Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta

1. CNS Other Infections Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta

2. Viral, atypical bacteria, fungal, TB Aseptic Meningitis

3. Etiologies: Viruses and Bacteria • - Adenovirus • - Arbovirus • - Enteroviruses • - Herpesviruses • - HIV • - Influenza A/B • - Japanese encephalitis • - Measles • - Mumps • - Rubella • - Rabies • - Lymphocytic choriomeningitic virus • - Bartonellahenslae • - Bordetellapertussis • - Borreliaburgdorferi • - Brucella spp. • - Chlamydia spp. • - Ehrlichia, Leptospria spp. • - Mycobacteria spp. • - Mycoplasma spp. • - Rickettsia spp. • - Treponemapallidum

4. Etiologies: Fungal and Others • Aspergillus fumigatus • Blastomyces dermatitidis • Candida spp. • Crytococcus neoformans • Coccidioides immitis • Histoplasma capsulatum • Toxoplasma gondii • Entamoeba histolytica • Acanthamoeba • Trichinella • Naegleria

5. 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

6. TB Meningitis

7. Clinical Staging

8. 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 unrupturedtuberculomas • * Neuroimaging will be very helpful • * Look for the primary TB site

9. 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

10. Encephalitis and Myelitis

11. 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

12. 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 • * Subacutesclerosingpanencephalitis is a now rare complication of measles infection • * Tick borne bacteria can also be implicated • Borrelia, Rickettsia,ehrlichiosis

13. 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

14. 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 (erythemamigrans)

15. 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)

16. Neuroimaging

17. 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

18. 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

19. Older children HSV: Clinical Presentation Neonatal 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

20. 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

21. 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

22. Acute Disseminated Encephalomyelitis ADEM

23. 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

24. 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

25. 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

26. Neuroimaging

27. 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

28. 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

29. Brain and Spinal CordAbscess

30. 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

31. 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: • CHD – a-hemolytic strep • Endocarditis – strep, S. aureus • Post-trauma – staph • Otitis/sinusitis – strep, Bacteroidesfragilis, Proteus spp., pseudomonas, H.flu

32. 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

33. 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

34. 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

35. 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

36. Abscesses: Imaging

37. Abscesses: Imaging

38. 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

39. 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

40. Cerebritis  Vasculitis

41. 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

42. 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)

43. 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

44. 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

45. 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

46. Aspergillus, Cryptococcus CNS Fungal Infections

47. CNS Fungal Infections

48. 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

49. 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

50. 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