Infections of the CNS

Viral Infections of the CNS

most involve either the meninges (aseptic meningitis) or cause a mild meningoencephalitis. Acute encephalitis is an unusual complication of common viral infections.

Genesis of viral encephalitides: virus must gain access to the CNS, replicate within the CNS, produce damage to the CNS

infrequent; slow recovery (3 months), usually incomplete

1. Herpes Simplex Virus -most common form of non-epidemic acute encephalitis; untreated mortality > 70%

Epidemiology: Humans are sole reservoir, one in 250,000 – 500,000 people/year, non-seasonal virus

HSV encephalitis(HSE):

precataclysmic phase: malaise, fever, headache, subtle behavioral change, pain in neck from stretching of meninges

florid phase: bizzare behavior, seizures, hemiplegia, disorientation, dysphasia, amnesia, coma

CSF: lymphocytic pleocytosis, proteinosis (50-200/uL – see table); modest protein elevation, normal glucose; may have RBC’s due to hemmorhagic component

MRI/CT: focal lesions, radiolucent/hemorrhagic, hyperintensity fronto-temporal, Ý signal on T2, more water present

Pathophysiologic correlates:

acetylcholine leak Þ excitatory neurotransmitter

HSE: seizures in 40%, due to inflammatory response

abnormal EEG in more: focal, slowing, spikes, periodic laterlized epileptiform discharges (PLEDS)

virus infects large, excitatory, long-projection neurons

Treatment:

acyclovir – interferes with viral reproduction
steroids: controversial
seizure and cerebral edema control (Dilanton, Tegretol, Hyperventilation for edema control)
mortality without treatment: 80%, with treatment: 30%

2. HIV – AIDS and the Nervous System

HIV has Three Neurologic Components

(1) neuroinvasive – enters the brain (carried by microglia and macrophages through BBB, hematogenous spread)
(2) neurovirulent – causes disease
(3) neurotropic – infects cells (microglial cells and Macrophages but NOT neurons!)

genetic strain rather than viral load determines development of HIV-dementia

CNS infected with variable quantities of HIV. Variable onset, severity and outcome, cognitive effects can occur early.

Neurologic Syndromes associated with HIV: due to immunocompromised state as well as direct effect of virus.

early manifestations: aseptic meningitis/encephalitis (Ý CSF), acute/chronic inflammatory demyelinating polyneuropathies (Guillan-Barre), mononeuritis multiplex/peripheral nerve vasculitis (rare), HIV associated polymyositis (Ý CPK levels), loss of cognition is a sign of AIDS; autoimmune (treat with immunomodulating therapy)

late manifestations: HIV-associated myelopathy

sensorimotor peripheral neuropathy – late in AIDS, affects feet first (may be result of toxic effects of anti-HIV drugs)

AIDS-dementia complex: mental slowness, forgetfulness, behavioral changes. Loss of fine motor control, gait, tremor. Mutism, incontinence, spasticity. (doesn’t involve cortex, and presents with subcortical features. No agnosias- lack of ability to perceive or recognize sensory stimuli).

end stage: coma, abullia- lack of motivation

Less Common Neurologic Presentations: stroke, polymyositis, movement disorders

AIDS-related CNS diseases

Primary Viral infection: HIV encephalopathy (encephalopathy means ‘any disease of the brain’)

presenting symptoms: dementia (90%), headache (39%), incoordination/gait distrubance (12%), aphasia (9%), seizures (9%), incontinence (9%)

AIDS-defining illnesses:severe and persistent constitutional signs, loss of cognition or opportunistic infection or neoplasm

lack of correlation between severity of dementia and neuropathological changes at autopsy

Opportunistic Viral Infection in AIDS patients

Progressive multifocal leukoencephalopathy (PML) – JC virus
Cytomegalovirus (CMV)
Herpes simplex virus types I, n ; Herpes varicella-zoster

Diagnostic Tests

MRI and CT: White matter abnormalities, atrophy

PET scan: Early AIDS, dementia – Ý activity; Late: ß activity; End: no blood flow , little activity

Nonviral Infections which affect AIDS patients

Most common Þ Toxoplasma gondi, cryptococcus neoformans

Fungal: Candida, Aspergillus, Coccidioides

Mycobacteria: Tuberculosis , Mycobacterium Avium/ Intracellulare Complex

Neoplasms: primary CNS lymphoma (second most common mass, first is toxoplasma), metastatic Kaposi’s sarcoma (bluish lesion on skin which can metastasize to brain – not common), systemic lymphoma with CNS involvement (common in AIDS, and metastasize to brain and meninges)

Toxoplasmosis of the CNS-most common focal CNS infection in AIDS patients; most human infections are asymptomatic

can infect the CNS and cause meningoencephalitis, encephalitis and retinochoriditis as a result of transplacental infection, or intracerebral mass lesions.

there is a propensity for lesions to localize to the basal ganglia, grey/white junctions, thalami, and white matter

pathogenesis: infect macrophagesÞ form trophozoitiesÞ multiply rapidly, kill cellsÞ necrotizing cysts form which form bradyzoites later

(3) Other Viral Infections of the CNS

viral meningitis – meningeal/ependymal cells infected with arbo- or enterovirus
Polio – Motor neurons infected with poliovirus
PML (Progressive Multifocal Leukencephalopathy) – Oligodendrocytes infected with JC virus

Bacterial Infections of the Nervous System

must accomplish the same three requirements of viral infection (access, replication and disease production). In addition, as cellular pathogens, they must avoid the host's protective mechanisms.

CSF Profile:

Cells	Glucose (n>45)	Protein (N<45)	Diagnosis:
150 lymphs	22	75	Fungal or Tbc Meningitis – 2^nd worst
8000 polys	13	250	bacterial meningitis – worst (H. Influenza, N. meningitidis, S. Pneumoniae)
4 lymphs	52	36	normal (5 white cells or less, 1 poly)
200 lymphs	58	40	viral meningitis (herpes) – 3^rd worst
20 polys	48	40	Stroke or vasculitis – 4^th worst

Opening CSF pressure is important, will be elevated in infection (>200mm CSF)

CSF will be cloudy in infection (clear normally) and will also have increased WBC

Meningitis – infection of leptomeninges

Encephalitis – infection of brain parenchyma

Menigioencephalitis – combination of above

Myelitis – infection of spinal cord

(1) Acute Meningitis

Causative agents: H. Influenza (use to be most common in children, now others more common due to vaccine), Streptococcus pneumoniae, Neisseria Meningitidis

in immunocompromised patients: toxoplasmosis, Cryptococcus, Aseptic meningitis; fever, leukocytosis and meningeal signs may be absent

Clinical Presentation: signs of meningeal irritation: stiff neck, neck pain, flexion resistance, Kernig’s and Brudzinski signs

fever: usually > 39° C; headache; mental status change (confusion, lethargy, delirium, seizures (meningoencephalitis can lower seizure threshold), coma (once patient goes into coma, chance of recovery is very small)

Predisposing Factors: malignancy, alcoholism, sickle cell disease, diabetes, splenectomy, steroid therapy, kidney dialysis

Complications: Ý intracranial pressure, seizures, hyponatremia, and subdural effusion

Bacterial vs. Viral Meningitis

	Viral	Bacterial
Shaking chills	Rare	Common
Peripheral blood leukocytes	Usually absent	Present
Altered sensorium	Absent or mild delirium	May be profound
CSF Cell count Glucose Protein	Viral <1000 normal variable	Bacterial >1000 low high

(2) Subacute meningitis – Tuberculosis or Fungal

Onset of symptoms less acute, degree of inflammation less severe, course more prolonged

Clinical Presentation: hydrocephalus, CN palsies, Ý ICP (N/V, Ataxia) plus headaches, fever and meningeal signs

CSF: Ý WBCs (50-500) – lymphocytes, ß glucose, Ý protein

Tuberculous Meningitis

secondary to tuberculosis elsewhere in the body (usually lung)
rupture of tubercle into the subarachnoid space

Pathology: cloudy, thickened meninges, dilated ventricles lined by exudate, panarteritis (inflammation of vessels) Þ stroke (this can happen in syphilis too)

Symptoms: subacute headache, vomiting, fever, nocturnal wakefulness, personality change, prodrome 2 wks-3 months

Signs: meningeal signs, mental status change. Late: papilledema, cranial nerve palsies, focal signs, 3^rd nerve palsies Þ optholmoplegia; can cause SIADH (syndrome of inappropriate ADH secretion)

Treatment: rifampin, INH

(3) Brain Abcess

Pathogenesis: bug lodges in some blood vessel Þ necrosis Þ (future focus of abscess) Þ gets surrounded by granulation tissue (fibroblasts and small capillaries) Þ Abscess.

capsule of brain abscess is made of collagen. Oxygen is needed to make collagen. Cortex receives most oxygen so thickened capsule occurs around cortex. Ependymal portion of the brain does not get as much oxygen so the capsule of the abcess is weak and more susceptible to bursting (bursts into ventricles Þ Ý ICP). When abscess bursts it causes rapid death because inflammation on ependymal surfaces.

source of infection: middle ear infection, lung infection, endocarditis, congenital heart disease, paranasal sinusitis, dental infection, face and scalp infections, meningitis

can be caused by: staph, strep, enterobact, anaerobes, Gram negative bacteria can infect infants

Symptoms: headache, Ý ICP (nausea, vomiting, lethargy or confusion), Seizures (focal or generalized)

Diagnosis: ring enhancing lesion on MRI could either be abscess or neoplasm (considered emergency)

give toxoplasmosis drugs, if no response to toxoplasmosis drugs, then biopsy – possible lymphoma

Clinical features: headache, fever, focal deficits, nausea, vomiting, seizures, nuchal rigidity, papilledema

Therapy: Penicillin + Chloramphenicol ; Nafcillin for staph (post-surgical or post-traumatic ); Surgery

CNS infections in immunocompromised hosts

the three major cellular defenses against infection are neutrophils, B-lymphocytes (via immunoglobulin production) and T-Lymphocytes (cell-mediated immunity). Defects in these defense mechanisms can be expected in certain characteristic settings, and lead to CNS infections with specific types of organisms.

Deficit	Setting	Type of Pathogen	Specific Pathogen
Neutrophil	neutropenia	endogenous flora introduced organisms (respirators, catheters)	Staphylococcus, Pseudomonas, Aspergillus
B-Lymphocyte Immunoglobulin	hereditary blood dyscrasias splenectomy	encapsulated bacteria	Pneumococcus, Hemophilus
T -Lymphocyte Macrophage	AIDS, transplants, steroids	intracellular pathogens	Cytomegalovirus, Listeria, Cryptococcus, Toxoplasma

Fungal infections of the CNS

while fungal infections are primarily thought of as opportunistic (i.e, requiring an immune compromised host), many fungal pathogens are capable of infecting immunocompetent hosts

Species	Incidence	Predisposing Factors	Normal Host	Principle Pathology
Cryptococcus	common	AIDS steroids	yes	meningitis
Coccidioides	regional	none required	yes	meningitis
Candida	common	prematurity neutropenia	rare	meningitis abscess
Aspergillus	occasional	neutropenia	rare	infarcts
Zygomycetes	occasional	DKA, steroids	no	infarcts

(1) Cryptococcus neoformans – the most common cause of fungal meningitis

distributed worldwide – found in bird excretion, soil, and animals. Vast majority of initial infectious occur through inhalation of small yeast forms from the environment. Once in host, cryptococci develop a thick polysaccharide capsule which is stimulated by physiologic concentrations of carbon dioxide found in the lung. Most pulmonary infections are asymptomatic, and organism can remain dormant until host defenses become weakened.
remarkable predilection for this organism to infect the subarachnoid space remains unexplained. An important virulence factor is the ability to produce melanin, which has been shown to protect certain microorganisms from host-derived oxidative damage.

(2) Aspergillus

can develop:

by direct extension from paranasal sinuses
following head trauma, surgery, or lumbar puncture
through hematogenous spread, particularly with prolonged neutropenia

ubiquitous molds found in soil, water, decaying vegetation, or any location with organic debris. The airborne spores are inhaled, and the lung is the usual site of primary infection
most cases of invasive aspergillus develop in neutropenic patients who have an underlying hematologic neoplasm
share in common with other molds a propensity to invade blood vessels leading to a hyphal angiitis with thrombosis in small and medium-sized blood vessels resulting in hemorrhagic infarction

Prion (proteinaceous infectious particle) Diseases

Jakob-Creutzfeldt disease most common

confined to CNS, transmitted by direct implantation or ingestion of prions (Mad Cow disease)

infectious prion is abnormal isoform of normal protein with abnormal b-pleated sheet; appears not to involve DNA or RNA

3 ways to get it:

(1) abnormal Prp gene
(2) sporadic (post-translational change where abnormal protein converts normal protein to abnormal)
(3) transmissible (contamination with abnormal isoform-eating it, or directly implanted in CNS)

prolonged duration, progressive clinical course, no inflammatory or immune response is generated

Pathophysiology – abnormal isoform cannot be degraded by the cell and appears to lead to splitting of the lipid bilayer of the cell membranes, eventually leading to cell death

Pathology – spongiform degeneration of the cerebral cortex, basal ganglia and cerebellum, occasionally with the formation of amyloid plaques in the cerebellum. There appears to be no host response (inflammation)