Pediatric Critical Care MedicineEmory University

Children’s Healthcare of Atlanta

CNS Other Infections

ASEPTIC MENINGITISViral, 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 StagingStage Signs and SymptomsStage 1 (Early)Days to weeks

Fever, HA, malaiseLethargy, behavior changesNo neuro deficitsNo alteration of consciousness

Stage 2 (intermediate)Weeks to months

Meningeal irritationMinor neuro deficits (CN)

Stage 3 (late)Months to years

Abnormal movementsConvulsionsStupor or comaSevere neuro deficits

Diagnosis* Isolation or identification of mycobacterium is the

gold standard for diagnosisPossible in about 80% of casesPCR, 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 neuronsPathogen detection by direct visualization, staining, etc

* Referred to as postinfectious encephalitis when in temporal association with viral infection or immunizationADEM when it includes spinal cord

* Can cause significant alterations in sensorium and seizuresMany 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 commonArbo: EEE, WEE, St. Louis, West Nile, JEEntero: polio, echo, coxsackie, etc

* Subacute sclerosing panencephalitis is a now rare complication of measles infection

* Tick borne bacteria can also be implicatedBorrelia, 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 cellsViral genome replication takes over, affecting the other

functions of the cell* Interferon in particular inhibits viral penetration,

replication, translation, and assemblyThe inflammatory process may turn on the host

Clinical Manifestations* Varies depending on affected site, severity, and

host factorsMay or may not involve meninges (rabies)

* Nonspecific symptoms in neonatesMay not have maternal h/o HSV

* Older children have acute onset of fever, HA, seizures, behavior changes, AMS, or coma, +/- prodromeDepends on site of involvementMay have paralysis or paraplegia if spinal cord involvedLook for rashes (erythema migrans)

Diagnosis* CSF findings are non-specific

Cells and protein may be normal or slightly elevatedMay see predominance of lymphs

* May get a diagnosis from culture, antigen detection, PCR, or antibody titersPCR stays positive for months, highly sensitive and

specific* EEG can help distinguish focal from generalized

encephalitisHSV has characteristic periodic lateralized

epileptiform discharges (PLEDs)

NeuroimagingEtiology Site of involvement on

MRIHSV Inferomedial temporal

and frontal lobesJapanese encephalitis Bilateral thalami and

basal gangliaRabies Hippocampal, cerebellar,

mesencephalic areasEastern 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 – acyclovirCMV – ganciclovir or foscarnetFlu A/B – amantadine/rimantadine (A only), oseltamivir (A and

B)No specific therapy for entero- and arbovirusesConsider 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 PresentationNeonatal 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 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

ADEMAcute 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 deficitsEvolution may occur over a few days

* Deficits depend on affected areasWhite matter, spinal cord, optic nervesAtaxia and extrapyramidal symptoms are commonUMN 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

* 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:CHD – a-hemolytic strepEndocarditis – strep, S. aureusPost-trauma – staphOtitis/sinusitis – strep, Bacteroides fragilis, Proteus spp.,

pseudomonas, H.flu

Abscesses: Etiologies

Abscesses: Pathogenesis* May occur via hematogenous or direct spread* Cyanotic heart disease is the most common

underlying condition (esp. TOF)Polycythemia higher viscosity microinfarctsBacteria 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 appropriatelyExcept 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– 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 mechanismsChemotaxis 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 shuntColonization at the time of surgeryRetrograde from the distal end of shuntHematogenous 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 INFECTIONSAspergillus, Cryptococcus

CNS Fungal InfectionsPredisposing Condition Fungal PathogenPrematurity Candida albicansPrimary immunodeficiency (CGD, SCID)

Candida, Cryptococcus, Aspergillus

Corticosteroids Cryptococcus, CandidaCytotoxic agents Aspergillus, CandidaSecondary immunodeficiency (AIDS)

Cryptococcus, Histoplasma

Iron chelator therapy ZygomycetesIV drug abuse Candida, ZygomycetesKetoacidosis, 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 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 WBC’sCell 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 negativeCandida 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

TreatmentFungus Initial

RegimenSecond 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 INFECTIONSNeurocysticercosis 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

NeurocysticercosisParenchymal 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

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 steroidsOphthalmic NCCCalcified 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 MALARIALast 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

understoodLikely multi-factorial mechanisms of neuro dysfunctionMay be due to obstruction of microvasculatureIncreased 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 hyperinsulinemiaIn 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 fastHypotension, arrythmiasWatch 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.