38. Infectious diseases of the CNS

Introduction

The different infections of the brain can be divided into different categories:

• Extra-axial inflammation (= meningitis)– inflammation external to the brain parenchyme
  • Acute bacterial meningitis
  • Acute viral meningitis/aseptic meningitis
  • Chronic meningitis
• Parenchymal inflammation – inflammation of the parenchyme
  • Viral encephalitis/meningoencephalitis
  • Parasitic encephalitis/meningoencephalitis
  • Fungal encephalitis/meningoencephalitis
• Focal suppurating inflammation
  • Cerebral abscess
  • Subdural empyema
  • Epidural empyema
• Prion diseases

Infectious agents may reach the CNS through several routes:

• Haematogenous spread
  • Systemic circulation
  • Veins of the face
• Local spread
  • Sinusitis
  • Otitis media
  • Periodontitis – infection of the gums
  • Osteomyelitis – infection of the bone
• Retrograde transport through peripheral nerves
  • Neurotropic viruses
• Direct implantation
  • During trauma
  • During surgery (iatrogenic)

Let’s look at the specific forms of infection.

Meningitis (extra-axial inflammation)

Meningitis is a serious infection of the meninges of the brain or spinal cord, most commonly viral or bacterial in origin. The classic triad of symptoms in meningitis is fever, headache and neck stiffness. Other symptoms include photophobia, impaired consciousness and irritability. Acute meningitis can be bacterial or viral in origin, while chronic meningitis most commonly is due to tuberculosis or spirochetes.

Acute bacterial meningitis can be caused by many different bacteria, but the typical organisms depend on the patient age. Bacterial meningitis is fatal if left untreated. The CSF contains neutrophils and has elevated protein and reduced glucose levels.

The most common causes are:

• Infants
  • E. coli
  • Group B streptococci
• Adults
  • Neisseria meningitidis
• Old age
  • Listeria monocytogenes
  • Streptococcus pneumoniae

In bacterial meningitis exudate is commonly found on the brain. Bacterial meningitis may spread to the surface of the brain, causing cerebritis, inflammation of the surface of the brain. Cerebritis may lead to cerebral abscess.

Acute viral meningitis, also called aseptic meningitis, is a much milder disease than bacterial meningitis. The symptoms themselves are milder, and the disease is usually self-limiting and doesn’t require treatment. The CSF shows lymphocytosis while protein and glucose levels are normal.

Virtually any virus can cause viral meningitis, but the most common causes are enteroviruses and HSV.

Chronic meningitis can be caused by mycobacterium tuberculosis or spirochete bacteria like treponema pallidum (neurosyphilis) and borrelia burgdorferi (neuroborreliosis).

Tuberculosis meningitis often affects the base of the brain (basal meningitis), from where it may affect cranial nerves and the pituitary gland. Tuberculosis meningitis may cause communicating hydrocephalus as it obstructs the outflow of CSF.

Meningovascular syphilis occurs as part of neurosyphilis, which occurs in the tertiary phase of syphilis. It occurs more frequently in HIV-infected persons. It may spread to the brain parenchyme, causing paretic neurosyphilis. It may also spread to the dorsal roots, causing tabes dorsalis.

Neuroborreliosis is a potential complication of Lyme disease. It may involve aseptic meningitis, facial paresis and polyneuropathy.

Encephalitis (parenchymal inflammation)

Inflammation of the brain parenchyme (encephalitis) is most frequently of viral origin but can be caused by any infective agent. If there is simultaneous inflammation of the meninges and brain parenchyme the condition is called meningoencephalitis.

Viral meningoencephalitis: Viral infection of the brain parenchyme almost always also causes meningitis, which is why the name viral meningoencephalitis is actually more accurate than encephalitis. Many viruses only cause meningoencephalitis in immunodeficient hosts. The CSF usually shows lymphocytosis and normal glucose and protein levels. PCR of the CSF can reveal the specific virus.

The most important forms of viral meningoencephalitis are:

• HSV encephalitis
• Varicella zoster encephalitis
• EBV encephalitis
• CMV encephalitis
• Polio encephalitis
• Rabies encephalitis
• HIV encephalitis
• Progressive multifocal leukoencephalitis
• Subacute sclerosing panencephalitis

Herpes simplex encephalitis is the most common cause of fatal sporadic encephalitis. Both HSV-1 and HSV-2 may cause it. Neonates may be infected by HSV-2 during delivery by an HSV-2 infected mother, causing encephalitis. It has a fulminant course, which quickly leads to death if untreated. Necrotizing, hemorrhagic inclusions bodies called Cowdry Type A can be found in Glial + neuron cells.

Varicella zoster encephalitis may occur as a side-effect of shingles in immunosuppressed patients. Inclusion bodies can be found in Glial and neurons.

Epstein-Barr encephalitis is rare.

Cytomegalovirus encephalitis may occur in utero as part of TORCH or in immunosuppressed adults. It causes periventricular necrosis followed by calcifications and cystic change.

Polio encephalitis is caused by poliovirus, a type of enterovirus. Polio is most known for infecting motor neurons in the spinal cord and brain stem, causing flaccid paralysis, but it can cause encephalitis as well. Most cases of polio infection cause no symptoms.

Rabies encephalitis is caused by the rabies virus, which enters the CNS by ascending along peripheral nerves at the wound site. Incubation time may be long as the virus travels slowly. Rabies encephalitis involves fever, hydrophobia and hypersalivation. It’s 100% lethal if untreated when symptoms occur.

HIV encephalitis may occur in the late stages of HIV infection, as the virus infects the microglial cells.

Progressive multifocal leukoencephalopathy (PML) is a condition where immunosuppressed people, especially those suffering from AIDS, experience reactivation of the JC virus (which basically everyone is infected with from childhood). It has a high mortality, as most die within a year.

Subacute sclerosing panencephalitis (SSPE) is a rare complication of measles, which occurs in around 1 out of 600 babies infected with it. It has an approximate 2 years survival.

Parasitic encephalitis may be caused by:

• Taenia solium (neurocysticercosis) – Cyst development in brain
• Naegleria (amebic encephalitis) – contaminated bathing water, almost 100% fatality, infects through nasal cavity
• Toxoplasma gondii (toxoplasmosis) – in immunosuppressed people

Fungal infections usually produce parenchymal granulomas or arbscesses, often associated with meningitis.

Fungal encephalitis may be caused by:

• Candida species (multiple microabscesses, +/- granuloma formation)
• Aspergillus species (distinctive pattern of widespread hemorragic infarction)
• Coccidioides species

Focal infections (abscess, empyema)

The epidural and subdural spaces can be involved in bacterial or fungal infections, causing abscess or empyema.

Epidural abscess often occurs due to local spreading of an adjacent infection, like sinusitis or osteomyelitis. The pathogen is most frequently staphylococcus aureus. Symptoms include headache, fever and seizures. If an abscess occurs in the spinal epidural space the spinal cord may become compressed, which is a neurosurgical emergency.

Subdural empyema often occurs after spreading of frontal sinusitis or otitis media. The pathogen is most frequently staph. aureus here as well. The symptoms are similar to those of epidural abscess except more severe. Subdural empyema may lead to sinus thrombosis, causing a haemorrhagic infarct of the brain.

Cerebral abscess is most frequently caused by bacteria like Bacteroides, Streptococci or staphylococcus aureus. The bacterium can reach the brain by two routes:

• Haematogenous spreading
  • Acute bacterial endocarditis
  • Bronchiectasis
• Local spreading
  • Mastoiditis
  • Paranasal sinusitis

Cerebral abscess causes symptoms both due to local destruction of brain parenchyme and due to increased intracranial pressure. Common symptoms are headache, vomiting, focal neurological deficits, seizures and fever.

Prion disease

Prion diseases are very rare neurodegenerative disorders caused by prions. Prions are misfolded proteins that cause normally-folded proteins to become misfolded upon contact. PrP is a normal membrane protein of nervous cells. Its normal conformation is PrPC, however an abnormal conformation called PrPSC also exists, which is resistant to breakdown. When PrPSC molecules come into contact with PrPC molecules the latter change conformation into PrPSC.

PrPSC clump together and accumulate in the cells, causing cell injury and apoptosis by unknown mechanism. The cerebral cortex eventually undergoes a spongiform transformation, meaning that it becomes “sponge-like”. The mean survival is 7 months after symptoms appear. PrP is the only protein that is implicated in prion diseases. There is no inflammation.

The first PrPSC molecule may occur sporadically due to spontaneous mutations, familiarly due to germ-line mutations in the PrP gene or acquired, due to ingestion of PrPSC. Because prions can be transmitted between humans and animals, prion disease is considered an infectious disease. It is unique in that the body can actually produce the infectious agent itself.

Multiple prion diseases exist:

• In animals
  • Scrapie – in sheep
  • Bovine spongiform encephalitis (mad cow disease) – in cows
• In humans
  • Creutzfeldt-Jakob disease
  • Variant Creutzfeldt-Jakob disease
  • Gerstmann-Sträussler-Scheinker disease
  • Fatal familial insomnia
  • Kuru

Creutzfeldt-Jakob disease is the most common prion disease in humans, although still very rare (1/ 1 000 000). It is sporadic (due to spontaneous misfolding or mutation) in the vast majority of cases, but familiar and iatrogenic cases exist. Familiar cases occur due to germ-line mutations in the PrP gene, while iatrogenic cases occur when prion-infected equipment is used during procedures.

A subtype of Creutzfeldt-Jakob disease called variant Creutzfeldt-Jakob disease occurs in persons who eat cattle meat that was infected with prions. It progresses more slowly than the other variant.

Kuru is a prion disease acquired by ritualistic cannibalism, especially in cannibalistic tribes in Papa New Guinea. It is basically eradicated after cannibalism was banned in 1954.

Familiar fatal insomnia is a very rare disease (around 100 cases documented so far) that is autosomal dominantly inherited. It involves progressively worsening insomnia, eventually leading to death.