 h, then <50 in acute viral meningitis.
• Red blood cells are 0-10 in acute bacterial meningitis vs. 0-2 in acute viral meningitis. They are 10-500 in HSV.
• Glucose is <30 in acute bacterial meningitis vs 40-80 in acute viral meningitis.
• Protein is >100 in acute bacterial meningitis compared to 50-100 in acute viral meningitis.

Diagnosis

• The typical CSF profile is lymphocytic pleocytosis of 25 to 500 cells/µL, normal or slightly elevated protein concentration [50-100 mg/dL], normal glucose concentration, and normal to mildly elevated opening pressure.
• CBC can show parallel CSF findings (↑Lymphocytes & Monocytes).
• No organisms on Gram's or Auramine-Rhodamine stained smears or India ink preparations of CSF.
• CSF cultures for bacteria or fungi are negative.
• Nucleic Acid Amplification (NAA) can be used, such as Enterovirus Consensus RT-PCR kit.

Viral Encephalitis

• Encephalitis is usually caused by viruses and happens in the brain parenchyma.
• Encephalitis can have associated meningitis or meningoencephalitis, and, in some cases, involvement of the spinal cord or nerve roots, or encephalomyelitis/encephalomyeloradiculitis.
• Is sporadic in HSV, VZV (less commonly in enteroviruses).
• Epidemics are caused by arboviruses, including Alphaviruses, Flaviviruses, and Bunyaviruses.
• CSF analysis is similar to acute meningitis.
• Confirmation by NAA.

Coxsackievirus, Echovirus, and Enteroviruses

• Enteroviruses are small picornaviridae that are non-enveloped, +ssRNA viruses with an icosahedral capsid that is lytic.
• This is the main cause of acute viral meningitis.
• They enter and multiply in the GI track, despite not being a prominent cause of gastroenteritis.
• There are multiple serotypes like 3 serotypes of poliovirus, 24 serotypes of coxsackievirus A, 6 serotypes of coxsackievirus B, 34 serotypes of echovirus, and enterovirus 4.
• Transmission happens by the fecal-oral route through food, water, hands, etc, which enters the body through the G.I. tract and spreads to the blood stream, which produces viremia, then goes onto infect other organs which includes the meninges.
• The viruses are stable and can survive in chlorinated swimming pools, the GI tract and sewage systems.
• Coxsackie viruses are an etiologic agent of foot and mouth disease & and causes herpangina vesicular diseases.
• Coxsackie viruses can cause acute viral meningitis and is diagnosed by NAA
• The disease is self limiting unless associated with encephalitis, or occurs in children under 1 year of age.

Arboviruses

• Vector-borne illnesses are typically caused by mosquitoes.
• Alphaviruses: Eastern Equine encephalitis virus and Western Equine encephalitis virus
• Flaviviruses: St. Louis encephalitis virus, West Nile virus, Japanese encephalitis virus
• Bunyaviruses: LaCrosse encephalitis virus
• The majority of individuals are asymptomatic with arboviruses, as few develop serious life threatening illness.
• Eastern equine encephalitis (EEE) is caused by a virus transmitted to humans and equines or horses by the bite of an infected mosquito, and has an incubation period of 4-10 days.
• The symptoms of Eastern equine encephalitis include sudden onset of fever, myalgia, and a headache of increasing severity. 1/3 with clinical encephalitis caused by EEE will die from the disease. EEE is endemic in the New England states.
• Western equine encephalitis (WEE) virus is an important cause of encephalitis in horses and humans in North America, mainly in western parts of the USA and Canada.
• The life cycle of WEE involves birds and mosquitoes.
• Symptoms include sudden onset with fever, headache, nausea, vomiting, anorexia and malaise, followed by altered mental status, weakness and signs of meningeal irritation
• St. Louis encephalitis (SLE) virus is the leading cause of epidemic Flavivirus encephalitis in the US and is the most common mosquito transmitted human pathogen in the US.
• The virus is distributed throughout the lower 48 states and since 1964, there have been ~5000 confirmed cases of SLE with an average of 193 cases per year (range 4 - 1,967).
• SLE illness ranges in severity from a simple febrile headache to meningoencephalitis, with an overall case-fatality ratio of 5-15 %.
• West Nile virus was first isolated in the West Nile Province of Uganda in 1937.
• The first outbreak of WNV encephalitis occurred in NY City, mostly in Queens, and in a few neighboring areas in late August and Sept. 1999.
• International travel and climate change played a role in its introduction to North America.
• La Crosse (LAC) encephalitis was first discovered in La Crosse, Wisconsin in 1963 and has since been identified in the Midwestern and Mid-Atlantic states.
• About 75 cases of LAC encephalitis are reported to the CDC each year, mostly in children under 16 years of age. LAC virus cycles between mosquitoes and vertebrate hosts in forest habitats

HSV 1 and 2

• Herpes simplex viruses HSV 1 and 2 have similar but not identical genomes.
• These are enveloped ds DNA viruses with an icosahedral nucleocapsid.
• Cytopathic effects is when Cowdry type A intranuclear inclusion happens and giant multinucleated cells happen. This can be seen on a Tzanck smear with Giemsa stain.
• Both HSV types can infect a variety of cells including epithelial cells at the site of entry of the mouth and genital areas that cause raised, fluid filled vesicles.
• These cells can be visualized microscopically using a Tzanck smear that stains smears of scrapings or swabs of the base of the lesion with the preferred stain being Giemsa.
• Serology is not useful due to a high seroprevalence in the population, so confirmation via PCR is also possible.
• After a primary infection around the mouth or genitals, HSV infects the innervating neuron, traveling by retrograde transport to the ganglion where they establish a latent infection. This happens in the trigeminal ganglia for oral HSV and the sacral ganglia for genital HSV.
• Both latent virions can reactivate in the ganglia, replicate and travel down the axons causing vesicular lesions containing infectious virus.

HSV Encephalitis

• Adult and pediatric post neonatal HSV encephalitis is usually caused by HSV-1 and is the most common viral cause of sporadic viral encephalitis.
• Reactivated HSV can spread either to the skin along the branches of the trigeminal nerve, and cause sores on the lips, or Herpes labialis, or to the brain, infecting the meninges.
• Patients often display bizarre behavior, personality changes, insomnia, and gustatory hallucinations.
• 70% of neonatal HSV infections are caused by HSV-2 or herpes genitalis, which is acquired during vaginal delivery by contact with secretions in the infected birth canal.
• Untreated, neonatal HSV infection can disseminate to the CNS in most cases and antiviral therapy may include acyclovir and its derivatives, valacyclovir, penciclovir and famciclovir.
• Varicella-zoster virus causes chicken pox and herpes zoster in reactivation.
• Chicken pox is acquired by inhalation or also by contact with skin vesicles.
• The virus replicates in the respiratory tract and then disseminates via bloodstream to skin and produces fluid filled vesicles of chickenpox.
• The virus then travels from the skin up sensory nerves by retrograde axonal transport and becomes latent in the nerve cell bodies of the dorsal root or cranial nerve ganglia.
• Very similar to HSVs in latency, reactivation, and neurotropism.
• There are vaccines for it like Zostavax over 60 and Shingrix vaccines over 50

JC Virus

• JC virus is a human polyoma virus non-enveloped dsDNA virus with an icosahedral capsid that enters through the respiratory tract and spreads to the kidneys.
• B cells and monocytes are infected through latency and reactivation occurs from immunocompromised patients where the virus spreads through the blood to CNS. This causes progressive multifocal leukoencephalopathy or PML.
• PML is a subacute demyelinating and necrotic disease that progresses to include paralysis of the arms and legs and death.
• Approximately 10% of people with AIDS develop PML with an 85% of all cases having a 90% mortality rate.
• Cases have decreased with the success of ART and the diagnosis is aided by CT or MRI imaging and PCR of CSF sample.

Rabies Virus

• Rhabdoviridae is a bullet shaped enveloped negative sense ssRNA virus that causes an acute encephalitis in all warm blooded hosts including humans.
• The disease outcome is almost always fatal as it is a zoonosis, but all species of mammals are susceptible. Only a few species like racoons and bats are important as reservoirs for the disease.
• The transmission is through a bite containing the virus containing saliva of an infected animal and after uptake into peripheral nerves, virus is transported to CNS via retrograde axoplasmic flow.
• During the period of cerebral infection, the classic behavioral changes associated with rabies develop.
• Rabies infection causes cytoplasmic eosinophilic inclusion bodies, or Negri bodies, in neuronal cells, especially pyramidal cells of the hippocampus and Purkinje cells of the cerebellum. There is Ag detection using direct immunofluorescence.
• RT-PCR from multiple samples are needed to confirm the infection like serum, CSF and skin.

Summary Points for CNS Infections

• Limited access to CNS by microbes
• CNS bacterial infections include meningitis and abscess
• Often severe to life threatening
• Immediate action like relieving pressure, stabilize, draw CSF, or empirical antibiotic
• CSF microbiology such as collecting prior to antibiotic administration as well as chemistry evaluation are crucial.
• Vaccination