1. MENINGITIS Laurie J Burton, MD PEM Fellows Conference December 6, 2006

2. OUTLINE • Pathophysiology • Cases • Neonatal meningitis • The bugs, the drugs • HSV, Listeria, Enterovirus • Dex for who? • CT before LP • Interpreting CSF / Lab testing

7. PATHOPHYS • The blood-brain barrier, which excludes most macromolecules and microorganisms, is due to the cellular configuration of the cerebral capillaries, the choroid plexus, and arachnoid cells • This barrier excludes not only most microbes, but also excludes immune defenses derived from serum

9. PATHOPHYS • Antibodies found in the normal CNS are derived from the serum. • Levels of IgG and IgA in the CSF are approximately 0.2 to 0.4 percent of the serum levels. • Since diffusion of macromolecules across the barrier is largely size dependent, IgM is present at even lower levels. • There is also no lymphatic system in the usual sense, and few, if any, phagocytic cells. • Complement is also largely excluded.

10. PATHOPHYSIOLOGY • Therefore, although the barrier deters invasion of infectious agents, it hampers their clearance once it is penetrated. • . Therefore, bacteria that enter this space undergo an initial phase of logarithmic growth, accounting for the often explosive onset of acute bacterial meningitis

14. DDX ORG • Bacterial infections — Partially treated bacterial meningitis, bacterial infection with a parameningeal focus (brain or epidural abscess), tuberculosis • Viral infections — Herpes simplex meningoencephalitis, cytomegalovirus, enteroviruses, rubella, lymphocytic choriomeningitis, varicella • Spirochetal infections — Syphilis, Lyme disease • Parasitic infections — Toxoplasmosis, Chagas' disease • Mycoplasma infections — M. hominis infection, Ureaplasma urealyticum infection • Fungal infection — Candidiasis, coccidioidomycosis, cryptococcus • Trauma — Subarachnoid hemorrhage, traumatic lumbar puncture • Malignancy — Teratoma, medulloblastoma, choroid plexus papilloma and

15. Case 1. • 5 week old with fever, irritability, poor feeding. History of maternal herpes in first trimester. • FSWU done, CSF only able to obtain enough for culture. • Ampicillin and cefotaxime started. Should you also start acyclovir?

16. HSV • DOL 0 - 4 weeks most common per Red Book • 1st week, more often disseminated (sepsis, elevated transaminases) • 2nd-3rd week more often meningitis

17. In a neonate (ie < 4 weeks old) • Just takes 1 vesicle

23. HSV • Significant % of neonates with HSV who do not manifest skin lesions • Consider in neonates with sepsis syndrome, elevated ALT/AST or PT/PTT, CSF pleocytosis or even RBCs especially with negative bacterial cultures

24. HSV • Neonatal HSV meningitis/encephalitis high morbidity and mortality regardless of treatment

25. HSV • In neonates, scraping of skin lesions and additional cultures from conjunctivae, throat, nasopharynx, stool, and urine specimens can aid in the diagnosis of CNS disease for HSV

26. HSV • In the majority of patients, HSV mucosal lesions precede signs and symptoms of meningeal inflammation with a mean interval of one week • Beyond the neonatal period, the incubation period ranges from two days to 12 days, with a mean of four days

27. HSV • Herpes CNS infections (meningitis, encephalitis) require 21 days of acyclovir • PCR available

28. MOLLARETS • Mollaret's meningitis is characterized by recurrent episodes of aseptic meningitis. Using polymerase chain reaction (PCR) based testing, HSV-2 has been strongly associated with Mollaret's meningitis, a form of benign recurrent aseptic meningitis • Additional few cases have been reported due to HSV-1 and EBV

29. Case • 2 week old infant with fever. Infant’s mother makes her own cheese and sausages • FSWU • On Gram stain of CSF…

32. LISTERIA • Furthermore, when organisms are seen, Listeria may resemble pneumococci (diplococci) or diphtheroids (Corynebacteria) or be Gram-variable and be confused with Haemophilus species Thus, Listeria should always be considered when "diphtheroids" are reported to be growing from blood or CSF cultures

33. LISTERIA • Listeria is the one cause of bacterial meningitis in which a substantial number of lymphocytes (>25 percent) can be seen in the CSF differential count

34. Tb meningitis • cerebrospinal fluid (CSF) white blood cell count of <1000/mm3, clear appearance of CSF, lymphocyte proportion of >30%, and protein content of >100 mg/dL.

35. LISTERIA • Cephalosporins are inactive in vitro and ineffective clinically • Ampicillin with gentamicin for synergy • Imipenem or meropenem excellent

36. LISTERIA • In the newborn, L. monocytogenes can present as an early onset sepsis in the first week of life, or more commonly, with a late onset after the first week of life (usually < 6 weeks, up to 2 months). • Early-onset disease primarily is sepsis, with high neonatal mortality in association with maternal illness and premature delivery. • With late-onset disease, babies generally are full-term and have no history of perinatal complications; cultures of CSF are more likely to be positive than are blood cultures

37. LISTERIA • ampicillin is added to the standard therapeutic regimen of cefotaxime or ceftriaxone plus vancomycin when L. monocytogenes is considered and to an aminoglycoside if a gram-negative enteric pathogen is of concern.

40. NEONA • DOL 7 irritable infant discharged DOL 2, “Full” fontanelle, poor feeding x 1 day • FSWU • Antibiotics? Or wait for CSF Gram stain to help guide correct coverage?

41. NEONA • Prolonged hospitalization, add vanco • Hardware, manipulation, add vanco • Otherwise amp and gent < DOL 7, amp and cefotaxime > DOL 7 • If Gram stain shows Gram + diplococci => add vanco

42. NEONAT • DOL 20, former premature infant, • T< 36 • Suspect clinical meningitis • FSWU done • Treatment?

43. NEWBORN • if GBS or Listeriosis is suspected (eg, on the basis of the Gram stain), add ampicillin because vancomycin concentrations in the CSF are not bactericidal for these organisms • GBS goes out to 3-4 months of age • Listeria can go out to 6-8 weeks of age

44. NEONATE • The clinical presentation of neonatal meningitis often is indistinguishable from that of neonatal sepsis without meningitis. • The most commonly reported clinical signs are temperature instability (T< 36), irritability, and poor feeding or vomiting

45. NEONATA Findings of neonatal bacterial meningitis, and their approximate frequencies are listed below: • Fever or hypothermia T< 36: 60% • Poor feeding/vomiting: 50 percent • Respiratory distress (tachypnea, grunting, flaring of the nasal alae, retractions, decreased breath sounds): 33 to 50 percent • Apnea: 10 to 30 percent • Diarrhea: 20 percent

46. NEONATE • GBS and Escherichia coli are the two most common organisms causing neonatal meningitis • when E. coli occurs after 6 days of age, galactosemia should be excluded…

47. NEONAT • Gram negative rods (esp E coli) in blood or CSF in infant > DOL 6, suspicion for galactosemia (vomiting, jaundice, HSM) • Send urine for reducing substances

48. Neonate-N. Mening • Neisseria meningitidis also can rarely cause meningitis in newborn infants. • 73 percent of neonates that had N. mening disease had meningitis

49. NEONATAL BACT • In a Canadian review of 101 infants with gestational age 35 weeks admitted to a tertiary care center with a diagnosis of neonatal meningitis between 1979 and 1998, the following organisms were cultured: • Group B Streptococcus — 50 percent of cases • E. coli — 25 percent • Other gram-negative rods — 8 percent • Listeria monocytogenes — 6 percent • Streptococcus pneumoniae — 5 percent • Group A Streptococcus — 4 percent • Haemophilus influenzae — 3 percent

50. NEON / LAB • Isolation of a bacterial pathogen from the CSF by culture or visualization by Gram stain • Increased CSF white blood cell (WBC) count (typically >1000 WBC/microL, but may be lower, especially with gram-positive organisms), with a predominance of neutrophils