Microbiology of CNS infections

Question 1

General concepts

Answer 1

• BBB (due to tight junctions btwn capillaries, choroid plexus, and arachnoid) prevents macromolecules and cells from entering the brain
• BBB also hampers the clearance of organisms once the BBB is penetrated
• Igs and immune cells are scarce in the brain except during infection, when the BBB breaks down
• During infections of the blood, large numbers of organisms are present and some rare variants are able to attack and enter the CNS

Question 2

Immune system and CNS

Answer 2

• Ab’s normally found in CSF are derived from serum, diffusion across BBB is size dependent (IgG/IgA>IgM)
• No lymphatics in CNS, very few phagocytic cells or complement in CNS
• During inflammation/trauma Ab’s leak into CSF and immune cells can move into CSF
• PMNs are dominant inflammatory cells in acute bacterial infections of CNS
• Mononuclear cells are dominant response to viral (T cells mostly) infections and subacute infections (TB and fungal) of the CNS

Question 3

Cellular structure

Answer 3

• No brain-CSF barrier, cellular gap btwn neurons is 10-15nm, so free movement of pathogens in CNS is restricted
• Surface receptors on CNS cells required for viral entry
• Toxins and virus can be carried by axoplasmic transport (along axons to cell body)
• Tetanus toxin is sequestered in vesicles at peripheral axon terminal
• Rabies virus also moved along axon
• Staph and enterobacters can directly enter CNS due to craniotomy and skull fractures, or spread from an adjacent sinus via surgical shunts or congenital defects
• Hematogenous spread is most common way of infecting CNS (rare variants in blood attack CNS)

Question 4

Meningitis

Answer 4

• A diffuse infection by bacteria, fungi, or viruses resulting in inflammation of pia-arachnoid meninges
• Infants are particularly sensitive, younger than 28 days is usually E coli, group B strep, or listeria
• Neonates represent less than 10% of meningitis cases but 50% of meningitis mortality
• Adult bacterial meningitis is mostly neisseria meningitidis and strep pneumonia (unless there is penetrating wound to skull or IC host)

Question 5

Acute vs Subacute meningitis

Answer 5

• Acute meningitis due to bacteria or viruses
• Viral meningitis more frequent than bacterial, but tends to be benign and seasonal
• Subacute meningitis includes TB and fungi
• Usually the fungus is cryptococcus, which can infect both immunocompetent and immunocompromised hosts
• Coccidioides and other fungi can also cause subacute meningitis

Question 6

Pathogenesis

Answer 6

• Most pathogens invade CNS from the blood, risk of CNS infection depends on magnitude of blood infection
• Pathogens in blood normally cleared by reticuloendothelial system, speed of removal being proportional to size (bigger the faster its cleared)
• Bacteria that have capsules or intracellular bacteria can escape phagocytosis
• Enteroviruses and arboviruses can escape clearance due to their small size
• Some viruses infect endothelial or choroid epithelial cells and then enter CNS

Question 7

Clinical manifestations of meningitis

Answer 7

• Primary symptoms (non-descript): headache, feaver
• Descriptive symptoms: nuchal (neck) rgidity (stiffness during forward flexion), brudzinski sign (neck stiffness causing reflex flexion of the legs) and kernig sign (limited extension of leg when flexed at knee)
• May cause reduced consciousness, seizures
• Purulent material collects around base of the brain, may cause cranial nerve palsies, obstruct CSF flow (hydrocephalus)
• Vasculitis develops, causing infarcts and mulitfocal neurological deficits
• Untreated is uniformly fatal

Question 8

Other possible manifestations of meningitis

Answer 8

• Rash of enterovirus infections
• Parotitis of mumps
• Multiple petechiae of meningococcemia

Question 9

CSF examination

Answer 9

• Acute bacterial meningitis evokes a PMN response in CSF and substantially reduces CSF sugar content
• Protein builds up rapidly in CSF w/ acute bacterial meningitis
• In subacte fungal meningitis inflammatory response is mostly mononuclear cells, CSF sugar reduction is slower, protein levels elevated (may be slightly)
• Viruses produce a mononuclear response, CSF protein may be elevated (possibly only slightly), but sugar is usually normal (may be slightly reduced)

Question 10

Rx of meningitis

Answer 10

• Must use agents that pass the BBB, use CDC guidelines
• Mortality of acute bacterial meningitis even w/ Rx is 15%
• Sequelae frequent in survivors
• Viral meningitis usually only requires Sx Rx since the disease is self-limiting

Question 11

Abscesses

Answer 11

• Brain abscesses develop from a contiguous focus of infection, or by hematogenous spread from a distant focus (lung, heart)
• Many abscesses have mixed flora of aerobic and anaerobic bacteria
• Most are due to bacterial seeding of already devitalized (dead) tissue

Question 12

Clinical manifestations of abscesses

Answer 12

• Primary manifestations are headache, focal signs, and seizures, often w/o fever
• Signs may be insidious
• CT and MRI should be performed, abscesses are ID’d by a hypo-dense region representing pus surrounded by an enhancing region representing neovascularization and edema around the fibrous abscess wall
• CSF usually sterile, must culture the abscess cavity

Question 13

Rx of CNS abscesses

Answer 13

• Must Rx with multiple antibiotics to cover multiple common organisms
• If encapsulated then it must be drained to prevent rupture into brain
• Spinal epidural and all subdural abscesses are emergencies, as spinal abscesses can lead to paralysis and anesthesia at and below the level of abscess

Question 14

Encephalitis

Answer 14

• An inflammation of the brain parenchyma usually due to viruses that produce wide-spread intracellular infections
• Life-threatening encephalitis usually due to herpes simplex viruses and arboviruses
• Pathogenesis: usually occurs first w/ systemic infection, either from new infection or recurrent latent infection
• Often localized to frontal and temporal lobes, infecting neurons and glial cells
• Rabies can be spread thru axons (entering from DRGs/spinal nerves)

Question 15

Clinical manifestations of encephalitis

Answer 15

• HSV encephalitis in the non-neonate: focal signs evolve over 1-2 weeks including headache, fever, hallucinations, bizarre behavior, hemiparesis, aphasia
• CSF may show no response of PMNs, but usually shows mononuclear cells
• CSF protein is usually elevated and sugar usually normal
• Can find IgM in CSF
• EEG and CT used to Dx

Question 16

Rx of encephalitis

Answer 16

• For HSV infections use acyclovir
• Other forms generally just require supportive care
• Vaccines for prevention

Question 17

Chronic CNS infections

Answer 17

• Spirochetes: secondary syphilis complications include meningovascular inflammation leading to stroke, progressive dementia
• Borrelia burgdorferi: erythema chronicum migrans (ECM) rash indicates, can lead to mild meningitis and facial palsy
• Retroviruses (HIV): acute meningitis or demyelinating polyneuritis can occur at time of seroconversion, recurrent meningitis and neuropathies can occur during seropostive period
• During AIDS, may develop dementia, myelopathy, and sensory neuropathy
• HTLV1: small portion develop slowly progressing myelopathy
• During these chronic infections there tends to be a mild mononuclear cell inflammatory response, mild elevation of protein levels

Question 18

Conventional viruses of chronic CNS disease

Answer 18

• Progressive multifocal leukoencephalopathy (PML) due to ubiquitous papovavirus (JC virus)
• Mostly in immunocompromised pts, causes demyelination
• Rubella is associated w/ chronic encephalitis after congenital infection

Question 19

Slow infections of the CNS 1

Answer 19

• Prion diseases (CJD) causes acute spongiform encephalopathy (after 30 yrs)
• There is a long incubation time, consisting of progressive build-up of infectivity
• Brain shows vacuolization of neurons and glial but no inflammation
• Progressive cognitive defects, death in less than 6 months

Question 20

Slow infections of the CNS 2

Answer 20

• PrPsc (misfolded PrP) is protease-resistant, hydrophobic glycoprotein that has become post-translationally modified and aggregates into amyloid rods
• PrPsc causes PrPc (normal) to misfiled into PrPsc
• Dx by western blot (proteinase K resistant)
• CJD can be variant (acquired, more aggressive) or sporadic (inherited, less aggressive)
• Sx’s of CJD: loss of muscle control, shivering, myoclonic jerks/tremors, loss of coordination, rapid dementia, death
• No Rx exists

Question 21

Parasites of Neurological disease

Answer 21

• Malaria: P falciparum causes cerebral malaria
• Amoebas and pork tapeworm (trichinosis) infect CNS
• Sleeping sickness from African trypanosomiasis
• Chronic cerebral granulomas from schtosoma japonicum
• Cystocercosis from taenia solum (most common parasitic neurological disease)

Question 22

CSF findings during CNS infections

Answer 22

• Healthy: 0-5 cells/ul, 15-45 mg/dl protein, 45-85 mg/dl glc (50-70% of blood glc), no pathogens
• Septic meningitis (bacteria): 200-20000 cells (mostly PMNs), >100 mg/dl protein (very high), >45 mg/dl glc (low), due to bacteria
• Aseptic meningitis (fungi): 100-1000 cells (mononuclear), 50-100 protein (high or normal), >45-85 glc (normal), due to TB, listeria, and fungi
• Aseptic meningitis (viruses): 100-1000 cells (mononuclear), 50-100 protein (high or normal), 45-85 glc (normal), due to viruses