Vinnytsуa National Pirogov Memorial Medical University Department of Children Infectious Diseases “Approved”

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Vinnytsуa National Pirogov Memorial Medical University
Department of Children Infectious Diseases


at sub-faculty meeting
28.08.2012, protocol №_1_

Head of Department

prof. _______I.I. Nezgoda

Study guide for practical work of students

Topic: “Central nervous system infections in children. Differential diagnosis”.

Course VI

English-speaking Students’ Medical Faculty

Duration of the class-150min

Composed by assoc. prof. L.M. Stanislavchuk



Chapter 1. Meningococcal disease

I. The theme urgency.

The gram-negative diplococcus Neisseria meningitides is a major infectious cause of childhood death in developed countries. The mortality rate remains around 10%. Isolated meningococcal meningitis (5% mortality rate) has a better prognosis than meningococcal septicemia (10-40% mortality rate). Infection with N meningitides is highest in children aged 6 months to 2 years; these children have lost the maternal antibodies and have not yet developed mature humoral immunity.

II. Primary aims of the study.

To teach students major methods of meningococcal disease diagnosis and treatment.

A student should know:

  1. Etiology of meningococcal disease.

  2. Epidemiology of meningococcal disease.

  3. Pathogenesis of meningococcal disease.

3) Classification and clinical manifestations of meningococcal disease.

4) Laboratory studies of meningococcal disease.

5) Complications of meningococcal disease.

6) Treatment of meningococcal disease.

7) Prevention.
A student should be able to:

1) Find out history

2) Interpret data of physical examination

3) Interpret data of laboratory studies

4) Formulate clinical diagnosis

5) Make differential diagnosis

6) Administer prehospital and in-patient treatment in meningococcal disease.

7) Prevention

III. Educative aims of the study.

To facilitate:

  1. The formation of deontology concepts and practical skills related to patients with meningococcal disease.

  2. To acquire the skills of psychological contact establishment and creation of trusting relations between the doctor and the patient and his parents.

3) The development of responsibility sense for timeliness and completeness of patient’s investigation.
IV. The contents of the theme.

Meningococcal disease, first described by Vieusseaux in 1805 as epidemic cerebrospinal fever, remains a significant health problem, particularly in the developing world. Although nasopharyngeal colonization rarely leads to disseminated disease, the fulminant, rapidly fatal course of meningococcemia is not soon forgotten.


Neisseria meningitidis is a gram-negative diplococcus that is often described as biscuit shaped. It is a common commensal organism of the human nasopharynx and has not been isolated from animal or environmental sources. The meningococcus is fastidious, and growth is facilitated in a moist environment at 35-37°C in an atmosphere of 5-10% carbon dioxide. It grows well on several enriched media, including supplemented chocolate agar. Mueller-Hinton agar, blood agar base, and trypticase soy agar. On solid media, colonies are transparent, nonpigmented, and nonhemolytic. N. meningitidis is identified by its ability to ferment glucose and maltose to acid and its inability to ferment sucrose or lactose. Indole and hydrogen sulfide are not formed. The cell wall contains cytochrome oxidase, which results in a positive oxidase test result.

The meningococci have been divided into serogroups based on antigenic differences in their capsular polysaccharides. Although 13 serogroups are currently recognized, groups A, B, C, W135, and Y account for most meningococcal disease. The other serogroups often colonize the nasopharynx but rarely disseminate. Lipooligosaccharides (e.g., endotoxin) and proteins found in the outer membrane complex are also used to serotype meningococcal strains.


Meningococcal dissemination occurs as endemic disease punctuated by outbreaks of cases that are often clustered geographically. True epidemics have become rare in developed countries but remain a significant problem in much of the developing world. Endemic disease appears to be caused by a heterogeneous group of meningococcal serotypes, and epidemics are caused by a single serotype. Analysis with multilocus enzyme genetic methods has confirmed that a meningococcal epidemic is caused by strains derived from a single clonotype.

The Centers for Disease Control (CDC) reported the results of a laboratory-based surveillance for meningococcal disease in a large United States population for the years 1989-1991. The average annual rate of invasive disease was 1.1/100,000 population, with an estimated 2,600 cases of meningococcal disease annually in the United States. The highest attack rates were during the winter and early spring months. Males accounted for 55% of the total cases, and 29% of the cases occurred in children younger than 1 yr, with the peak incidence of disease being 26/100,000 infants younger than 4 mo. Forty-six per cent of the cases occurred in children 2 yr of age or younger, and an additional 25% of the cases occurred in persons 30 yr of age or older. Serogroup B and serogroup C meningococci accounted for nearly equal proportions of disease (46% and 45%, respectively), but 69% of group C disease occurred in persons older than 2 yr. Fifty-eight per cent of the patients were reported to have meningitis. N. meningitidis was isolated from blood in 66% of cases, cerebrospinal fluid (CSF) in 51%, and joint fluid in 1%.

Subsequent data indicate that the proportion of cases caused by serogroup Y is increasing. The United States has also experienced an increased incidence of outbreaks of serogroup C disease. Eight outbreaks occurred during 1992-1993, and most of these outbreaks had attack rates exceeding 10 cases per 100,000 population.

Meningococcal disease, particularly group A, remains a major health problem in much of the developing world. Many areas, such as China and Africa, have an endemic rate of disease of 10-25/100,000 persons and major periodic epidemics (100-500/100,000). Epidemic disease typically involves individuals who are older than those with endemic disease.


N. meningitidis is thought to be acquired by a respiratory route. Colonization of the nasopharynx with meningococci usually leads to asymptomatic carriage, and only rarely does dissemination occur. Colonization can persist for weeks to months. Carriage rates vary from 2-30% in a normal population during nonepidemic periods but are higher among children in daycare centers and in conditions of crowding. The carriage rate can approach 100% in a closed population during an epidemic.

Meningococcal nasopharyngeal colonization is facilitated by the secretion of proteases that cleave the proline-rich hinge region of secretory IgA and render it nonfunctional. Meningococci and gonococci produce this enzyme, but nonpathogenic Neisseria organisms do not. Meningococci then adhere selectively to nonciliated epithelial cells. Pili appear to be of major importance in the attachment of meningococci to the human nasopharynx. The bacteria enter nonciliated epithelial cells by endocytosis and are carried across the cell in membrane-bound vacuoles.

Meningococci disseminate from the upper respiratory tract through the bloodstream. Serum antibody leading to complement-mediated bacterial lysis has been shown to block this dissemination, and a deficiency of antimeningococcal antibody is associated with the development of meningococcemia. Bactericidal antibody is directed against the capsular polysaccharide, subcapsular protein, and lipooligosaccharide antigens. Newborn infants have protective antibody that is primarily IgG of maternal origin. As this antibody wanes, infants 3-24 mo of age experience the highest incidence of meningococcal disease. By adulthood, most individuals have developed natural immunity against N. meningitidis from nasopharyngeal colonization with N. meningitidis and colonization of the gastrointestinal tract with enteric bacteria that express cross-reactive antigens. Infants have a high carriage rate of an unencapsulated, nonpathogenic neisserial strain, N. lactamica, that leads to the development of bactericidal antibody against the meningococcus.

The importance of the complement system in host defense against N. meningitidis is underscored by the fact that individuals with primary or acquired complement deficiency have an increased risk of developing meningococcal disease, and 50-60% of individuals with properdin, factor D, or terminal-component deficiencies develop bacterial infections that are caused almost solely by N. meningitidis. Recurrent infection is common with terminal component deficiencies but is uncommon with properdin deficiency. Acquired complement deficiency also carries an increased risk and can be seen with systemic diseases that deplete serum complement. Examples are systemic lupus erythematosus, nephrotic syndrome, multiple myeloma, and hepatic failure.

The group B capsule is a homopolymer of sialic acid, which is known to inhibit alternative complement pathway activation. Antibody that activates the classic pathway can overcome this inhibition. The lack of specific antibody coupled with inhibition of the alternative pathway may explain the prevalence of serogroup B meningococcal disease in young children.


Disseminated meningococcal disease is associated with an acute inflammatory response. Hemorrhage and necrosis may be seen in any organ system and appear to be mediated by intravascular coagulation with deposition of fibrin in small vessels. The major organ systems involved in fatal cases of meningococcemia are the heart, central nervous system, skin, mucous and serous membranes, and adrenals. Myocarditis is found in more than 50% of patients who die of meningococcal disease. Cutaneous hemorrhages, ranging from petechiae to purpura, occur in most fatal infections and are associated with acute vasculitis with fibrin deposition in arterioles and capillaries. Diffuse adrenal hemorrhage may occur in patients with fulminant meningococcemia (i.e., Waterhouse-Friderichsen syndrome). Meningitis is characterized by acute inflammatory cells in the leptomeninges and perivascular spaces. Focal cerebral involvement is uncommon.

The interaction of endotoxin released by N. meningitidis and the complement system probably is key in the pathogenesis of the clinical manifestations of meningococcal disease. Complement activation correlates with the concentration of meningococcal lipooligosaccharide in the plasma. The concentration of circulating endotoxin is directly correlated with activation of the fibrinolytic system, development of disseminated intravascular coagulopathy (DIC), multiple organ system failure, septic shock, and death. The level of endotoxemia correlates with the concentration of circulating cytokines, which are released from endotoxin-stimulated monocytes and macrophages. The concentrations of tumor necrosis factor-alpha and interleukins have been directly associated with fatal meningococcal disease.


The spectrum of meningococcal disease can vary widely, from fever and occult bacteremia to sepsis, shock, and death. Recognized patterns of disease are bacteremia without sepsis, meningococcemic sepsis without meningitis, meningitis with or without meningococcemia, meningoencephalitis, and infection of specific organs.

A well-recognized entity is occult bacteremia in a febrile child. Upper respiratory or gastrointestinal symptoms or a maculopapular rash can be evident. The child often is sent home on no antibiotics or oral antibiotics for a minor infection. Spontaneous recovery without antibiotics has been reported, but some children have developed meningitis.

Acute meningococcemia initially can mimic a virus-like illness with pharyngitis, fever, myalgias, weakness, and headache. With widespread hematogenous dissemination, the disease rapidly progresses to septic shock characterized by hypotension, DIC, acidosis, adrenal hemorrhage, renal failure, myocardial failure, and coma. Meningitis may or may not develop. Concomitant pneumonia, myocarditis, purulent pericarditis, and septic arthritis have been described. More often, meningococcal disease is manifested as acute meningitis that responds to appropriate antibiotics and supportive therapy. Seizures and focal neurologic signs occur less frequently than in patients with meningitis caused by pneumococcus or Haemophilus influenzae type b. Rarely, meningoencephalitis can occur with diffuse brain involvement.

A review of 100 children with invasive meningococcal disease revealed that 71% presented with fever, 4% with hypothermia, and 42% with shock. Skin lesions occurred in 71% of the cases with petechiae and/or purpura and in 49% with both. Purpura fulminans developed in 16%. Other rashes described were maculopapular, pustular, and bullous lesions. Additional presenting symptoms and signs were irritability in 21%, lethargy in 30%, and emesis in 34%. Diarrhea, cough, rhinorrhea, seizure, and arthritis occurred much less frequently (6-10%). Leukopenia and low platelet counts affected 21% and 14%, respectively, and the white blood cell counts ranged from 900-46,000/mm3 . N. meningitidis was isolated in blood culture from 48% of the children, and meningitis was diagnosed in 55%. Six children had meningococci isolated from CSF in the absence of CSF pleocytosis, hypoglycorrhachia, or organisms detected by Gram stain. Five of eight children who presented with arthritis had N. meningitidis isolated from joint aspiration fluid. Eight per cent of the children had radiographic evidence of pneumonia on presentation.

Uncommon manifestations of meningococcal disease include endocarditis, purulent pericarditis, pneumonia, septic arthritis, endophthalmitis, mesenteric lymphodenitis, and osteomyelitis. Primary purulent conjunctivitis can lead to invasive disease. Sinusitis, otitis media, and periorbital cellulitis also can be caused by the meningococcus. Primary meningococcal pneumonia is associated with pleural effusions or empyema in 15% of cases. N. meningitidis is a rare isolate of the genitourinary tract in asymptomatic or symptomatic individuals and has been the causal organism in urethritis, cervicitis, vaginitis, and proctitis.

Chronic meningococcemia is a rare manifestation of meningococcal disease that can occur in children and adults. It is characterized by fever, nontoxic appearance, arthralgias, headache, and rash. The rash resembles that of disseminated gonococcal infection. Symptoms are intermittent, with the rash often appearing with fever. The mean duration of illness is 6-8 wk. Blood cultures may initially be sterile. Without specific therapy, complications such as meningitis can result.


Definitive diagnosis of meningococcal disease is made by isolation of the organism from a usually sterile body fluid such as blood, CSF, or synovial fluid. Isolation of meningococci from the nasopharynx is not diagnostic for disseminated disease. Blood and CSF are the usual sources of organism isolation. The blood culture yields N. meningitidis in about half of the cases of disseminated disease, and culture or Gram stain usually reveals the organism in those with meningitis. Culture or Gram stain of petechial or papular lesions has been variably successful in identifying meningococci. Bacteria can occasionally be seen on Gram stain of the buffy coat layer of a spun blood sample.

In meningitis, the morphologic and clinical characteristics of CSF are those of acute bacterial meningitis. CSF cultures can be positive in patients with meningococcemia but without clinical evidence of meningitis or CSF pleocytosis. CSF cultures may be negative if the patient has received previous antibiotic treatment.

Particle agglutination using latex beads, which has replaced counterimmunoelectrophoresis, can detect meningococcal capsular polysaccharide in CSF, serum, joint fluid, or urine. This is especially useful when results are positive in the setting of partially treated infections with negative cultures. The available latex agglutination tests do not detect group B meningococcus, the most common cause of endemic meningococcal infections, and therefore have limited usefulness. Latex agglutination is not a substitute for proper Gram stain and culture techniques.

Other laboratory findings may include elevated sedimentation rate and C-reactive protein, leukocytopenia or leukocytosis, thrombocytopenia, proteinuria, and hematuria. Patients with DIC coagulation have decreased serum concentrations of prothrombin and fibrinogen.

Differential Diagnosis.

This includes acute bacterial or viral meningitis, Mycoplasma infection, leptospirosis, syphilis, acute hemorrhagic encephalitis, encephalopathies, serum sickness, collagen vascular diseases, Henoch-Schonlein purpura, hemolytic-uremic syndrome, and ingestion of various poisons. The petechial or purpuric rash of meningococcemia is similar to that in any patient with a disease characterized by generalized vasculitis. These diseases include septicemia due to many gram-negative organisms; overwhelming septicemia with gram-positive organisms; bacterial endocarditis; Rocky Mountain spotted fever; epidemic typhus; Ehrlichia canis infection; infections with echoviruses, particularly types 6, 9, and 16; coxsackievirus infections, predominantly of types A2, A4, A9, and A16; rubella; rubeola and atypical rubeola; Henoch-Schonlein purpura; Kawasaki's disease; idiopathic thrombocytopenia; and erythema multiforme or erythema nodosum due to drugs or infectious or noninfectious disease processes. The morbilliform rash occasionally observed may be confused with any macular or maculopapular viral exanthem.


Aqueous penicillin G is the drug of choice and should be given in doses of 250,000-300,000 U/kg/24 hr, administered intravenously in six divided doses. Cefotaxime (200 mg/kg/24 hr) and ceftriaxone (100 mg/kg/24 hr) are acceptable alternatives. Chloramphenicol sodium succinate (75-100 mg/kg/24 hr IV in four divided doses) provides effective treatment for patients who are allergic to beta-lactam antibiotics. Therapy is continued for 5-7 days.

Isolates of N. meningitidis have been reported from Spain, South Africa, and Canada as being relatively resistant to penicillin, defined as having a minimal inhibitory concentration of penicillin of 0.1-1.0 mu/mL. Moderate resistance is caused, at least in part, by altered penicillin-binding protein 2. High-level resistance due to beta-lactamase production has been reported from South Africa. The CDC estimated that about 4% of meningococcal disease in 1991 in the United States was caused by N. meningitidis strains that were relatively resistant to penicillin. None of the strains isolated produced beta-lactamase. The clinical significance of moderate penicillin resistance is unknown. The CDC decided that routine susceptibility testing of clinical meningococcal isolates is probably not indicated in the United States at this time, but continued surveillance is necessary.

Patients with acute meningococcal infections should be monitored carefully.


Acute complications are related to the inflammatory changes, vasculitis, DIC, and hypotension of invasive meningococcal disease. These can include adrenal hemorrhage, arthritis, myocarditis, pneumonia, lung abscess, peritonitis, and renal infarcts. The vasculitis can lead to skin loss with secondary infection, tissue necrosis, and gangrene. Skin sloughing can necessitate the use of skin grafts. Bone involvement can lead to growth disturbance and late skeletal deformities secondary to epiphyseal avascular necrosis and epiphyseal-metaphyseal defects. Limb amputation has been reported for patients with purpura fulminans.

Meningitis rarely is complicated by subdural effusion or empyema or by brain abscess. Deafness is the most frequent neurologic sequela, but the reported incidence varies from 0-38%. Other rare sequelae include ataxia, seizures, blindness, cranial nerve palsies, hemiparesis or quadriparesis, and obstructive hydrocephalus.

The late complications of meningococcal disease are thought to be immune complex mediated and become apparent 4-9 days after the onset of illness. The usual manifestations are arthritis and cutaneous vasculitis. The arthritis is usually monarticular or oligoarticular. Effusions are usually sterile and respond to nonsteroidal anti-inflammatory agents. Permanent joint deformity is uncommon. Because most patients with meningococcal meningitis are afebrile by the 7th hospital day, the persistence or recrudescence of fever after 5 days of antibiotics warrants an evaluation for immune complex-mediated complications.


Despite the use of appropriate antibiotics, the mortality rate for disseminated meningococcal disease remains at 8-13% in the United States. Poor prognostic factors include hypothermia, hypotension, purpura fulminans, seizures or shock on presentation, leukopenia, thrombocytopenia, and high circulating levels of endotoxin and tumor necrosis factor. The presence of petechiae for less than 12 hr before admission, hyperpyrexia, and the absence of meningitis reflect rapid progression and poorer prognosis.

Screening for complement deficiency after resolution of the acute infection is recommended for individuals with meningococcal disease. In one series of 20 patients with a first episode of meningococcal meningitis, meningococcemia, or meningococcal pericarditis, three had a deficiency of a terminalpathway component and three had deficiencies of multiple complement components associated with underlying systemic diseases.


Close contacts of patients with meningococcal disease are at increased risk of infection and should be carefully monitored and brought to medical attention if fever develops. Prophylaxis is indicated as soon as possible for household, daycare, and nursery school contacts. Prophylaxis is also recommended for persons who have had contact with patients' oral secretions. Prophylaxis is not routinely recommended for medical personnel except those with intimate exposure, such as with mouth-to-mouth resuscitation, intubation, or suctioning before antibiotic therapy was begun. Rifampin is given (10 mg/kg; maximum dose, 600 mg) orally every 12 hr for 2 days (total of four doses). The dose is reduced to 5 mg/kg for infants younger than 1 mo. Other effective antimicrobial agents are ciprofloxacin (500 mg orally as a single dose for adults) and ceftriaxone as a single intramuscular dose (125 mg for children < 15 yr and 250 mg for adults). Penicillin does not eradicate nasopharyngeal carriage, and patients treated with penicillin should receive chemoprophylactic antibiotics before hospital discharge.


A quadrivalent vaccine composed of capsular polysaccharide of meningococcal groups A, C, Y, and W135 is licensed in the United States. The vaccine is immunogenic in adults but is unreliable in children younger than 2 yr. The group B polysaccharide is poorly immunogenic in children and adults, and no vaccine is available against this serogroup. Routine immunization of the United States population is not recommended at this time, but the vaccine is routinely given to all American military recruits.

Immunization is useful to control outbreaks of meningococcal disease of the
serogroups represented in the quadrivalent vaccine. It is also recommended for travelers to countries with a high incidence of meningococcal disease. Immunization of close contacts of individuals with A, C, Y, or W135 disease should be considered, because it has been useful in the prevention of secondary cases. Individuals with anatomic or functional asplenia and those with complement component deficiencies should be immunized.

Polysaccharide-protein conjugate vaccines are being developed for the prevention of meningococcal disease, and subcapsular proteins and detoxified lipooligosaccharides are being investigated as possible vaccines.

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