N. meningitidis is one of the most frequent causes of meningitis. Infection with N. meningitidis can also take the form of a fulminant meningococcemia, with intravascular coagulation, circulatory collapse, and potentially fatal shock, but without meningitis. In each case, symptoms can occur with extremely rapid onset and great intensity. Outbreaks of meningitis, most common in winter and early spring, are favored by close contact between individuals, such as occurs in schools, institutions, and military barracks. Severe epidemics also occur periodically in developing nations, such as in sub-Saharan Africa and Latin America. N. meningitidis tends to strike young, previously well individuals and can progress over a matter of hours to death.

A. Structure

 Like N. gonorrhoeae, N. meningitidis is a nonmotile, gram-negative diplococcus, shaped like a kidney bean, which always appears in pairs (Figure 1). It is also piliated and the pili allow attachment of the organism to the nasopharyngeal mucosa where it is harbored both in carriers and in those with meningococcal disease. When meningococcus is isolated from blood or spinal fluid, it is invariably encapsulated. The meningococcal polysaccharide capsule is antiphagocytic and, therefore, the most important virulence factor. [Note: Antibodies to the capsule carbohydrate are bactericidal.]

Fig1. Smear of purulent cerebrospinal fluid showing Neisseria meningitidis.

1. Serogroups: The polysaccharide capsule is antigenically diverse, which allows the identification of at least 13 capsular polysaccharide types, called serogroups (Figure 2). Most infections are caused by serogroups A, B, C, W-135, and Y, although approximately 90 percent of cases of meningococcal disease are caused by serogroups A, B, and C. Serogroup A is usually responsible for massive epidemics in developing countries. In the United States, N. meningitidis serogroup B is the predominant cause of disease and mortality, followed by group C. Organisms that do not have a capsule are called unencapsulated.

 2. Serotypes: A second classification system called serotyping (serotypes 1, 2,...20) is also a serologic classification (see Figure 2) that is based on the properties of the outer membrane proteins . The meningococcus expresses PorA- and PorB-type porins. There is no predicable relationship between serogroups and serotypes.

Fig2. Antigenic determinants of Neisseria meningitidis.

B. Epidemiology

Transmission occurs through inhalation of respiratory droplets from a carrier or a patient in the early stages of the disease. In addition to contact with a carrier, risk factors for disease include recent viral or mycoplasma upper respiratory tract infection, active or passive smoking, and complement deficiency. In susceptible persons, pathogenic strains may invade the bloodstream and cause systemic illness after an incubation period of 2 to 10 days. The incidence of meningococcal disease in the United States is highest among infants younger than age 1 year (Figure 3). An incidence peak among adolescents and young adults led the Centers for Disease Control to recently recommend vaccination of this at-risk group. Humans are the only natural host.

Fig3. Incidence of meningococcal infection according to age.

 C. Pathogenesis

 Antiphagocytic properties of the meningococcal capsule aid in the maintenance of infection. LOS, released during autolysis and in outer membrane vesicles, is responsible for the toxic effects found in disseminated meningococcal disease.  gonococci and meningococci make an IgA protease that cleaves IgA1 and, thus, helps the pathogens to evade immunoglobulins of this subclass. [Note: Nonpathogenic Neisseriae do not make this protease.]

D. Clinical significance

N. meningitidis initially colonizes the nasopharynx, resulting in a largely asymptomatic meningococcal pharyngitis. In young children and other susceptible individuals, the organism can cause disseminated disease by spreading through the blood, leading to meningitis and/or fulminating septicemia. N. meningitidis is currently a leading cause of meningitis.

 1. Meningitis: The epithelial lining of the nasopharynx normally serves as a barrier to bacteria. Therefore, most persons colonized by N. meningitidis remain well. As a rare event, meningococci penetrate this barrier and enter the bloodstream where they rapidly multiply (meningococcemia). In patients with fulminant septicemia, meningococci can be detected in peripheral blood smears—an unusual occurrence. If the disease is not severe, the patient may have only a fever and other nonspecific symptoms. However, the organism can seed from the blood to other sites, for example, by crossing the blood-brain barrier and infecting the meninges. There they multiply and induce an acute inflammatory response, accompanied by an influx of polymorphonuclear leukocytes, resulting in a purulent meningitis. Joint symptoms and a petechial and/or purpuric rash are also commonly observed in meningococcal infections (Figure 4). Within several hours the initial fever and malaise can evolve into severe headache, a rigid neck, vomiting, and sensitivity to bright lights—symptoms characteristic of meningitis. Coma can occur within a few hours. The gold standard for diagnosis of systemic meningococcal infection is the isolation of N. meningitidis from a usually sterile body fluid, such as blood or cerebrospinal fluid (CSF). In performing a Gram stain on CSF, the clinical sample is centrifuged to concentrate the organisms, because 105 to 106 bacteria per ml are required for this test.

Fig4. Petechial and/or purpuric rash and neck extension characteristic of meningococcal meningitis.

2. Septicemia: Meningococci can cause a life-threatening septicemia in an apparently healthy individual in less than 12 hours. Up to 30 percent of patients with meningitis progress to fulminant septicemia. In this condition, the clinical presentation is one of severe septicemia and shock, for which the bacterial endotoxin (LOS) is largely responsible. Acute, fulminant meningococcal septicemia is seen mainly in very young children (the Waterhouse-Friderichsen syndrome). It is characterized by large, purple, blotchy skin hemorrhages, vomiting and diarrhea, circulatory collapse, adrenal necrosis, and death within 10 to 12 hours.

 E. Laboratory identification

 Under the light microscope, N. meningitidis obtained from CSF and skin lesion aspirates appear as gram-negative diplococci, often in association with polymorphonuclear leukocytes . Carriers can be detected by culturing swabs from the nasopharyngeal region.

1. Culture conditions: Meningococci are cultured on chocolate agar with increased CO2. The sample must be plated promptly or, if this is not possible, transport medium must be used to extend the viability of the organism to be cultured. Unlike gonococci, meningococci are usually cultured from CSF or blood, which are normally sterile; therefore a selective medium is not required, and plain chocolate agar is sufficient. [Note: Thayer-Martin medium is required for samples obtained from a skin lesion or nasopharyngeal swab, to eliminate contaminating organisms.]

2. Additional tests: All Neisseria species are oxidase-positive. To differentiate between species, sugar utilization tests are used (Figure 5). N. meningitidis utilizes both glucose and maltose, whereas N. gonorrhoeae uses only glucose (see Figure 5). In bacterial meningitis, the CSF shows increased pressure, elevated protein, decreased glucose (partly resulting from its consumption as a bacterial nutrient), and many neutrophils. The presence of an infecting organism or of antigenic capsular sub stance confirms the diagnosis. Figure 6 compares the characteristics of N. gonorrhoeae and N. meningitidis.

Fig5. Neisseria meningitidis produces acid from oxidation of glucose and maltose, but not from sucrose. The acid turns the pH indicator phenol red from red to yellow.

fig6. Differential bacteriologic features of Neisseria gonorrhoeae and Neisseria meningitidis.

F. Treatment and prevention

 Bacterial meningitis is a medical emergency. Accordingly, antibiotic treatment cannot await a definitive bacteriologic diagnosis. High fever, headache, and a rash typical of meningococcal infection are treated immediately in an effort to prevent progression to fulminant septicemia which has a high mortality rate. Blood cultures should be drawn and antibiotic therapy should not be delayed while waiting for lumbar puncture to be performed. Pretreatment with antibiotics can substantially diminish the probability of a positive CSF culture but the diagnosis can often still be established from the pretreatment blood cultures; and organisms may continue to be visible on Gram stain of the CSF. Meningitis can be effectively treated with penicillin G or ampicillin (both of which can pass the inflamed blood-brain barrier) in large intravenous doses. When the etiology of the infection is unclear, cefotaxime or ceftriaxone is recommended. Prompt treatment reduces mortality to about 10 percent. Because of the intense inflammatory reaction that accompanies bacterial meningitis, many authorities recommend a dose of the corticosteroid dexamethasone shortly prior to, or together with, the first dose of antibiotic.

 1. Diagnosis: Gram stains on CSF can be performed immediately, and latex agglutination tests with serogroup-specific anticapsular antibody can be used to obtain rapid presumptive identification of serogroup-specific meningococci in CSF.

2. Vaccines: A conjugate meningococcal vaccine (MCV4) was approved in the United States in 2005 for use in adolescents and adults ages 11 to 55 years, and has replaced the unconjugated polysaccharide vaccine. MCV4 is a tetravalent vaccine that contains capsular polysaccharides from serogroups A, C, W-135, and Y con jugated to diphtheria toxoid. The conjugated vaccines elicit a T cell dependent memory response that increases the effectiveness of the vaccine, resulting in an improved primary response to the vac cine and a strong response on subsequent exposure to the pathogen. The serogroup B polysaccharide capsule is a self-anti gen and therefore does not elicit an effective immune response. Figure 7 summarizes vaccines and serogroups.

Fig7. Characteristics of the common serogroups of Neisseria meningitidis.

3. Prophylaxis: Prophylactic rifampin is given to family members because of the inevitability of their close contact and thus expo sure. Other drugs used for prophylaxis include oral ciprofloxacin and intramuscular ceftriaxone. Figure 8 summarizes the diseases caused by Neisseria species.

Fig8. Summary of Neisseria diseases. Indicates first-line drugs; indicates alternative drugs.