MENINGITIS

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

3
(No Transcript)
4
(No Transcript)
5
(No Transcript)
6
(No Transcript)
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

8
(No Transcript)
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

11
(No Transcript)
12
(No Transcript)
13
(No Transcript)
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 lt 4 weeks old)
• Just takes 1 vesicle

18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
(No Transcript)
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. Infants mother
  makes her own cheese and sausages
• FSWU
• On Gram stain of CSF

30
(No Transcript)
31
(No Transcript)
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 (gt25
  percent) can be seen in the CSF differential count

34
Tb meningitis

• cerebrospinal fluid (CSF) white blood cell count
  of lt1000/mm3, clear appearance of CSF, lymphocyte
  proportion of gt30, and protein content of gt100
  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 lt 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.

38
(No Transcript)
39
(No Transcript)
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 lt DOL 7, amp and
  cefotaxime gt DOL 7
• If Gram stain shows Gram diplococci gt add vanco

42
NEONAT

• DOL 20, former premature infant,
• Tlt 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 (Tlt 36), irritability,
  and poor feeding or vomiting

45
NEONATA

• Findings of neonatal bacterial meningitis, and
  their approximate frequencies are listed below
• Fever or hypothermia Tlt 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 gt 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 gt1000 WBC/microL, but may be lower,
  especially with gram-positive organisms), with a
  predominance of neutrophils

51
NEONATE LAB

• Neonates can have normal CSF parameters and yet
  meningitis
• If clinical suspicion for meningitis is high,
  empirically treat and ignore normal results

52
NEONAT

• Neonates lt DOL 7, mothers treated antenatally for
  Group B strep, 75 successful
• ie 25 can still get Group B strep sepsis or
  meningitis

53
NEONATE

• gt1 month of age vancomycin cefotaxime or
  ceftriaxone
• Gram stain may modify eg ADD ampicillin for the
  presence of gram-positive cocci or bacilli (rods)

54
Proven enteroviral meningitis

• The odds of a CSF white blood cell being
  mononuclear increased by 15.7 (95 confidence
  interval -3.8 to 38.0 P .11) for each day
  of symptoms. Fifty percent of patients with
  symptoms of 1 day or less had predominance of
  mononuclear cells among CSF white blood cells
• Soft correlation though, other factors such as
  amount of meningeal irritation

55
(No Transcript)
56
(No Transcript)
57
(No Transcript)
58
EV -LAB

• White blood cells (WBC) Pleocytosis usually
  ranges from 10 to 500 cells/microL (higher values
  can be seen with some viruses) mononuclear
  leukocytes predominate in most cases, although
  polymorphonuclear (PMN) leukocytes have been
  described early and late in the course of EV
  meningitis.
• Normal WBC counts can be seen in EV and more
  rarely with HSV meningoencephalitis
• Glucose Normal or slightly reduced, usually 40
  percent or more of the serum value.
• Protein Normal to slightly elevated protein,
  usually less than 150 mg/dL.

59
N. MENING

• w/ meningococcemia, most children (72 percent)
  had one of the three sepsis symptoms (eg, leg
  pain, abnormal skin color, or cold hands and
  feet) at a median time of 8 hours after onset of
  illness, 11 hours sooner than the median time of
  hospital admission (19 hours).

60
N. mening

• Inotropic supportdopamine, dobutamine,
  adrenaline (epinephrine)may be started and then
  given in combination if response is suboptimal.
• Eventual infusion of fluid up to several times
  the circulating blood volume may be needed.

61
N. MENING-Archiv 9/02

• N. mening notorious (8)for normal CSF and
  culture- tx all cases of suspected N. mening for
  meningitis
• Gram stain in 70-80 of meningitis, could miss
  30
• Immunodeficient child, add fungal and
  mycobacterial analyses

62
N. MENING

• The vital signs often show a low blood pressure
  with an elevated pulse rate. The patient should
  be examined for postural hypotension as a sign of
  early vascular instability.

63
N. MENIN

• The mucous membranes of the soft palate, ocular
  and palpebral conjunctiva must be carefully
  examined for signs of hemorrhage. Over 50 percent
  of patients will have petechiae upon presentation
• Fever and petechiae below the nipple line
  just takes 1 petechiae

64
Tumbler test
65
(No Transcript)
66
(No Transcript)
67
(No Transcript)
68
(No Transcript)
69
(No Transcript)
70
(No Transcript)
71
(No Transcript)
72
Duration of Antimicrobial Therapy for Meningitis
Based on Isolated Pathogen

• Microorganism Duration of therapy, days
• Neisseria meningitidis 7
• Haemophilus influenzae 7
• Streptococcus pneumoniae 10-14
• Streptococcus agalactiae 14-21
• Aerobic gram-negative bacilli 21
• Listeria monocytogenes 21
• Neonatal HSV 21

73
LATEX AGG

• Latex Agglutination
• false-positive results
• Practice Guideline Committee does not recommend
  routine use
• most useful for the patient who has been
  pretreated with antimicrobial therapy

74
Latex Agglutination

• Organisms available
• Neisseria Meningitis
• HIB
• S. pneumo
• Group B strep
• Cryptococcal (HIV, immunocompromised)

75
PCR

• Organisms available
• HSV
• Enterovirus
• ? Faster PCR assay for Enterovirus?
• Turn around lt 4 hours
• Avoid hospitalization
• ? 2007? (Reimbursement issue)

76
Case

• 3 month old fever, persistent irritability,
  bulging fontanelle
• FSWU
• In addition to empiric antibiotics, should you
  use dexamethasone?

77
Case (continued)

• What if you pushed cefotaxime alone and the Gram
  stain looked liked this?
• Would you now add dexamethasone?

78
(No Transcript)
79
DEX

• What Is the Role of Adjunctive Dexamethasone
  Therapy in Patients with Bacterial Meningitis?
• Neonates
• At present, there are insufficient data to make
  a recommendation on the use of adjunctive
  dexamethasone in neonates with bacterial
  meningitis

80
DEX

• The 2003 statement by the Committee on Infectious
  Diseases of the American Academy of Pediatrics on
  the use of steroids for pneumococcal meningitis
  is as follows "For infants and children 6 weeks
  of age and older, adjunctive therapy with
  dexamethasone may be considered after weighing
  the potential benefits and possible risks.."

81
Dex

• Is there a downside to Dex?
• ? Unclear if it affects CSF penetration by
  antimicrobials, since reduce inflammation.
• Could be most true for vancomycin, which well
  known to have poor CSF penetration

82
DEX

• Dexamethasone should be initiated 10-20 min prior
  to, or at least concomitant with, the first
  antimicrobial dose, at 0.15 mg/kg every 6 h for
  2-4 days.
• Adjunctive dexamethasone should not be given to
  infants and children who have already received
  antimicrobial therapy, because administration of
  dexamethasone in this circumstance is unlikely to
  improve patient outcome

83
DEX

• Meningococcal meningitis appears to have the
  lowest risk of major neurological sequelae
  compared with pneumococcal and H. influenzae
  meningitis
• HIB gtgt S. pneumo gtgt N. Mening (in terms of
  neurologic sequelae.) Dexamethasone efficacy
  seems to be in that order as well.

84
Dex

• Bottom line
• Fairly good evidence to use in the pediatric
  population older than 1 month old age, especially
  if suspect HIB or S. pneumo meningitis as
  potential pathogen

85
DEX

• Clinical scenarioAn 18 year old student is
  brought to the Emergency Department having been
  found collapsed in her room. She had been seen by
  her friends earlier in the day, when she reported
  that she had a severe headache. On examination,
  she is found to have a temperature of 38.40C, a
  GCS of 12 (E3 M6 V3) and slight neck stiffness.
  She is noted to be more settled with the lights
  out. There is no papilloedema and no focal
  neurological signs. You make an initial diagnosis
  of bacterial meningitis, but in view of the
  depressed level of consciousness request a CT
  Brain before lumbar puncture is carried out. This
  will take at least one hour to be organised, and
  in the meantime, you decide to proceed with
  intravenous ceftriaxone. You are unsure whether
  she would benefit from the administration of
  dexamethasone prior to her antibiotics.

86
Dex

• European Dexamethasone in Adulthood Bacterial
  Meningitis Trial
• In this prospective, randomised, double-blind,
  multicenter trial, which included 301 adults with
  bacterial meningitis, treatment with
  dexamethasone was associated with a reduction in
  mortality (relative risk of death, 0.48 95 CI
  0.24 to 0.96 p 0.04).
• Therefore, dexamethasone should be given to all
  adults with bacterial meningitis and should be
  initiated before or with the first dose of
  antibiotics.

87
DEX

• Currently there is not sufficient published
  evidence to recommend early use of dexamethasone
  in order to improve neurological outcome in
  children with meningococcal meningitis.
• One study showed possibly disadvantageous as far
  as hearing is concerned

88
PROGNOSIS

• In one meta-analysis of bacterial meningitis,
  83.6 percent of the surviving children in
  developed countries and 73.9 percent in
  developing countries had apparently complete
  recovery. The most common sequelae present after
  hospital discharge in the remaining children
  were
• Deafness 10.5 percent, including bilateral
  severe or profound deafness in 5.1 percent
• Mental retardation 4.2 percent
• Spasticity and/or paresis 3.5 percent
• Seizures 4.2 percent

89
PROGNOSIS/ EARLY TX

• The factors contributing to the time required to
  institute therapy were illustrated by a survey of
  93 children presenting to the emergency
  department of two university-affiliated hospitals
  The mean time to initiation of antibiotic
  therapy was two hours. The median time from
  triage to contact with a physician was 45
  minutes, and the time from lumbar puncture until
  the administration of antibiotics was 30 minutes.
  Only one child was treated within 30 minutes

90
(No Transcript)
91

• What if antibiotics are given before LP is done?

92
STERLIZ OF CSF

• Among children with meningococcal meningitis who
  were treated with a parenteral dose of an
  extended-spectrum cephalosporin, three of nine
  LPs were sterile within one hour (occurring as
  early as 15 minutes) and all were sterile by two
  hours.
• Sterilization of the CSF was slower with
  pneumococcl meningitis. The first negative
  culture was obtained four hours and five of seven
  were negative by ten hours.

93
LP

• Lumbar puncture should be deferred
• signs of cerebral herniation
• focal neurological signs / papilledema
• cardiorespiratory compromise
• risk for brain abscess
• Immunocompromised
• Congenital heart with right to left shunt
• ? Skin/soft tissue infection at LP site
• ? bleeding disorder
• (? based on single case reports)

94
LP

• Signs of cerebral herniation
• Check pupils before you LP
• Irregular respirations
• Abnormal tone
• GCS lt 8
• Focal signs
• Contraindications to LP, even if CT normal

95

• What about the patient with fever and seizure? ie
  who do you need to LP?

96
FEBR SZ

• A recently published guideline (Arch Dis Child
  05) for the management of a child with a febrile
  seizure recommends antibiotic treatment for
  children who
• have meningismus
• were drowsy before the seizure
• have altered consciousness gt 1hour after seizure

97
FEBR SZ

• Duration of febrile seizure gt 15 minutes,
  significantly higher rate of bacterial meningitis
  (1 vs 18 range in literature)

98

• What about Gram stains?

99
GRAM STAINS ORG

• Gram positive diplococci suggest pneumococcal
  infection
• Gram positive cocci or coccobacilli suggest group
  B streptococcus
• Gram positive rods and coccobacilli suggest
  listerial infection
• Gram negative (intracellular) diplococci suggest
  meningococcal infection
• Small pleomorphic Gram negative coccobacilli
  suggest Haemophilus influenzae

100
(No Transcript)
101
(No Transcript)
102
(No Transcript)
103
(No Transcript)
104
CSF LAB

• CSF parameters in Harriet Lane (cells, protein,
  glucose)
• Preterm (neonate)
• Term (neonate)
• Child (gt neonate)

105
SUMMARY

• Dex
• Neonates - No
• Everyone else - Yes
• Not HIB or S.pneumo No
• NO if antibiotics are already given

106
SUMMARY

• Neonates- subtle clinical signs or none, normal
  initial labs possible
• No vancomycin unless Gram positive cocci in
  pairs/chains (Pneumococcus)
• Amp/gent lt DOL 7
• Amp/cefotax gt DOL7

107
SUMMARY

• Remember
• 1 vesicle in the neonate
• 1 petechiae, especially below the nipple line

108
SUMMARY- Whats the Bug?

• Gram diplococci
• Gram cocci
• Gram rods
• Gram diplococci
• Gram - rods