208 terms

CNS Infections

• Identify and define the signs and symptoms of meningitis in adults, infants and children • Describe the physical exam findings associated with meningitis (Kernig's sign, Brudzinski's sign, Papilledema, Spinal rigidity) • Formulate a work-up for CNS infections (including appropriate lab and radiographic studies) • Name the contraindications for performing a lumbar puncture • Describe the possible complications of a lumbar puncture • Differentiate bacterial, viral and tuberculosis meningitis bas…
Stiff Neck
Classic triad of Bacterial Meningitis (85%)***
Bulging Fontanelle (late sign in 1/3 neonates)

Neck stiffness is rare (15% at most)
Meningitis in Newborns
Bacterial Meningitis in Children and adolescents
Full Neurologic Exam (cranial nerves, mini mental status, tone, DTRs, strength)
Nuchal Rigidity
Spinal Rigidity
Kernig's Sign
Brudzinski's Sign
CNS Infections
Commonly an early sign of meningeal irritation

Refers to neck stiffness that prevents flexion
Nuchal Rigidity
-Also a signs of meningeal irritation
-Erector spinae muscle spasm limits spine movement
-Opisthotonos (rigid arched back) may occur (Cannot flex the patient at all)
Spinal Rigidity
Patient supine
Flex hip and knee to 90 degrees
Hold hip immobile and extend distal lower extremity

Positive Test suggests Meningeal Irritation
Resistance to knee extension
Pain in hamstrings
Kernig's Sign
Patient supine
Immobilize trunk against bed
Flex neck bringing chin to chest

Positive Test suggests Meningeal Irritation
Involuntary hip flexion
Brudzinski's Sign
Swelling of the optic disk due to increased intracranial pressure
Causes include:
Brain tumor or abscess
Cerebral trauma or hemorrhage
Arachnoidal adhesions
Cavernous or dural sinus thrombosis
Idiopathic intracranial hypertension (pseudotumor cerebri), a condition with elevated CSF pressure and no mass lesion
Rash is nonspecific for meningitis

Petechia and Purpura (both do not blanch) are commonly associated with meningococcal meningitis
Rashes associated with meningitis
Rapid onset. Usually High fever. Sometimes Altered Mental Status
Bacterial Meningitis
Usually altered mental status. Rapid onset.
Slower onset (over 3-4 days). Rarely altered mental status.
Viral Meningitis
Fever X 1 day
Headache X 2 days
Stiff neck X 1 day
Altered mental status
Nuchal rigidity
Typical Problem List of Bacterial Meningitis
Lumbar Puncture
Differentiating between viral, bacterial & other causes of meningitis

Leukocytosis, thrombocytosis, thrombocytopenia/anemia

Blood Culture
Important for identifying organism in bacterial meningitis with septicemia and when LP is contraindicated
Work-Up for CNS infections
Local infection at lumbar puncture site

Suspicion of a cerebral mass lesion/increased ICP (PAPILLEDEMA!!):
Large brain abscess
Brain Tumor (especially posterior fossa)
Subdural Hematoma
Intracranial Hemorrhage
LP Contraindications
Uncorrected Bleeding Disorder
Severe Thrombocytopenia
Focal neurological symptoms/signs, decreased level of consciousness (LOC)
Acute spinal trauma
LP Contraindications
Patient positioning
Lateral decubitus position
Sitting position

Mark midline spinous process between iliac crests
Corresponds with L3-L4 or L4-L5 interspace
LP Technique
Relatively common
Post LP headache
Post LP back pain (<1/3 of patients, due to local soft tissue trauma)
LP Complication
Infection e.g. spinal abcess, meningitis (estimated at 0.2%)
Spinal subdural / epidural hematoma (predominantly in patients with a coagulopathy)
Nerve root or spinal cord injury/irritation

Transtentorial or cerebellar herniation (risk 0-5% in patients known to have an intracranial mass and high ICP)

Complications secondary to low intracranial pressure
Hearing loss, CN VI paresis
Intracranial subdural hygroma / hematoma
LP Complications
Elevated Lymphocytes
Protein and Glucose Normal
Viral meningits***
Elevated Neutrophils
Low Glucose
Elevated Protein
Bacterial Meningitis (eat the glucose and poop out the protein)
Gram+ cocci
Normal flora
Lancet shaped
alpha hemolytic - partial hemolysis
Polysaccharide capsule
Strep pneumoniae
Gram- diplococci
Polysaccharide capsule
A,B,C,Y and W135 serogroups
Neisseria meningitidis
Gram- coccobacilli
Capsule serovar b (Hib)
Main cause of epiglottitis
H. influenzae type-B
Virulence factors
Polysaccharide capsule - antiphagocytic --> protection

IgA protease - facilitates mucosal colonization and invasion --> protection

Pneumolysin - transmembrane pore-forming toxin --> damage
Other factors: teichoic acid, peptidoglycan fragment...--> inflammation
Strep pneumoniae
Diffuse vascular damage - endothelial damage, inflammation of vessel walls, thrombosis, disseminated intravascular coagulation - caused by action of endotoxins (LPS and LOS: lipooligosaccharides[No O antigen])

Petechial rash

Outbreaks in university dormitories, military barracks, i.e. crowded conditions
Meningococcal meningitis
Virulence factors:
Pili - binding to epithelial cells
IgA protease - mucosal colonization
Polysaccharide capsule type-b = poly-ribitol-phosphate (PRP) - anti-phagocytic
Endotoxin (LPS) - inflammation
H. influenzae type b
At risk: unvaccinated young children

Invasion into deeper tissues (invasion goes between epithelial cells)
H. influenzae type b
white blood cells + gram(+) cocci in pair or chain
alpha-hemolytic - green colonies
optochin sensitivity
bacitracin resistant
S. pneumoniae
gram(-) diplococci within polymorphonuclear cells
growth on BLOOD agar
Thayer-Martin agar: a modified (selective) chocolate agar
optimal growth with 5% CO2
N. meningitidis
white blood cells + gram(-) coccobacilli or rods
chocolate agar - provides both X & V factors needed (will not grow on blood agar)
H. influenzae type b
Latex particle agglutination test to identify capsular antigens in CSF
Neisseria meningitidis
Common virulent factor in meningitis-causing bacteria
Capsule (CLICKER)
16yo with high fever and hemorrhagic skin rash. Headache, photophobia, and neck stiffness.
Neisseria meningitidis (CLICKER)
gradual onset over a few weeks
starts with malaise, apathy and anorexia
then photophobia, neck stiffness, impairment of consciousness
serious complications and sequelae

also involved in brain abscesses
Tuberculous meningitis
Neisseria meningitidis***
Purulent exudate covers the surface of the brain and fills the sulci
Pneumococcal meningitis
Filled with neutrophils
Acute suppurative bacterial meningitis
Virchow-Robin space
Leptomeningeal vessel with necrosis of the vessel wall.

Gram+ rods that cause transplacental infection in the neonate.
Listeria monocytogenes
Antimicrobial chemoprophylaxis for close contacts of Bacterial meningitis patients
Vancomycin & 3rd generation cephalosporin (Ceftriaxone) - crosses the BBB
Bacterial Meningitis Treatment
7-valent conjugate vaccine - infants and young children
23-valent polysaccharide vaccine
Penumococcal Meningitis
Meningococcal polysaccharide vaccine (MPSV4) - adults over 55

Meningococcal conjugate vaccine (MCV4) - all children at routine preadolescent visit (11 to 12); recommended for people at increased risk

Both prevent 4 types of meningococcal disease A,C,Y,W-135 (not B because poor immunogen)
Meningococcal Meningitis
Hib conjugate vaccine
Haemophilus meningitis
GBS produce a diffusible heat-stable protein (CAMP factor) that enhances Beta-hemolysis of Staphylococcus aureus***

Streptococcus agalatiae -Identification Test
Neonate with beta hemolytic colonies - fever, respiratory distress, lethargy. Gram positive rod. Cause of the disease?
Listeria monocytogenes
Mortality rate - 20% to 30%
HIGHEST number of deaths caused by foodborne bacterial diseases
Listeria monocytogenes
Manifestations are host-dependent
Self-limited febrile gastroenteritis - immunocompetent persons
Bacteremia - during pregnancy - Listeria proliferate in placenta --> neonatal infections - stillbirth, meningitis
Sepsis and CNS infections - elderly and immunocompromised persons
-Widely distributed in nature
-Reservoir - intestine of animals and humans
-Small Gram(+) rods
-Non-spore forming, facultative anaerobes
-Growth - broad temperature range: 1C to 45C
Motile at 25C
Non-motile at 37C
Listeria monocytogenes
-ingestion of contaminated food: unpasteurized dairy products and undercooked animal products
-transplacentally in utero
-transmission during delivery

Risk groups for invasive diseases - immunocompromised individuals, pregnant women and their fetuses and neonates, and the elderly
Listeria monocytogenes
L. monocytogenes -Attachment and entry into nonphagocytic cells
L. monocytogenes- pore forming exotoxin; escape from vacuole or phagolysosome --> release into cytosol.
Listeriolysin O (LLO)
L. monocytogenes- surface protein; actin polymerization --> motile comet tails
- disease, which typically is noninvasive
-fever, myalgias, and diarrhea - last 1-3 days
Febrile gastroenteritis (Listeria infection)
-early-onset sepsis - "granulomatosis infantiseptica"
-in utero via transplacental transmission --> stillbirth or disseminated infection
-abscesses and/or granulomas in multiple organs
-late-onset meningitis - through vaginal transmission
Neonatal infections (Listeria infection)
-Listeria has a predilection for brain stem, meninges
-meningitis, encephalitis
-brain abscess in 10% of infections --> high mortality
CNS infections (Listeria infection)
occult - fever, malaise, no obvious focus during pregnancy - Listeria proliferate in placenta
Bacteremia (Listeria infection)
Nonmotile at 37C
Gram+ rods
Listeria monocytogenes
GBS, E.Coli +/- Listeria
Neonatal Bacterial Meningitis
Specific antibiotic for Listeria
Gentamicin/Cefotax + Ampicillin
Neonatal Bacterial Meningitis Treatment
screening of pregnant women for vaginal colonization
clinical factors determine risk - prolonged membrane rupture, fever...
intrapartum prophylaxis is protective (penicillin or ampicillin)
Neonatal meningitis prevention
Bacterial meningitis in a 35yo man - gram positive coccobacilli - high protein, low glucose, neutrophils in CSF

Coccobacilli = Rods = Not a cocci
Listeria monocytogenes (CLICKER)
Fibrosis of the meninges can cause this complication of meningitis
Complication of Neonatal Meningitis: Severe brain atrophy
Direct cytolytic effect of Virus
HSV, West Nile virus; poliovirus; JC virus
Inflammatory or immune mediated effects of virus
HIV, flaviviruses
Vasculitic effects of virus
VZV encephalitis
Common causes of aseptic meningitis
Majority of cases are caused by Enteroviruses (members of the Picornaviruses) esp. Coxsackie B and echoviruses.

5 types = 70% of cases; most occur in late summer and early fall.

~20,000 cases/year in the US; 90% of cases in pts <1 yr old.

Enteroviral CNS disease is generally milder than arbovirus (arthropod-borne) disease, or bacterial or fungal meningitides, and is self limiting.
Aseptic meningitis and/or encephalitis
Picornavirus family member; non-enveloped ssRNA virus. Three serotypes known.

Incidence is < 0.03/million in the US to 1/5000 in some parts of Africa.
Most infections are asymptomatic.

A minor illness presents with malaise, fever and sore throat.

The major (paralytic polio) illness has a sudden onset of symptoms: headache, fever, vomiting and neck stiffness. This lasts about a week.

In a minority of these pts, paralysis occurs. Any or all muscles can be affected.
Paralysis is of the motor neuron type with flaccidity of affected muscles.

Bulbar polio shows involvement of the cranial nerves, resulting in
paralysis of the pharynx, requiring mechanical support for respiration.
Transmitted via the fecal-oral route.

Virus replicates in the oral cavity and gut, then infects neurons via the blood.

Poliovirus has an affinity for motor neurons. Causes paralysis by infecting and killing cells in the anterior horn of the spinal cord (LMN= flaccid paralysis).
Polio Pathogenesis
Killed virus vaccine - SALK - protection in the gut - less risk in immunocompromised children (avoid developing encephalitis)

Live virus vaccine - SABIN - get 2 layers of protection - in the gut and serum
Polio vaccines
Member of the Rhabdoviridae. Bullet-shaped morphology; enveloped ssRNA virus.

100% (only 8 known survivors!) lethal encephalitis.

A zoonotic disease, spread mostly via bites from infected animals, aerosol contagion is known to occur.
About 50,000 deaths/year worldwide; only 1-3 deaths/year in the US. However, 20-40,000 post-exposure vaccinations are required each year in the US.

In the US, exposure to bats is the most common cause of rabies. Dog bites are the most common means of transmission worldwide. Always inquire as to pt's travel and animal exposure history when suspecting rabies.
the most common wild animal reservoirs of rabies in the US
Skunks, foxes, racoons
Despite the severity of the disease, pathology in the CNS is minimal, and pathogenesis is poorly understood. Immunopathogenesis doesn't appear to contribute to the disease.

Virus travels up axons via retrograde movement and has a particular affinity for hippocampal neurons.
Rabies pathogenesis
Diagnostic of rabies infection
Negri bodies***
Incubation period: 4-12 weeks. Appearance of symptoms dependent upon proximity of bite to CNS.

Symptoms: initially non-specific. Pain around bite area, muscle spasms, tremors, agitation.
Rabies-clinical course
Encephalitic (furious) = more common. Symptoms include excitement, tremors, muscular contractions and convulsions, phobic spasms (esp. muscles of swallowing), increased sensitivity of the nervous system, and hypersalivation.

Paralytic (dumb): symptoms include lack of aggression, paralysis of muscles, speech and respiration.
Two forms of Rabies
Virus is present in saliva, tears, skin, and brain**
Treatment: none, once symptoms appear.

Antivirals, IFNg, steroids and other immunosuppressants have been tried but are not effective.

Coma induction has been tried and only successful in 3/12 cases.
Rabies: response
Wounds should be washed thoroughly AND pt given:

Passive immunization: Human anti-rabies immune globulin should be administered promptly AND:

Vaccine: Inactivated viral vaccine should be used within 8 days of suspected contact. Vaccine is given i.m. in 3-5 doses at 0, 3, 7, 14 and 28 days.
Rabies: response
Animals free of symptoms for 10 days after biting can be considered rabies-free. Brains of killed animals should be examined for Negri bodies, and by PCR.

With animal bites, regard ANY wild animal (bat, raccoon, fox, etc) as rabid unless the area is known to be rabies free, or until the animal can be tested.
Rabies: response
Results from the reactivation of latent varicella zoster virus (VZV) infection.
It presents as the painful, often debilitating eruption of a rash, usually unilateral, along a dermatome.
Herpes zoster (shingles)
Operationally defined as pain that persists for more than 3 months after the resolution of the skin lesions of Herpes Zoster.
Post-herpetic neuralgia (PHN)
Affects 106 people/year, (50-70% >50 yrs of age). At least 10-20% of patients with HZ will progress to PNH (50% of these will be >60). Reactivation results from a decline in VZV-specific T cell immunity.

Changes in sensation in the dermatome, resulting in either hypo- or hyperesthesia, are common.
HZ and PHN
Treatment: First-line treatments include anti-convulsants (gabapentin or pregabalin), and lidocaine patches.
PHN intervention
Second-line treatments include opioids, topical capsaicin, and tri-cyclic anti-depressants such as amitriptyline or nortriptyline.

NSAIDS are ineffective.
PHN intervention
There is no evidence that use of anti-virals prevents PNH.

Prevention: Live, attenuated vaccine (Zostavax) is approved for the prevention of HZ in persons > 60 years of age. (the same one given to children)
PHN intervention
Infections manifest as either Herpes simplex encephalitis (HSE), which is mainly due to HSV-1.

Neonatal HSE is usually due to HSV-2, but Adult HSE is due to HSV-1. HSV encephalitis accounts for 10-20% of cases of acute encephalitis
HSV infection
Herpes simplex meningitis (HSM), which is mainly due to HSV-2.

HSV-2 now ranks second among the causes of viral meningitis in adolescents and adults.

HSE/HSM may result from primary infection, or from reactivation infection, with spread into the CNS. How HSV enters the CNS is unknown.
HSV infection
HSE is a medical emergency!!!

Untreated, the mortality rate is 70%.

Even when treated, survivors of HSE can be left with a permanent memory impairment, abnormalities in personality and behavior, epilepsy or dementia.
HSV infection
HSE is usually accompanied by headache, confusion, lethargy, seizures and progressively deteriorating mental aberrations.

HSE characteristically produces focal hemorrhagic*** necrosis of the temporal or frontal lobes (which contrasts with other viral encephalitides).
HSV infection
manifests similarly to other meningitides, typical as a complication of primary genital herpes.
Herpes simplex meningitis (HSM)
More common in Mollaret's syndrome (a syndrome of benign recurrent episodes of aseptic meningitis).
IV Acyclovir reduces HSE mortality to 20-30%. Steroids are sometimes given as well, but are not considered standard treatment.
HSV treatment
PCR analysis of the CSF for the presence of HSV DNA is the procedure of choice.

Cranial CT or MRI as soon as possible after presentation.

CSF lymphocytosis is observed in >90% of pts. RBCs in CSF are typical for HSV encephalitis, but NOT diagnostic.
Diagnosis of HSV infections
Member of the Flavivirus family.

Now established in the US since 1999. The strain circulating in North America has >99.8% nucleotide homology with viruses isolated in Israel.
West Nile Virus
Main carrier in the USA is the mosquito Culex pipiens.

Predominant hosts are birds.

Epidemics are associated with massive mortality in local bird and horse populations.
West Nile Virus
About 80% of WNV infections are asymptomatic, and only 1/150 infections yield symptomatic illness from neuroinvasive disease (NID, see next slide).

About 20% of infections yield West Nile fever: an acute, self-limited flu-like illness with sudden onset: fever, headache, myalgia, headache, nausea and vomiting. 50% of pts will have a rash on face and trunk.
West Nile Virus Infection
Advanced age (>55) is the greatest risk factor for Neuroinvasive Disease
West Nile Virus infection
Neuroinvasive disease appears as either aseptic meningitis, encephalitis, poliomyelitis, or in many cases, a combination of these syndromes.

Multifocal chorioretinitis appears to be a specific marker of WNV infection.
West Nile Virus infection
Pts most at risk are >70 yrs old. Highest mortality rates for these is ~8-10%. The overall mortality rate for WNV infection is ~4%.

Younger affected pts may have polio-like symptoms, with motor neuron infection leading to flaccid paralysis.
West Nile Virus pathogenesis
Tremor is seen in up to 80% of pts, unlike other viral meningitides. Neck pain, pleocytosis, myalgia, vomiting, chills are also very common.
WNV meningitis
Consists of fever, headache and altered mental status, and majority of pts have postural or kinetic tremor, unlike other viral encephalitides (except StLE or JBE).
WNV encephalitis
Pts have a rapid onset of asymmetric flaccid limb paralysis.
WNV poliomyelitis
CSF findings show granulocytic
pleocytosis, in ~50% of pts, elevated
protein and normal glucose

ELISA for IgM anti-viral antibodies is the mainstay of diagnosis.
WNV lab diagnosis
Mosquito-borne. About 20-200 cases annually in the US; tends to occur in episodic outbreaks. Most infections are subclinical, but has an 8% mortality rate (higher in elderly pts) in those who become clinically ill. Neurologic sequelae are common.
St. Louis encephalitis (StLE) (flavivirus encephalitides)
World-wide, the largest cause of epidemic encephalitis. Common throughout southern, eastern, and southeast Asia; ~30-50,000 cases/year and 10-15,000 deaths occur annually (mortality rate of 20-30%) and neurologic sequelae are common. Mosquito-borne.

Most cases occur in children <10 yrs.

Vaccine: Inactivated virus vaccine available for travelers to endemic regions.
Japanese B encephalitis (JBE) (flavivirus encephalitides)
Most medically important pathogen is Eastern equine encephalitis. Mosquito-borne.

Mostly occurs in the eastern US. Infections are very rare, but tend to occur in local outbreaks. A 2006 outbreak of seven cases occurred in New Hampshire, with two fatalities.

Most infections are asymptomatic, but EEE has a mortality rate of ~33%.

Acute symptoms are typical of encephalitis.

Those who recover from encephalitis have permanent neurologic sequelae.
Togavirus encephalitides
One sign of primary HIV infection can be aseptic meningitis, manifested by headache, confusion, seizures or cranial nerve palsies. Seen in up to 17% of cases of primary HIV infection and may be associated with faster disease progression.

In most patients, the clinical findings resolve without treatment.
Neuropathogenesis of HIV
HIV-infected cells (in particular monocytes) appear to infiltrate the CNS very soon after peripheral infection and provoke a neuropathological response involving all cell types in the brain.

Despite overt neuronal pathology, HIV does not directly infect neurons.
Neuropathogenesis of HIV
Neuronal dysfunction or death is largely an indirect consequence of disrupted function of macrophages, microglia, and astrocytes, and the cellular toxins released by infected cells.

This can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction, and frank dementia.
Neuropathogenesis of HIV
HAD-HIV-associated dementia is a neurodegenerative syndrome that is clinically characterized by progressive cognitive, motor and behavioral abnormalities, and is associated with high viral loads. Seen in 20-40% of pts with advanced AIDS, and 7% of HIV- 1-infected patients treated with HAART.

HAD is an AIDS-defining disorder.
Neuropathogenesis of HIV
MND- Mild neurocognitive disorder is seen in ~30% of HIV+ pts. Diagnosed by having at least two of the following: impaired attention or coordination, mental slowing, impaired memory, slowed movements, or impaired coordination. MND does NOT progress to HAD.

Mental deficits are much less pronounced in MND than in HAD.
Neuropathogenesis of HIV
Standard treatment for HAD is HAART, combined with aggressive treatment of associated psychiatric problems (such as mood, anxiety, or substance use disorders).
HIV intervention
Nonenveloped DNA virus.

Member of the Polyoma virus subfamily of the Papovaviridae).

JC virus is an opportunistic pathogen. Infection is widespread (60-90% of the population is antibody-positive) and nearly all infections are asymptomatic.
JC polyoma virus infection
Causes progressive multifocal leukoencephalopathy (PML), a degenerative demyelinating disease, in immunosuppressed pts. 80% of PML pts have HIV/AIDS.

After toxoplasmosis, PML is the most common opportunistic infection to affect the CNS (~10-14% of pts, even in the age of HAART).
JC polyoma virus infection
JC virus is cytolytic for glial cells and oligodendrocytes.

PML frequently presents as hemiparesis, ataxia,
visual disturbances (hemianopia) or higher cortical
dysfunction [ex. dysphasia or agnosia rather than global
impairment], with rapid progression to death.

Mortality rate is 30-50%; survivors have devastating neurologic deficits.
Progressive multifocal leukoencephalopathy (PML)
Neuroimaging, particularly brain MRI, is crucial for early diagnosis of PML.

Detection of JC DNA in CSF via PCR is required for a definite diagnosis of PML.

HAART and immune reconstitution are the only effective treatments for PML.
PML intervention
Most likely virus in meningitis in 2year-old patient?
Enteroviruses (CLICKER)
Definitive Diagnostic Test for Herpes Virus Encephalitis?
Symptoms of Meningitis
Temperature Instability (Hypothermia or Fever)
High pitched crying
Refusal to eat
Weak sucking response
Respiratory distress
Bulging Fontanelle (late sign in 1/3 neonates)
Newborns and Infants
Attempt to passively flex the patient's neck and touch his chin to his chest
If nuchal rigidity is present, this maneuver triggers pain and muscle spasms
The patient may also notice nuchal rigidity when he attempts to flex his neck during daily activities
May herald life-threatening subarachnoid hemorrhage or meningitis
It may also be a late sign of cervical arthritis
Nuchal Rigidity
Kernig's Sign
Brudzinski's Sign
Gram(-) large rods with thick mucoid capsule cause meningitis in the aged
Klebsiella pneumoniae
Gram(+) cocci in normal vaginal flora
Streptococcus agalactiae
When would you worry about HSV and start acyclovir?
high RBC in CSF without a "traumatic tap", focal neurologic deficits, simple partial seizure, etc
General sequelae in 10-20% of the cases of bacterial meningitis: mental retardation, learning disabilities, hearing loss
Suppurative Meningoencephalitis
-complication of bacterial CNS infections
Cerebral abscess: liquefactive center with yellow pus surrounded by a thin wall.

Abscesses usually result from hematogenous spread of bacterial infection, but may also occur from direct penetrating trauma or extension from adjacent infection in sinuses.
-transmission during delivery
-infected amniotic fluid
-ruptured amniotic membranes and prematurity increase risk

-GBS - polysaccharide capsule
-E. Coli - K1 polysaccharide capsule
Neonatal Meningitis pathogenesis from colonized mother
Polysaccharide capsule - antiphagocytic

Peptidase - inactivates C5a (major chemo-attractant of PMNs)

Hydrolytic enzymes - tissue destruction and systemic spread
Streptococcus agalactiae (GBS)
Strains containing the K1 polysaccharide capsule

Pili involved in adherence to brain microvascular endothelial cells

E. coli
sensitive and specific
identification of GBS antigen in urine or in CSF

Latex particle agglutination (LGA) test of urine -rapid screening for GBS, E coli, and S. pneumoniae

CSF and blood cultures
Diagnosis of Neonatal Meningitis
Microscopy - blood or CSF
Gram stain

Culture of blood or CSF
Blood agar - Beta-hemolytic
Motility test

CSF analysis
pleocytosis, elevated CSF protein levels, low CSF glucose levels
Listeria monocytogenes Diagnosis
Pregnant women should avoid eating uncooked food thought to be of particular risk (coleslaw, soft cheese, unpasteurized milk, hotdogs...)

Improve the safety of processed meats through meticulous in-plant sanitation and post-packaging pasteurization

Education for high-risk consumers to reduce their risk of listeriosis
Listeriosis Prevention
Complication of Neonatal GBS Meningitis: Multiple Abscesses
Complication of Meningitis: Hydrocephalus

Exits of the fourth ventricle become obstructed by fibrosis
Viral (aseptic) encephalitis/meningitis
JC virus
Prion disease
Viral infections of the CNS
-Direct cytolytic effects
-Inflammatory or immune mediated effects
-Vasculitic effects

Viruses enter the brain by crossing the blood-brain barrier directly (polio), by being transported by infected lymphocytes or macrophages (flaviviruses, HIV), or by retrograde axonal transport (polio, rabies).
Pathology of viral infections of the CNS
Because VZV is latent in most ganglia, HZ can occur anywhere on the body.

The most frequent sites affected are the thoracic nerves followed by the ophthalmic division of the trigeminal nerve (herpes zoster ophthalmicus).
HZ and PHN
Multiple reactivation
Young Age
Very localized rash
HSV Clinical Features
Elderly Age
Dermatomal Rash
VZV Clinical Features
HIV-infected cells (in particular monocytes) appear to infiltrate the CNS very soon after peripheral infection and provoke a neuropathological response involving all cell types in the brain.

Despite overt neuronal pathology, HIV does not directly infect neurons.
Neuropathogenesis of HIV
Neuronal dysfunction or death is largely an indirect consequence of disrupted function of macrophages, microglia, and astrocytes, and the cellular toxins released by infected cells.
Neuropathogenesis of HIV
This can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction, and frank dementia.
Neuropathogenesis of HIV
Viral Meningitis Treatment
-Treatment = primarily supportive care
Antivirals for some (acyclovir = HSV), passive immunity & vaccine for rabies, steroids for inflammation
-Prognosis is good for a self-limited Viral Meningitis
-There are currently no vaccines available for the most common etiologies of viral meningitis
-Vaccines: MMR, influenza, varicella, herpes zoster, rabies, Japenese encephalitis
-Good hygiene (frequent hand washing), avoiding crowded living spaces (prisons, dorms), avoid mosquito bites
Necrotizing Hemorrhagic Neonatal HSV Encephalitis

70% of cases are caused by genital HSV acquired during delivery
slide 30*
CMV infections causes:
-Cortical atrophy
-Periventricular calcifications
Slide 35*
Encapsulated yeast
Natural habitat = soil - enriched with bird droppings
Major cause of fungal meningitis
In patients with depressed cell-mediated immunity (AIDS)
Cryptococcus neoformans
Pathogenesis antiphagocytic polysaccharide capsule

marked tropism for CNS
Cryptococcus neoformans
Infection by inhalation-->
invade blood from primary site of infection (lungs) --> brain --> Subacute to chronic meningitis
Cryptococcus neoformans
Clinical presentation
-slow onset - weeks
-headache, visual disturbances, abnormal mental status and seizures
Cryptococcus neoformans
rarely visible in CSF
CSF: lymphocytes, high protein and low glucose
culture possible in less than 50% of cases
demonstrating complement-fixing antibodies in the serum
Coccidioides immitis
Dimorphic Fungus
environmental form: hyphae breaking up into arthroconidia
tissue form: spherules filled with endospores
Habitat: soil - desert sand
Coccidioides immitis
Cryptococcal Scalp Infection in a Lymphoma Patient

Thick mucoid capsule
Slide 44*
Silver Stain - Cryptococcus Neoformans
Slide 45*
-Fungal infections typically progress slowly
-Difficult to diagnose due to the fact that they are slow growing, if they show up at all on cultures
-Often the only clue is that the patient continues to get worse on empiric antibiotics & antivirals
-May have eosinophilia (>5%)
-Can test for specific IgM
Fungal infection Diagnosis
Antifungals (Amphotericin B - known for its severe & potentially lethal side effects - nephro & hepatotoxic)

Prevention = good hygiene; no vaccines available
Fungal infection Treatment & Prevention
Free-living amoebae
Habitat - warm fresh water (lakes)
Naegleria spp.
-causes primary amebic meningoencephalitis
-affects children and young adults
-transmission: swimming in fresh water - shallow water during warm weather
-often fatal
Naegleria fowleri
3 stages: cysts, trophozoites and flagellated forms

Infective forms = trophozoites and flagellated forms

Enter the body via the olfactory neuroepithelium then reach the CNS
--> purulent, hemorrhagic inflammatory reaction
Naegleria fowleri
Clinical picture
-rapid onset
-severe headache, fever, nausea, altered sense of smell or taste
-progresses rapidly, frequently to coma and death in a few days
Naegleria fowleri
Laboratory Diagnosis
-CSF: purulent, bloody, lots of neutrophiles, high protein, low glucose
-wet mount - motile trophozoites in CSF
-Trichome- or Giemsa-stained smear - trophozoites
-Culture on plates seeded with gram(-) bacteria or tissue culture

Treatment: Amphotericin B
Naegleria fowleri
Opportunistic free-living amoebae

found in soil; fresh, brackish, and sea water; sewage; swimming pools; contact lens equipment
Acanthamoeba spp.
Several species are implicated
-cause granulomatous amebic encephalitis
-affect immunocompromised individuals
-associated with contamination of contact lenses with nonsterile cleaning solutions
Acanthamoeba spp.
-Intracellular parasite
-Infects most species of warm blooded animals, including humans (50% of population is infected)
-Causes toxoplasmosis
the most common parasitic human disease throughout the world
Toxoplasma gondii
Cats: definitive hosts
Toxoplasma develops in cat's intestinal cells. Oocysts passed in feces and mature into infective oocysts in the environment

Intermediate hosts: many other animals and humans
Toxoplasma gondii
Transmission to human
-ingestion of undercooked infected meat containing cysts
-ingestion of oocysts from fecally contaminated hands or food
-transplacental transmission
-blood or organ transplant
Toxoplasma gondii
After ingestion oocysts mature to tachyzoites --> invade macrophages --> transported through lymphohematogenous system to all organ systems

Cyst development especially in brain, heart and skeletal muscles
Cyst can persist for life of host
Cyst can rupture --> parasitologic relapse
Toxoplasma gondii Pathogenesis
In immunocompetent hosts
commonly chronic & asymptomatic
10% to 20% may develop lymphadenopathy and/or a flu-like illness
benign and self-limited
Toxoplasma gondii Pathogenesis
In immunocompromised hosts
-highly lethal disease
-toxoplasmic encephalitis = often reactivation of chronic infection
-symptoms related to location of lesions: hemiparesis, seizure, visual impairment, confusion
Toxoplasma gondii Pathogenesis
Primary maternal infection --> fetus may be infected

If toxoplasma crosses placenta early --> severe congenital infections: intracerebral calcification, chorioretinitis, hydro- or microcephaly...and stillbirth

If toxoplasma crosses placenta later --> may be inapparent; untreated inapparent congenital infections lead to progressive blindness or neurologic problems (retardation, hearing loss...)
Congenital Toxoplasmosis
Serologic testing
-rising or high titers of IgM
-indicate active infection

Observation of parasites in tissue biopsies or body fluids

-intraperitoneal inoculation into mice or tissue culture --> presence of Toxoplasma organisms in the mice peritoneal fluid 6 to 10 days post inoculation

Toxoplasmosis Diagnosis
Treatment recommended for
-immunocompromized patients
--> sulfadiazine + pyrimethamine

Pregnant women
-pyrimethamine should not be used in the first trimester of pregnancy because teratogenic
-clindamycin and spiramycin
Toxoplasmosis Treatment
Toxoplasmosis - Papanicolaou Stain

Cysts with Bradyzoites
Toxoplasma in CNS can cause Granulomatous inflammation

-Epithelioid Cells
Toxoplasma Retinitis
Thick, periarteriolar kyrieleis plaques surround perilesional vessels
Retinal scarring due to Toxoplasma retinitis
Neurocysticercosis- caused by Taenia solium (Cestode)
Presents with back pain (90%) and fever (60%)

Neurologic deficits appear late in the course
-Paresthesia, bowel and bladder dysfunction, radicular pain, weakness
-abnormal reflexes and motor and sensory deficits
Spinal Epidural Abscess Presentation
Increased risk: diabetes mellitus; intravenous drug use; recent spinal trauma, surgery, or epidural anesthesia; and other comorbid conditions, such as HIV infection
Spinal Epidural Abscess Risk
Thoracic or Lumbar spine is the most common location

Cervical spine infections are associated with worse outcomes

Rapid recognition and treatment, which may include surgical drainage, can prevent or minimize permanent neurologic sequelae
Spinal Epidural Abscess
Rare but potentially life-threatening disease
Requires early detection and prompt management
Defined as an inflammation that involves a collection of pus between the dura and the bones of the skull or spine
-Spinal epidural abscess
-Intracranial epidural abscess
Spinal Epidural Abscess
Loose association between the dura and vertebral bodies
lumbar and thoracic spine are more commonly affected
Tight adherence of the dura to the skull limits expansion of intracranial epidural abscess
often resulting in dangerously increased intracranial pressure
Pathophysiology of Epidural Abscesses
10-30% result from direct extension of local infection
vertebral osteomyelitis, psoas abscess, or contiguous soft-tissue infection

~50% are due to hematogenous seeding
most likely source is a soft-tissue process

15-22% due to invasive procedures or instrumentation
In some cases (up to 30% in some series), the source of the spinal epidural abscess is not identified
Causes of Spinal Epidural Abscess
MRI*** is the cornerstone of diagnosis in both intracranial epidural abscess and spinal epidural abscess
-greatest diagnostic accuracy
-first choice in the diagnostic process
-sensitivity is 90%-95%, and its specificity >90%
-Gadolinium enhancement increases sensitivity for detecting spinal epidural abscess
Work-up for Spinal Epidural Abscess
CBC, blood culture, culture of abscess

CT scanning with intravenous contrast may demonstrate fluid collections in the epidural space (cheaper and faster)
Work-Up for Spinal Epidural Abscess
A combined medical-surgical approach
emergent surgical decompression and drainage of purulent material
Antibiotic-based therapy, sometimes combined with CT-directed needle aspiration
used only in patients with contraindications to surgery
Treatment of Spinal Epidural Abscess
Empirical antibiotic therapy should include coverage of gram-positive cocci, particularly staphylococci (including MRSA), and gram-negative bacilli

Vancomycin has been the standard agent for gram-positive infections

Third- and fourth-generation cephalosporins and meropenem offer gram-positive (except MRSA) and gram-negative coverage in addition to CNS penetration

Always tailor coverage once culture data are available
Antibiotics for Spinal Epidural Abscess
Death or permanent neurologic sequelae occur in a substantial proportion of patients

The degree of neurologic recovery after surgery correlates with the duration and initial severity of the neurologic defect
Spinal Epidural Abscess Complications
Clinical presentation
-slow onset - weeks
-headache, visual disturbances, abnormal mental status and seizures

-CSF: lymphocytes, high protein and low glucose
-capsulated yeasts - INDIA INK stained prep.
-culture - Sabouraud agar
-Capsular antigen detection: latex agglutination test (serum or CSF)
Cryptococcus neoformans
Dimorphic Fungus
-environmental form: hyphae breaking up into arthroconidia
-tissue form: spherules filled with endospores
-Habitat: soil - desert sand
Coccidioides immitis
-rarely visible in CSF
-CSF: lymphocytes, high protein and low glucose
-culture possible in less than 50% of cases
-demonstrating complement-fixing antibodies in the serum
Coccidioides immitis
Primary site of infection = lung
Arthroconidia --> Spherules (resistant to phagocytoses)-->
Blood --> Disseminated coccidioidomycosis; Brain: chronic meningitis
Coccidioides immitis
Only 2 stages, cysts and trophozoites
Infective forms = trophozoites

Enter body via the lower respiratory tract, ulcerated or broken skin
Invade the central nervous system by hematogenous dissemination
diffuse necrotizing granulomatous encephalitis

Cysts and trophozoites are found in tissue
Subacute or chronic granulomatous amebic encephalitis
-headaches, altered mental status, and focal neurologic deficit
-progresses over several weeks to death

In addition, Acanthamoeba spp. can cause granulomatous skin lesions and, more seriously, keratitis and corneal ulcers following corneal trauma or in association with contact lenses
Acanthamoeba infection
Granulomatous amebic encephalitis - Ketoconazole and AmphotericinB
Keratitis - propamidine and miconazole nitrate with neomycin
Acanthamoeba infections
-stained smears of biopsy specimens (brain tissue, skin, cornea) or of corneal scrapings - trophozoites and cysts
-culture - same as Naegleria
-identification by direct immunofluorescent antibody
Acanthamoeba infections