Meningitis: clinical syndrome characterized by inflammation of the meninges Meningococcal meningitis –Caused by Nisseria meningitidis –first described by Vieusseux during an outbreak in Geneva, Switzerland in 1805 Contagious High case fatality rate Persistent neurological deficits

disease spectrum: –occult sepsis with rapid recovery to fulminant disease Fatality rate –Before1920s: 70% –overall now: 9 to 12% –meningococcal sepsis: 40% 11 to 19% have sequelae –hearing loss –neurological disability –loss of a limb

Exclusively human, Gram negative, aerobic diplococci 13 serogroups: A,B,C,H,I,K,L,M,X,Y,Z,29E, W135 Further classified into 20 serotypes, 10 subtypes & 13 immunotypes Most infections caused by serogroup A,B,C,Y,W135

Capable of changing the genetic material & switching from 1 serogroup to another Common inhabitant of nasopharynx 8-20% of adults are asymptomatic carrier Mainly affect young children (<7 months) Also in order child & young adults

90% is from 3 serogroups: A, B & C –A & C in Asia & Africa –B & C Europe & Americas All may cause epidemics though the risk differs. Serogroup A –historically been the main cause of epidemic –still dominates in Africa during both endemic & epidemic periods

Epidemic rate –Less than 1-3/100,000 in developed nations –10-25 per 100,000 in developing countries cases among infants < 1 month –>50% caused by serogroup B

World’s highest disease burden sub-Saharan Africa, stretching from Senegal in the west to Ethiopia in the east Epidemics occur in seasonal cycles between November & June Epidemics last 8-15 years decline rapidly in rainy season mechanisms are thought to be related to variations in herd immunity

major epidemics of meningococcal disease in Asia –China 1979 & 1980 –Vietnam 1977 –Mongolia & –Saudi Arabia 1987 –Yemen 1988 Europe & the Americas –lower incidence of epidemics

Direct contact or via droplets from respiratory or throat secretions Average incubation period: 4 days (2-10 days) household risk if exposed: increase by x Transmission highest in 1 st week Humoral immunity Incidence highest in 6-24 months of age Some may be carrier for many years before becoming ill

Risk factors –Asplenia –Deficiency of properdin –Deficiency of antibody-dependent, complement mediated immune lysis –Household crowding –Active & passive smoking –Antecedent URTI (mycoplasma pneumonia or virus) –Chronic underlying illness hepatic failure, SLE, multiple myeloma –HIV

2 forms of meningococcal disease –Meningitis & meningococcal septicemia Invasive meningococcal disease –Bacteremia without shock (acute mild meningococcemia) –Bacteremia with shock but no meningitis (fulminant meningococcemia) –Shock & meningitis –Meningitis alone –Chronic benign meningococcemia

Hematogenous spread 50-55% of pts w meningococcal disease Similar to other acute purulent meningitis

Intense headache Fever Stiff neck Nausea Vomiting Photophobia Lethargy, drowsiness Rash Altered mental status ( elderly) Prolonged course w fever

Subacute infection, progresses over several days Irritability Projectile vomiting Seizures –usually with a focal onset –typically during the first few days Infants –may have insidious onset –stiff neck & other classic signs may be absent

nuchal rigidity lethargy, delirium, coma, convulsions only 70% has classic triad of fever, neck stiffness, & change in mental status. petechial or purpuric rash –12-18H after onset –62% in >30yo, 81% in younger pts –usually on the trunk, legs, mucous membranes, & conjunctivae –Occasionally on the palms & soles –may progress to purpura fulminans, associated with multiorgan failure

meningococcal septicemia –Less common –rapid circulatory collapse & hemorrhagic rash. Waterhouse-Friderichsen syndrome –widespread petechial hemorrhages –Hemorrhagic adrenalitis –septic shock –disseminated intravascular coagulation (DIC) Neurologic sequelae –sensorineural deafness, mental retardation, spasticity & seizures

<1% can present with –Spiking fever (over days to several weeks) –Arthralgia –Arthritis –Recurrent rash (chronic benign meningococcemia) 20% later developed meningitis

Compartmentalized metastatic infections Pericarditis –Early (first few days): may demonstrate organism –Late (1-2 weeks): sterile Septic arthritis –late onset, after resolution of meningococcemia –Isolated, spontaneous Others: –cellulitis, endophthalmitis, conjunctivitis, pneumonia, siadenitis, pelvic inflammatory disease

Gram Stain –positive in 70-90% –GRAM NEGATIVE DIPLOCOCCI both inside & outside of polymorphonuclear cells Direct antigen detection w latex agglutination Culture from CSF –Positive in 80% PCR –Not affected by prior initiation of antibiotics –sensitivity 97% & specificity 99.6% –available within 2H Meningococcemia: skin biopsy

Meningitis: only CSF generally positive Body fluid may be positive in early onset compartmentalized infections Blood culture –during febrile episodes are not consistently positive –Usually negative when afebrile

Latex agglutination: detect capsular antigen of meningococcal serogroups A, B, C, Y, W135 Rapid, serogroup specific but not reliable Negative GN or Ag detection does not rule out meningococcal disease

Empirical treatment: based on the most likely organism Institute antibiotics ASAP after LP Avoid delays Yield increased if specimen is examined ASAP –eg CSF should be examined within 1H CSF sterilization may occur more rapidly after initiation of parenteral antibiotics complete sterilization within 2H

Typical CSF abnormalities: –Increased opening pressure –Pleocytosis of polymorphonuclear leukocytosis predominantly neutrophils –Decreased glucose (compare w serum glucose) –Increased protein

Contrasted computed tomography –prior to lumbar puncture (? Risk of coning) –Demonstrates meningeal enhancement Magnetic resonance imaging contrasted –demonstrates meningeal lesions, cerebral edema, & cerebral ischemia

Potentially fatal, should be treated as a medical emergency Admission is necessary though isolation may not be necessary Important to –Early recognition –Prompt initial parenteral antibiotics –Close monitoring

Dexamethasone (controversial in adults) 3 rd generation cephalosporin –ceftriaxone or cefotaxime +/- Vancomycin Acyclovir

Decrease cerebral edema & neuronal injury Recommended for all suspected pneumococcal meningitis 0.15 mg/kg q6H x 2-4 days 1 st dose min before or at least concomitant with the antibiotics

Significantly reduce unfavorable outcome & death to be continued if confirmed S. pneumoniae Data inadequate to recommend adjunctive dexa in meningitis caused by other bacterial pathogens

Penicillin or Ampicillin Ceftriaxone (or cefotaxime) –if penicillin resistance Despite adequate & early treatment, 5- 10% die, typically within 24-48H after onset

Prevention of sporadic meningococcal disease of close contacts of infected patients Eradication of the carrier status Mass chemoprophylaxis to control large outbreaks are not recommended –multiple sources of exposure & prolonged risk of exposure

Ciprofloxacin 500 mg in a single dose –easiest option in adults. Children could receive either –a single IM injection of ceftriaxone, or –4 oral doses of rifampin over 2 days, according to BW. commonly used –rifampin, ciprofloxacin, ceftriaxone, minocycline, & spiramycin. Oily chloramphenicol –in areas with limited health facilities

Polysaccharide vaccines –Available >30 yrs ago –bivalent (groups A & C), trivalent (groups A, C & W), or tetravalent (groups A, C, Y & W135) outer membrane proteins (OMP) for serogroup B –No polysaccharide vaccines for serogroup B –Used in Cuba, New Zealand & Norway Meningococcal conjugate vaccine –against group C: since 1999 –Tetravalent A, C, Y & W135 conjugate vaccines: used since 2005 in Canada, USA & Europe.

advantages of conjugate vaccine –higher & more sustainable immune response against group A meningococcus –reduces the carriage & transmission of the bacteria in the throat –expected to confer long-term protection –cheaper –particularly effective in protecting children < 2yo, who do not respond to conventional polysaccharide vaccines.

Primary vaccination: for older than 2 yrs (2-55yo) recommended for adults & children at high risk 3 months to 2 yrs under special circumstances (approved by FDA in August 2013) High-risk persons –military recruits –contacts to index cases –travellers to areas of high incidence or outbreaks –patients with asplenia –adolescents with HIV infection –persons with terminal complement disorders

Vaccines available –Meningococcal A & C –Menomune A, C, Y, W-135 –Mencevax A, C, Y, W-135 not routinely recommended compulsory for the Hajj pilgrims & Umrah following the 1987 serogroup A meningococcal disease outbreak. Since 1988, Malaysian Hajj pilgrims had received the bivalent A & C vaccine Beginning 2002 Hajj, Saudi health officials require certification of quadrivalent meninggococcal vaccination covering serogroups A, C, Y, & W-135 for all entering pilgrims.

Meningococcal meningitis has high mortality & morbidity rate. All meningitides including the meningococcal meningitis should always be treated as medical emergency. Early recognition & treatment are mandatory to prevent complications chemoprophylaxis & mass vaccination to prevent further transmission, in susceptible individuals

Quadrivalent: A,C, Y, W-135 Bivalent: A & C Primary vaccination: for older than 2 yrs (2-55yo) 3 months to 2 yrs under special circumstances (approved by FDA in August 2013) Children: 2 doses 3 months apart Ab response is serogroup specific & independent Protective levels of ab are usually achieved within 7 days of vaccination

Serogroup A polysaccharide: induce ab as early as 3 months of age Adult: 4-5 yrs Serogp C: poorly immunogenic in children Both serogp A &C: good immunogenicity, clinical efficacy≥ 85%

Ab level & clinical efficacy reduced markedly during the first 3 yrs of vaccination Detectable up to 10yrs of vaccination Multiple doses of serogroup A or C poly saccharide may cause tolerance Adverse effects mild –Pain & redness (4-56%) –Transient fever (4%) Severe reaction: rare

Drawback: absence of activity against serogroup B meningococci Use of group B capsule in a vaccine risks the induction of autoimmunity Ab response to group B is limited after natural infection hence group B capsular polysaccharide is poor candidate for vaccine replacement.

Quadrivalent Induces T cell dependent response Improve immune response, priming immunologic memory & leading to a booster response to subsequent doses Long lasting immunity Induces Herd immunity 70% expected to be preventable

Safe Immunogenic Reduces the nasopharyngeal carriage rate Contraindicated in known allergy to any component of vaccine including the diphtheria toxoid Routine childhood vaccination not recommended Relative ineffectiveness in age <2yo ( highest risk of sporadic disease & realtively short duration of protection)

Routine vaccination recommended for certain gp w high risk –Autonomic or functional asplenia –Lab personnel & healthcare worker w are routinely exposed to N meningitidis WHO: mass vaccinate every district in epidemic & alert phase Single dose of polysaccharide for travelers> 18 months of age to epidemic or high rate of endemic meningococcal disease

Persons high risk for infection, particularly children who were first vaccinated < 4 yo To consider revaccination after 2-3 yrs if risk still high