CNS Other Infections
Pediatric Critical Care Medicine
Emory University
Children’s Healthcare of Atlanta
ASEPTIC MENINGITIS
Viral, atypical bacteria, fungal, TB
Etiologies: Viruses and Bacteria
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- Adenovirus
- Arbovirus
- Enteroviruses
- Herpesviruses
- HIV
- Influenza A/B
- Japanese encephalitis
- Measles
- Mumps
- Rubella
- Rabies
- Lymphocytic choriomeningitic
virus
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- 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
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Aspergillus fumigatus
Blastomyces dermatitidis
Candida spp.
Crytococcus neoformans
Coccidioides immitis
Histoplasma capsulatum
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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 (150-200)
 * 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:
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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 nonneonates
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 don’t 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 20-30
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, GN’s,
streptococci, and staph
 * Neonates most commonly get GN’s: Citrobacter,
Enterobacter, Proteus
 * In other populations the organism depends on predisposing
factors:
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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
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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
– But…CSF 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:
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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
• Don’t 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 highdose 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 WBC’s
 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
Considerations
Candida
Amphotericin B +
flucytosine x 2 wks
Fluconazole x 8-10
weeks
Remove shunt if
appicable.
Cryptococcus
Ampho B +
flucytosine x 2 wks
Fluconazole x 8-10
weeks
Repeat LP after
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 non-immune
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
– That’s 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 doesn’t 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.