CNS Other

Infections
Pediatric Critical Care Medicine
Emory University
Childrens Healthcare of Atlanta

ASEPTIC MENINGITIS
Viral, atypical bacteria, fungal, TB

Etiologies: Viruses and

Bacteria
- Adenovirus
- Arbovirus
- Enteroviruses
- Herpesviruses
- HIV
- Influenza A/B
- Japanese encephalitis
- Measles
- Mumps
- Rubella
- Rabies
- Lymphocytic
choriomeningitic virus

Bartonella henslae
Bordetella pertussis
Borrelia burgdorferi
Brucella spp.
Chlamydia spp.
Ehrlichia, Leptospria spp.
Mycobacteria spp.
Mycoplasma spp.
Rickettsia spp.
Treponema pallidum

Etiologies: Fungal and

Others
Aspergillus fumigatus
Blastomyces
dermatitidis
Candida spp.
Crytococcus
neoformans
Coccidioides immitis
Histoplasma
capsulatum

Toxoplasma gondii
Entamoeba histolytica
Acanthamoeba
Trichinella
Naegleria

TB Meningitis
Most serious complication of TB infection
Fatal without effective treatment, significant
morbidity even with treatment
In children CNS involvement occurs during
primary infection (rather than reactivation)
Usually results from hematogenous spread from a
primary focus (lungs)
Variable presentation, but usually onset is
insidious
More rapid in infants and young children

TB Meningitis

Clinical Staging
Stage

Signs and Symptoms

Stage 1 (Early)
Days to weeks

Fever, HA, malaise

Lethargy, behavior changes
No neuro deficits
No alteration of consciousness

Stage 2 (intermediate)
Weeks to months

Meningeal irritation
Minor neuro deficits (CN)

Stage 3 (late)
Months to years

Abnormal movements
Convulsions
Stupor or coma
Severe neuro deficits

Diagnosis
* Isolation or identification of mycobacterium is the
gold standard for diagnosis
Possible in about 80% of cases
PCR, ADA, ELISA have varying degrees of accuracy

* Typically 10-500 WBCs, with predominance of lymphs

* CSF glucose <40, protein moderately elevated (150200)
* CSF can be normal in children with unruptured
tuberculomas
* Neuroimaging will be very helpful
* Look for the primary TB site

Treatment
Typically requires at least 3 or 4 drug therapy
Isoniazid, rifampin, pyrazinamide +/- ethambutol or
streptomycin

WHO recommends at least a 4 month course for

TB meningitis
Steroids have been shown to significantly reduce
the neurologic sequelae of TBM
They often require a shunt for hydrocephalus
Prognosis varies but depends on clinical stage
at the time treatment is started

ENCEPHALITIS AND
MYELITIS

Encephalitis
* Refers to inflammation of the brain parenchyma
* Pathology shows:
Inflammation and destruction of neurons
Pathogen detection by direct visualization, staining, etc

* Referred to as postinfectious encephalitis when in

temporal association with viral infection or
immunization
ADEM when it includes spinal cord

* Can cause significant alterations in sensorium and

seizures
Many patients require ICU

Etiology
* In neonates, the most common etiology is HSV
(usually type 2), but also entero- and adenovirus
* In older children arthropod-borne viruses
(arboviruses) and enteroviruses are the most
common
Arbo: EEE, WEE, St. Louis, West Nile, JE
Entero: polio, echo, coxsackie, etc

* Subacute sclerosing panencephalitis is a now rare

complication of measles infection
* Tick borne bacteria can also be implicated
Borrelia, Rickettsia, ehrlichiosis

Pathogenesis
* Once a virus crosses the epithelium (usually at a
mucosal surface) viral replication occurs, followed
by viremia
* Viruses can penetrate the CSF from the blood, or
by spread from peripheral neurons (rabies and HSV)
* Once in the CNS the virus attaches to host cells
Viral genome replication takes over, affecting the other
functions of the cell

* Interferon in particular inhibits viral penetration,

replication, translation, and assembly
The inflammatory process may turn on the host

Clinical Manifestations
* Varies depending on affected site, severity, and
host factors
May or may not involve meninges (rabies)

* Nonspecific symptoms in neonates

May not have maternal h/o HSV

* Older children have acute onset of fever, HA,

seizures, behavior changes, AMS, or coma, +/prodrome
Depends on site of involvement
May have paralysis or paraplegia if spinal cord involved
Look for rashes (erythema migrans)

Diagnosis
* CSF findings are non-specific
Cells and protein may be normal or slightly elevated
May see predominance of lymphs

* May get a diagnosis from culture, antigen

detection, PCR, or antibody titers
PCR stays positive for months, highly sensitive and
specific

* EEG can help distinguish focal from generalized

encephalitis
HSV has characteristic periodic lateralized
epileptiform discharges (PLEDs)

Neuroimaging
Etiology

Site of involvement on
MRI

HSV

Inferomedial temporal
and frontal lobes

Japanese encephalitis

Bilateral thalami and

basal ganglia

Rabies

Hippocampal, cerebellar,
mesencephalic areas

Eastern equine
encephalitis

Disseminated brain stem

and basal ganglia

Management
* Children with suspected encephalitis warrant ICU
monitoring
* Antimicrobial therapy is appropriate until bacterial
meningitis has been ruled out
* Antiviral therapy should be started when appropriate:
HSV acyclovir
CMV ganciclovir or foscarnet
Flu A/B amantadine/rimantadine (A only), oseltamivir (A and
B)
No specific therapy for entero- and arboviruses
Consider IVIG in immune compromised patients

HSV Encephalitis
HSV is the most common cause of fatal
encephalitis in childhood
Mostly HSV-1 after neonatal period

Encephalitis can result from both primary and

recurrent HSV infection
Primary CNS if via olfactory and trigeminal nerves

Disseminated HSV in the neonate affects the CNS

by hematogenous spread

HSV: Clinical Presentation

Neonatal

Older children

Skin vesicles, scarring

Eye involvement
(chorioretinitis, optic
atrophy)
Brain (microcephaly,
encephalomalacia)
Disseminated disease
(sepsis, ARDS, MODS)

Older children have

typical symptoms of
encephalitis
Behavior, personality,
and speech changes
are particular to HSV
Progression may still
be rapid and fatal in
non-neonates

Diagnosis
* Swabs from
conjunctiva,
nasopharynx, rectum,
skin lesions
* MRI may show
temporal or frontal
involvement
* PLEDs on EEG
* HSV PCR is 95 %
sensitive and 100%
specific (gold standard)
* Please dont do a brain
biopsy

HSV: Treatment and

Prognosis
ACYCLOVIR 20 mg/kg q8h for 14-21 days in
neonates
10 mg/kg q8h in older children

Need a negative CSF PCR before stopping therapy

Steroids have not been proven in children
Early treatment reduces morbidity and mortality
Relapse occurs in 12% of adult patients
Disseminated neonatal disease has 50% mortality
and 50% of survivors have significant sequelae

ADEM
Acute Disseminated Encephalomyelitis

ADEM: Introduction
ADEM is an inflammatory demyelinating disorder
of the CNS
Mostly seen in children and young adults
Can be multiphasic (must distinguish from MS)
Often preceeded by respiratory or GI viral illness
Has also been reported after immunizations
MMR and rabies vaccines

ADEM: Clinical
Presentation
* Mean age of presentation is 7 years, slightly >
males
* Fever, HA rapidly progresses to AMS and
multifocal neuro deficits
Evolution may occur over a few days

* Deficits depend on affected areas

White matter, spinal cord, optic nerves
Ataxia and extrapyramidal symptoms are common
UMN signs in affected limbs

* Fulminant presentation with rapid deterioration is

rare, but usually occurs in children < 3 yrs

ADEM: Diagnosis
The Brighton collaboration has published a very
complicated clinical definition of ADEM
Based on varying levels of diagnostic certainty
histopathology, imaging, presentation, etc

CSF is not helpful in making a diagnosis of ADEM

May show pleocytosis or be normal
10% of cases have oligoclonal bands
Myelin basic protein may be increased

EEG may show focal or generalized slowing

Neuroimaging

ADEM: Treatment
Mainstay of treatment is methylprednisolone 2030 mg/kg/day for 3-5 days
Taper over 3-6 weeks

Plasmapheresis and IVIG have also been used

Considered when meningoencephalitis cannot be
excluded
Concern that steroids would worsen possible infection
Combing either of these with steroids show no added
benefit

ADEM: Prognosis
Most children with mild to moderate illness and
appropriate treatment achieve good recovery
Acute mortality is rare
Fulminant cases are at higher risk of mortality

1/3 of cases have residual deficits

Motor, visual, autonomic, developmental, epilepsy

Relapses may occur during the steroid taper

Recurrent attacks can occur after full recovery

BRAIN AND SPINAL CORD

ABSCESS

Brain and Spinal Cord

Abscess
May occur as a primary infection or as a

complication of bacterial meningitis (more rare)

Rogers says that intensivists like them because
they are a serious, potentially fatal infection that
requires immediate intervention

Abscesses: Etiologies
* Most common pathogens include anaerobes,
GNs, streptococci, and staph
* Neonates most commonly get GNs: Citrobacter,
Enterobacter, Proteus
* In other populations the organism depends on
predisposing factors:
CHD a-hemolytic strep
Endocarditis strep, S. aureus
Post-trauma staph
Otitis/sinusitis strep, Bacteroides fragilis, Proteus spp.,
pseudomonas, H.flu

Abscesses: Pathogenesis
* May occur via hematogenous or direct spread
* Cyanotic heart disease is the most common
underlying condition (esp. TOF)
Polycythemia higher viscosity microinfarcts
Bacteria love it!

* Chronic pulm infection, bacterial endocarditis,

and immune compromise also increase risk
* Direct spread may occur from chronic otitis,
mastoiditis, sinusitis, trauma, NS procedures
* Meningitis is a rare cause if treated appropriately
Except in neonates with GN meningitis

Abscesses: Pathogenesis
* Bugs localize at the gray-white junction
cerebritis
* Stage 1: Early cerebritis (Day 1-3)
Leukocyte infiltration, focal edema, no clear demarcation

* Stage 2: Late cerebritis (Day 4-9)

Central liquefaction necrosis (yum!), fibroblast infiltration,
capsule formation

* Stage 3: Continued capsule formation

* Stage 4: Late capsule formation (2 weeks out)
Dense fibrous capsule, marked edema

Abscesses: Pathogenesis
Entire process may take 4-6 weeks
May progress faster or rupture into ventricular
system
Sites of infection vary but cerebral are most
common
Kids with CHD get them in MCA distribution
Otitis can spread to unilateral temporal lobe or
cerebellum

Abscesses: Diagnosis
LP would be contraindicated in a patient with
brain or spinal cord abscess
ButCSF may show pleocytosis, protein, normal glc

Blood cultures and cultures from other potential

foci would help
Get imaging

Abscesses: Imaging

Abscesses: Imaging

Abscesses: Treatment
Surgical drainage or excision is required in many
cases
Usually under CT guidance

Smaller abscesses may be manageable with

antibiotics alone
Empiric therapy is usually a 3rd/4th gen
cephalosporin + metronidazole
Add vanc if staph is suspected
Tailor therapy once an organism is defined
IV therapy for at least 6 weeks

Abscesses: Prognosis
Mortality is high in several groups:
Newborns, young infants
Children with multiple large abscesses and CHD
Intramedullary abscess of spinal cord (vs. subdural or
epidural spinal abscesses)

Rupture of an abscess can be life-threatening

Residual defects are common
Hemiparesis, CN palsies, cognitive defects, epilepsy

Early decompression improves outcome

Cerebritis Vasculitis

Shunt Infections
2/3 of all shunt infections are caused by staph
spp
Staph epi, aureus, and other coag-negative types have
been frequently isolated in several series

GN enterics (E.coli, Klebsiella, Proteus,

Pseudomonas) make up 6-20%
Strep causes 8-10%
Multiple organisms are found in 10-15%
Incidence has declined over the past few years
70-85% of infections are within 6 months of surgery

Pathogenesis
* Shunts are foreign bodies and interfere with
natural host defense mechanisms
Chemotaxis and phagocytosis

* Staph can also form biofilm which increases

bacterial adherence and decreases effect of
antibiotics
* Infection may occur through different mechanisms:
Wound or skin breakdown over shunt
Colonization at the time of surgery
Retrograde from the distal end of shunt
Hematogenous seeding (infrequent)

Clinical Presentation
Fever, headache, vomiting, lethargy, altered
mental status
Check for wounds and look for cellulitis along the
shunt
Infection may spread to the distal end of the
shunt and cause peritonitis

Diagnosis
Isolation of organisms from CSF or equipment
Other CSF studies are variable

If there is associated shunt malfunction there may

be an increase in ventricular size on CT
Distal shunt infections can also cause abdominal
pseudocysts

Treatment
Antibiotics are a mainstay of treatment
Some propose shunt removal or externalization only if
there is no response to antibiotics

Associated ventriculitis may clear more quickly

with externalization
Cover staph with cloxacillin or vanc + an
aminoglycoside
Rifampin is often added

Intraventricular therapy is sometimes indicated

CNS FUNGAL INFECTIONS

Aspergillus, Cryptococcus

CNS Fungal Infections

Predisposing Condition

Fungal Pathogen

Prematurity

Candida albicans

Primary immunodeficiency (CGD,

SCID)

Candida, Cryptococcus,
Aspergillus

Corticosteroids

Cryptococcus, Candida

Cytotoxic agents

Aspergillus, Candida

Secondary immunodeficiency
(AIDS)

Cryptococcus, Histoplasma

Iron chelator therapy

Zygomycetes

IV drug abuse

Candida, Zygomycetes

Ketoacidosis, renal acidosis

Zygomycetes (Mucor)

Trauma, foreign body

Candida

CNS Fungal Infections

Dont forget about the fungi that can cause
disease in a healthy host:
Cryptococcus, Histoplasma, Blastomyces, Coccidioides,
Sporothrix

Fungal infections are on the rise worldwide due to

increasing prevalence of HIV

Fungal Meningitis
Most common causes are Cryptococcus
neoformans, C. immitis, Candida, and Aspergillus
Fungal meningitis in general has a more insidious
onset than bacterial
Symptoms may develop over days
Always consider it with subacute/chronic presentation

C.neoformans may develop more quickly in

patients on high-dose steroids or with HIV

Fungal Meningitis
Rhinocerebral syndrome is a major presentation
of zygomycosis
Rhizopus and Mucor spp
Associated with poorly controlled DM
Orbital pain, nasal discharge, facial edema, proptosis

May invade carotids, trigeminal nerve and

adjacent brain structures
May also present with sudden neuro deficit due to
vasculitis
Can rarely cause mycotic aneurysmal bleed

Diagnosis
* Have a low index of
suspicion in immune
compromised patients
with fever and CNS
signs
* CSF usually has high
protein, low glucose,
and 20-500 WBCs
Cell count may be LOW
(<20) with AIDS or high
dose steroids

* India ink prep can

identify >50% of
C.neoformans cases (up
to 80% in AIDS)

Diagnosis
- Cultures are
frequently negative
Candida takes days to
grow, histo/coccidio take
weeks

- Methenamine stain of
an aspirate or biopsy
can help identify
Aspergillus and
Zygomycetes, which
can cause tissue
invasion and necrosis

Treatment
Fungus

Initial
Regimen

Second
Regimen

Other
Consideration
s

Candida

Amphotericin B
+ flucytosine x
2 wks

Fluconazole x 8- Remove shunt if

10 weeks
appicable.

Cryptococcus

Ampho B +
flucytosine x 2
wks

Fluconazole x 8- Repeat LP after

10 weeks
2wks of ampho.
Stop steroids.

Coccidio

Ampho x 4wks

Fluconazole or
ampho 4eva

Serial
monitoring of
CSF

Aspergillus

High dose
ampho +
excision

PO vori or
ampho x 1 yr

Excision is key.

Prognosis
Depends on underlying disease process
Why are they immune suppressed?

Candida meningitis has a mortality of 10-20%

Only 50% of patients with coccidioidal meningitis
survive initial treatment
Survivors have a high risk of relapse

A cryptococcal vaccine has been developed, not

sure if it is available yet

PARASITIC CNS
INFECTIONS
Neurocysticercosis
and Cerebral Malaria

Neurocysticercosis
- Most common parasitic
CNS infection.
Important cause of
epilepsy in the tropics.

- Most cases present with

seizures.
1/3 present with raised ICP.

- Endemic in Latin
America, Mexico, India,
sub-Saharan Africa, and
China.
Including developed
countries.
>1000 new cases are
diagnosed in the US each
year.

Taenia solium Life Cycle

Neurocysticercosis
Parenchymal

Extraparenchymal

Seizures in 70-90% of
patients
1/3 will have raised ICP
4% have focal neuro
deficits
May have encephalitis

Rare in children
Obstructive
hyrdocephalous or
chronic meningitis
Spinal involvement

Numerous cysts
Diffuse cerebral edema
Poor prognosis

Radicular pain
Cord compression
Transverse myelitis

Ophthalmic involvement
Vision deficits

Neurocysticercosis

Treatment
- Praziquantel and albendazole are both effective
- But albendazole is better tolerated and penetrates CSF
better.
15 mg/kg/day x 28 days

- There are some times to NOT use cysticidal therapy:

Markedly raised ICP inflammatory response will be bad, give
only steroids
Ophthalmic NCC
Calcified lesions parasite is already dead

- Use steroids to reduce cerebral edema or if there is

encephalitis
- Repeat CT in 3-6 months to assess lesions

CEREBRAL MALARIA
Last one!

Cerebral Malaria
Clinical syndrome characterized by CNS
dysfunction associated with Plasmodium
falciparum infection
Becoming more common in developed countries
due to increases in international travel and
migration
Pathophysiology is different in children who grew
up in endemic areas vs. those who are nonimmune

Etiology
P. falciparum causes almost all life-threatening
malaria.
Transmitted by anopheline mosquitos

Sporozoites enter the bloodstream and visit the

liver before invading erythrocytes
Trophozoites and schizonts are sequestered in
the microcirculation of vital organs
Obstructs blood flow and impairs function of
parenchymal cells
Thats bad

Epidemiology
Endemic in tropical areas
Southeast Asia, Central/South America, Africa

300-500 million cases and 1.5-3 million deaths

annually
One of the top 3 infectious disease killers worldwide

Pathogenesis
- Plasmodial infections stimulate monocyte
release of cytokines (TNF, IL-1, IL-6)
- Pathogenesis of cerebral malaria is not well
understood
Likely multi-factorial mechanisms of neuro dysfunction
May be due to obstruction of microvasculature
Increased CSF lactate production

- Global ischemia doesnt seem occur

- Pathologic hallmark is engorgement of cerebral
capillaries with infected erythrocytes

Clinical Presentation
- Suspect it in any child who has visited (or even
landed in an airport!) an endemic area and develops
CNS symptoms.
- Fever, HA, irritability, altered mental status.
- Seizures are common.
- Retinopathy (including hemorrhages)
- Metabolic acidosis
- Hypoglycemia (associated with poor prognosis)
In non-immune adults it is from hyperinsulinemia
In African children it is impaired gluconeogenesis.

-Hemolytic anemia, may be severe.

Diagnosis
CSF is usually acellular consider other diagnosis
if there is pleocytosis
Protein and glucose are normal, CSF lactate is up
Associated with GN sepsis
Parasite count ranges from barely detectable to
>20%
May not be detectable at first
Need blood smears q6h x 48hrs to rule out

Treatment
- Children with severe malaria need parenteral therapy:
Cinchona alkaloids (quinine, quinidine)
Artermisinin compounds (not available in N. America)

- Side effects include cinchonism, but serious CV effects

may occur if drugs are given undiluted or too fast

Hypotension, arrythmias
Watch QT during infusion

- Supportive care is important, many children die in the

first 24 hours.
- Watch glucose, fluid balance, renal function, HCT.
- Exchange transfusion may be indicated for parasitemia
>10% or if not responding to therapy.
- Steroids appear to increase bleeding and offer no
benefit.

Prognosis
Mortality in non-immune patients is 15-26%
Many patients die in the first 4 days from renal
failure or pulmonary edema
African children have similar mortality but they
die in the first 24 hours
Often from herniation, severe hypoglycemia, anemia

Survivors have significant neurologic sequelae

Prevention
No vaccine is available for malaria.
Prophylaxis is recommended for travelers.
Mefloquine or atovaqone-proguanil.

Protection from mosquito bites is also important.

Repellant, netting, protective clothing.