Pediatric Critical Care Medicine

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CNS Other Infections
Pediatric Critical Care Medicine Emory
University Childrens Healthcare of Atlanta
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Aseptic Meningitis

• Viral, atypical bacteria, fungal, TB

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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

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Etiologies Fungal and Others

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

• Toxoplasma gondii
• Entamoeba histolytica
• Acanthamoeba
• Trichinella
• Naegleria

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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

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TB Meningitis
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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
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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 lt40, 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

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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

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Encephalitis and Myelitis
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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

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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

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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

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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)

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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)

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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
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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

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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

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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

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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

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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

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ADEM

• Acute Disseminated Encephalomyelitis

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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

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ADEM Clinical Presentation

• Mean age of presentation is 7 years, slightly gt
  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 lt 3 yrs

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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

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Neuroimaging
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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

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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

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Brain and Spinal Cord Abscess
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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

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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

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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

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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

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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

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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

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Abscesses Imaging
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Abscesses Imaging
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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

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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

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Cerebritis ? Vasculitis
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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

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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)

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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

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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

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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

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CNS Fungal Infections

• Aspergillus, Cryptococcus

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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
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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

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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

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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

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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 (lt20) with AIDS or high
  dose steroids
• India ink prep can identify gt50 of
  C.neoformans cases (up to 80 in AIDS)

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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

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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.
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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

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Parasitic CNS Infections

• Neurocysticercosis and Cerebral Malaria

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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.
• gt1000 new cases are diagnosed in the US each year.

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Taenia solium Life Cycle
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Neurocysticercosis

• Parenchymal

• Extraparenchymal

• Seizures in 70-90 of patients
• 1/3 will have raised ICP
• 4 have focal neuro deficits
• May have encephalitis
• Numerous cysts
• Diffuse cerebral edema
• Poor prognosis

• Rare in children
• Obstructive hyrdocephalous or chronic meningitis
• Spinal involvement
• Radicular pain
• Cord compression
• Transverse myelitis
• Ophthalmic involvement
• Vision deficits

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Neurocysticercosis
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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

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Cerebral Malaria

• Last one!

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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

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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

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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

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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

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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.

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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
  gt20
• May not be detectable at first
• Need blood smears q6h x 48hrs to rule out

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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 gt10 or if not responding to therapy.
• - Steroids appear to increase bleeding and offer
  no benefit.

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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

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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.