B. The Johns Hopkins Hospital. Information provided by George Kunz, M.D., Department of Pathology.
Case Report: The patient is a 24 year old man who was in good health until a few days prior to admission when he developed headache, fever, and a stiff neck. He was seen in the emergency department at an outside hospital. He was prophylactically given a short course of a second-generation cephalosporin but was soon discharged with a diagnosis of a "viral illness". Two days later, he was admitted to The Johns Hopkins Hospital with continued fever and mental status changes. A brain CT showed diffuse cerebral edema with accentuation of the gray-white matter junction. His peripheral WBC count was 20280 cells/cu mm. A lumbar puncture and blood cultures were done. The cerebrospinal fluid was cloudy with 2295 WBC/cu mm (80% PMNs), 406 RBC/cu mm, glucose <2 mg/dL, and protein 230 mg/dL. A Gram stain of CSF revealed a few Gram-negative diplococci and numerous polymorphonuclear neutrophils (PMNs). CSF and blood cultures were positive for penicillin-susceptible Neiserria meningitidis.

Organism: Neisseria meningitidis, also known as meningococcus, is a Gram negative diplococcus in the genus Neisseria. The other human pathogen in this genus is Neisseria gonorrhoeae¹. These two species inhabit moist mucous membranes of human beings. They are non-motile and capnophilic and grow optimally between 35-37° C. Like other Gram negative organisms, meningococcus has a three-layer "membrane" consisting of a inner phospholipid cytoplasmic membrane, a thin middle peptidoglycan layer, and an outer membrane of lipooligosaccharide (LOS), proteins, and phospholipid². Unlike N. gonorrhoeae, meningococcus also possesses a polysaccharide capsule, an important virulence factor for this organism.² Other important virulence factors include the presence of LOS in the outer membrane (also know as 'endotoxin') and an immunoglobulin A (IgA) protease^1,2.

The polysaccharide capsule helps meningococcus resist phagocytosis by PMNs, especially during initial infection when opsonizing antibody for a particular meningococcal strain is not present¹. Meningococcus can be divided into 13 different serogroups (A, B, C, D, H, I, K, L, X, Y, Z, W135, and 29E) based on variation in the capsule². The serogroups can be further subdivided in serotypes based on antigenically distinctive outer membrane proteins and LOS antigens². Endotoxin, by contrast, is produced by other Gram negative bacteria, and its release into the circulation produces the clinical manifestations of meningococcemia, including fever and shock¹. IgA protease cleaves the Fab and Fc portions of IgA antibody present on mucosal surfaces, thus rendering it ineffective and enhancing bacterial adherence.

Human beings are the only natural host for meningococcus, with the oro- and nasopharynx being the main locations for colonization and asymptomatic carriage. The rate of carriage in the population is related to age, socioeconomic class, and the presence of virulent strains in the environment. The duration of carriage can be transient, intermittent, or chronic and varies depending on the individual and serogroup. For instance, the general population has carriage rates of 8-20% with older children and young adults having higher rates of between 20 and 40%. When a virulent strain is present in a community, a higher proportion of people tend to carry the virulent strain, even though the overall carriage rate does not change. The organism is passed between individuals through respiratory droplets. Therefore, crowded living conditions tend to facilitate its spread.

Clinical Manifestations: There are two important clinical manifestations of N. meningitidis infection, namely, meningitis and menningococcemia¹. Meningitis caused by N. meningitidis is overall the second most common cause of bacterial meningitis in the United States after pneumococcal meningitis^2,3. It occurs most frequently in children younger than five years³. Signs and symptoms include confusion, headache, fever, nuchal rigidity, and vomiting. Twenty to forty percent of meningococcal infections manifest as meningitis³. However, when widespread dissemination of N. meningitidis occurs, the signs and symptoms of meningococcemia are present. These include the rapid development of petechiae (especially of mucous membranes, the trunk, and lower extremities), or a non-pruritic, rubella-like rash. When the disease is progressive and fulminant, petechiae can coalesce to form cutaneous hemorrhagic necrosis and purpura fulminans. Other clinical manifestations of meningococcemia include disseminated intravascular coagulation (DIC), arthritis, peritonitis, and cardiac abnormalities such as purulent pericarditis with tamponade^2,3. A rare form of meningococcemia is Waterhouse-Friderichsen syndrome, which has high fever, shock, widespread Purpura, DIC, and adrenal insufficiency¹. Predictors of poor clinical outcome include the presence of shock, a low WBC count, rash, and altered mental status on presentation². Overall, the case-fatality rate for meningococcal meningitis is 3%³.

Laboratory Diagnosis: The primary means of laboratory diagnosis are the Gram stain culture of blood and/or cerebral spinal fluid (CSF)¹. In 50-70% of cases of meningococcal meningitis, Gram stain of CSF will reveal intracellular and extracellular Gram-negative diplococci^2,3. CSF culture is performed on blood and chocolate agars. When the cultures are obtained from normally non-sterile sites such as the oropharynx, a selective Thayer-Martin medium containing vancomycin, polymyxin, and nystatin is used^2,3. The two pathogenic Neisseria species can be distinguished by differential sugar fermentation, since meningococci ferment maltose and gonococci do not¹. Latex agglutination can also be used for diagnosis but lacks the sensitivity and specificity of direct Gram stain and culture of CSF. For this reason, latex agglutination should only be used in partially treated patients in whom CSF findings are consistent with meningitis, i.e. have increased PMNs, low glucose, and high protein in their CSF. Tests for serum antibodies are generally not useful. Serogrouping of N. meningitidis is most commonly done by slide agglutination but can also be done with direct antigen tests for capsular polysaccharides. Serotyping is used mainly for epidemiological purposes.

Treatment: The treatment of choice was uniformly high dose penicillin G. However, with the advent of penicillin-resistant strains, the preferred alternative antibiotics are third generation cephalosporins or chloramphenicol. The minimum course of therapy is 7 days. Chemoprophylaxis with rifampin is done for close contacts of the patient since it eliminates the pharyngeal carriage state. Sulfonamides are no longer used due to the high prevalence of resistant strains³.

References
Levinson WE and E Jawetz. Medical Microbiology and Immunology, 3^rd Edition. Appleton &
Lange, Norwalk, 1994; 76-79.

Konenman EW, et al. Introduction to Diagnostic Microbiology. JB Lippincott Company,
Philadelphia, 1994; 166-186.

Samore, MH and AW Karchmer. Infections due to Neisseria. Scientific American Medicine, www.samed.com. DC Dale, Editor-in-Chief, November 1998; Chapter 3, Section 7.