Meningococcal Meningitis

Etiology

Neisseria meningitides is the organism responsible for meningococcal meningitis and is the second most common causative organism for bacterial meningitis in the United States.[1] This bacterium is an anaerobic, bean, or kidney-shaped gram-negative diplococci. It grows in chocolate agar and blood agar at room temperature with 5%-10% atmospheric carbon dioxide. Neisseria meningitides are catalase-positive, oxidize glucose and maltose that changes pH, and helps to differentiate from gonococci, which cannot oxidize maltose. The organism grows in selective Thayer-Martin media, which contains antibiotics like vancomycin, colistin, and nystatin by preventing the growth of other gram-negative bacteria, gram-positive bacteria, and yeast. N. meningitidis colonizes mostly in the naso-and oropharynx but can colonize in other body parts like the anal mucosa, conjunctiva, and urogenital tracts. It possesses multiple virulent factors: Pilli, opacity proteins, lipo-oligosaccharides, capsular polysaccharide, and factor H binding protein. The polysaccharide capsule protects the bacterium from complement-mediated phagocytosis and lysis.[2] 

Serotypes are classified according to the polysaccharide capsule it contains. Out of 13 serotypes, A, B, C, X, Y, Z, W-135, and L are mostly responsible for human disease.[3] Unencapsulated strands found in asymptomatic carriers rarely have been the cause of invasive disease.[4] Lipo-oligosaccharide is similar to lipopolysaccharide of gram-negative bacilli.[5] LOS acts as endotoxin and activates the pro-inflammatory cytokine pathway of the host to cause meningococcal sepsis.[6] LOS interacts with immune cells of the host to initiate the release of inflammatory mediators like TNF- alpha, IL-1, IL-6, and INF-gamma to cause shock.[7][8][9]

Risk Factors

Neisseria meningitidis infection depends upon various environmental and host factors. Based on experience with military recruits, the nasopharyngeal carrier state is the primary factor for the transmission and development of meningitis.[10] That is why tetravalent vaccination against N. meningitides has been started since 1972 among military recruits in the USA.[11] Early and late complement deficiency has been associated with increased susceptibility to meningococcal infection.[12] There is an increased risk of acquiring an invasive meningococcal infection in patients with HIV/AIDS.[13] The incidence of meningococcal infection is more among people who have sex with others with HIV than those who have sex with people without HIV.[14] People under eculizumab have about 1000 or 2000 times increased risk of fatal meningococcal infection.[15]

Epidemiology

N. meningitidis was estimated to be responsible for 1.2 million cases of infection per year, as well as approximately 135,000 deaths worldwide.[16] Infants and adolescents are most vulnerable to developing meningococcal disease due to elevated rates of nasopharyngeal colonization and waning maternal antibodies. In the United States, the annual incidence rate of meningococcal meningitis between 2006 and 2015 was 0.28 cases per 100000, and 2.50 cases per 100000 for infants aged less than one year.[17] Due to large and persistent epidemics, the highest incidence rates of meningococcal disease are found in the “meningitis belt” of sub-Saharan Africa, with rates ranging from 20 to 1000 per 100000.[18]

Furthermore, the serogroups causing meningococcal disease vary geographically. Meningococcus serogroup A predominates in Africa and regions of Asia, whereas serogroups B, C, and Y predominate in other areas, including North America and Europe.[19] In the United States, serogroups B, C, and Y are the predominant serogroups causing meningococcal meningitis, each accounting for one-third of cases.[20] Among those, serogroup B is the cause of 50% of meningococcal cases in infants, whereas serogroup C is commonly seen in adolescents, and serogroups B and Y in older adults.[16]

Between 2006 and 2015:[17]

• Annual incidence changed from 0.40 cases to 0.14 cases per 100,000.
• For serogroup B infection, incidence changed from 0.25 to 0.05 cases per 100,000.
• For serogroup C infection, incidence changed from 0.38 to 0.01 cases per 100,000.[20]
• For serogroup Y infection, incidence changed from 0.42 to .02 cases per 100,000.
• Besides those serogroups, the incidence of infection from other serogroups remained constant.

The incidence of infection in the male population is slightly higher than females. Among races, the incidence rate in African-Americans is found to be 0.27 cases per 100,000, whereas the incidence rate of infection in other races is 0.20 cases per 100,000. Despite medical advancements in the prevention of this disease, mortality rates remain in a range between 5% and 15% for those treated, and as high as 50% in those without treatment.[21]

Pathophysiology

The pathophysiology of N. meningitidis involves a series of sequential steps. The process begins when the bacterium colonizes the nasopharynx. The only known reservoir for N. meningitidis is the upper respiratory tract, although only a few will develop invasive disease.[22] The bacterium incubates for a period to 1 to 10 days and then further penetrates the submucosa. In 10 to 20% of cases, the bacterium invades the bloodstream. Once present in the plasma, host defenses, which include bactericidal antibodies, complement, and phagocytic cells, may prevail and eliminate bacteria. In cases, where host defenses fail to clear bacteria, the patient enters the bacteremic phase. Bacteria may now invade meninges and other local sites, which can rapidly lead to meningitis and fatal septicemia.[23]

History and Physical

Prompt recognition and immediate initiation of treatment are of utmost importance in the management of bacterial meningitis. The meningococcal disease presents with signs and symptoms which can vary from an undifferentiated febrile illness to fulminant septic shock. Rapid progression of symptoms over hours is typical and can be helpful when trying to differentiate meningitis from a self-limiting viral infection.[10]

The classic triad of neck stiffness, fever, and altered mental status is a more specific sign for meningitis. Infants can present with a variety of non-specific symptoms, which include lethargy, irritability, and in some cases bulging fontanelles. Older children and adults will present with headaches, fever, photophobia, vomiting, neck stiffness, and altered mental status. Meningococcal disease often presents with a petechial rash to the lower extremities, which occurs following the initial non-specific symptoms, although this symptom can also be present in pneumococcal meningitis.[24] Out of fever, neck stiffness, altered mental status, and rash, 89% of the patients had at least two signs.[25] The patients can also have myalgias, which are more painful than those associated with viral influenza. The provider should also be concerned about the signs and symptoms of early sepsis, like leg pain, cold hands & feet, and abnormal skin color (e.g., pallor or mottling).[26] 

Physical Examination

Patients can present with abnormal vital signs, including fever, tachypnea, tachycardia, and hypotension. Hypotension with elevated pulse rate is suggestive of early vascular instability. The patient should be fully undressed to look for petechiae and ecchymosis and to perform a thorough skin exam. Meningeal irritability can be confirmed by provocative tests like Kernig and Brudzinki sign. When the knee of the patient in the supine position with flexed hip and knee at the right angle is slowly extended, there is the appearance of resistance or pain on an extension beyond 135 degrees i.e., positive Kernig sign.[27] 

In the same way, Brudzinski sign is positive when the patient is in the supine position and shows reflex flexion of the hips and knee after passive flexion of the neck. At the same time, the examiner keeps one hand behind the patient’s head and other on the chest, preventing the rising of the patient from a supine position.[27] The absence of these signs does not exclude systemic meningococcal infection. A thorough neurologic exam should be performed looking for alteration in mental status, as well as any focal deficits.

Evaluation

Initial blood tests should include full blood cell count, electrolytes, coagulation studies, and blood cultures.[28] Lumbar puncture is necessary for a definitive diagnosis, but if clinical suspicion is high, diagnostic tests should not delay antibiotic administration. 

Lumbar Puncture: Diagnosis can be made from bacterial isolation of N. meningitidis from cerebrospinal fluid, blood, and skin lesions. CSF can be obtained via lumbar puncture. CSF fluid typically reveals high opening pressure, pleocytosis (WBC more than 1000/microliters), high protein concentration (more than 500 mg/dl), low glucose (less than 45 mg/dl or less than 2.5 mmol/L), and CSF: serum glucose ratio of less than 0.4.[19] Of note, CSF sterilization may occur within the first two hours of antibiotic administration, but again this should not delay antibiotic treatment.[29] 

CSF fluid should also be sent for Gram staining, standard culture, and polymerase chain reaction (PCR). Gram staining is diagnostic in 85% of patients with meningococcal meningitis. Bacteriologic culture establishes a definitive diagnosis. These should be grown on chocolate blood agar at 35 degrees C. N. meningitidis tends to be positive in around 50% of blood cultures and approximately 75% of cerebrospinal fluid. The cerebrospinal fluid assay can be done with latex agglutination, PCR, rapid dipstick test, and loop-mediated isothermal amplification (LAMP). CSF studies with PCR can also be obtained, although these commonly tend to yield false-negative results. PCR has more advantages than culture for diagnosis of meningococcal infection as it is rapid, can detect different strains of even non-viable bacteria.[30] LAMP is a highly accurate rapid test for the diagnosis of meningococcal infection at an emergency than PCR or culture.[31][32]

Imaging: Imaging studies, specifically CT scans, can also be performed if the patient meets the criteria for CT before LP. The criteria include age greater than 60, presence of focal neurologic deficits, altered mental status, immunodeficiency, new-onset seizures, history of central nervous system disease, and papilledema.[23]

Treatment / Management

Meningococcal meningitis is a medical emergency presenting with severe sepsis syndrome, fever, petechiae, and ecchymosis require prompt resuscitation and antibiotic administration.[33]

Resuscitation: Meningococcal disease can cause life-threatening organ dysfunction. On arrival, the patient’s hemodynamic stability and need for acute interventions should be evaluated. Early intubation should be considered in patients with evidence of airway compromise, ongoing shock, intractable seizures, or elevated intracranial pressure.[28] Given meningococcal disease often results in vascular collapse and septic shock, resuscitation should also include stabilizing blood pressure and providing sufficient tissue perfusion. Hemodynamic support should consist of fluid resuscitation and the addition of vasopressors as needed.

Antibiotics: Antibiotic dose should be given as soon as meningitis is suspected and should not be delayed awaiting confirmatory studies. Lumbar puncture is performed as soon as possible as parenteral antibiotic therapy clears out meningococci from CSF in less than six hours.[34] Local guidelines should dictate antibiotic treatment. On initial encounter when the patient presents with an undifferentiated acute bacterial meningitis, administration of broad-spectrum antibiotics is appropriate pending bacterial isolation. Seven days course of antibiotic therapy is usually sufficient to treat suspected cases of meningococcal meningitides.[35] Initial treatment for adults should include the administration of a third-generation cephalosporin (such as cefotaxime or ceftriaxone, i.e., twice daily dose) in combination with vancomycin, with the addition of ampicillin for those greater than 50-years-old to cover L. monocytogenes.[35] (A1)

Third-generation cephalosporins have great coverage against N. meningitides.[36] Once N. meningitis has been confirmed, penicillin (IV/IM usual dose 300,000 units/kg per day with an upper limit of 24 million units/day or 4 million units IV every 4 hours) is recommended as monotherapy due to its low cost and narrow spectrum.[24] For minimum inhibitory concentration (MIC) <0.1 mcg/ml, the patient treated with penicillin[35] whereas MIC of 0.1 to 1 mcg/dl, third-generation cephalosporin is preferred. In case patients who cannot tolerate beta-lactam or during epidemics or resource-limited settings, chloramphenicol (100 mg/kg per day IV up to maximum dose 4 g/kg) is the choice of treatment for meningococcal meningitides.[37](A1)

Steroids: Traditionally, patients receive an empiric dose of steroids (dexamethasone), but the use of corticosteroids is controversial and may be of more benefit in patients with meningitis due to S.pneumoniae and H.influenzae.[23] 

Prevention

The N. meningitidis can be prevented by applying measures under the following subcategories.[38]

Pre-exposure:

Droplet Precaution: The patient with suspected or confirmed N. meningitidis should follow droplet precaution. This should be continued until after 24 hours of effective antibiotics administration.

Vaccination: In the United States, a quadrivalent meningococcal conjugate vaccine (Menactra or Menveol) is administered to:[20]

1. All individuals between age 11 and 18 years of age i.e., at age 11 or 12, and a booster dose at age 16 years.

2. Individuals 10 years or less or 19 years or less of age with increased risk of invasive meningococcal disease:

• Travelers to hyperendemic or epidemic area of meningococcal disease
• Military recruits
• Lab worker handling N. meningitidis
• Functional or anatomic asplenia
• Complement component deficiency
• Individual under treatment with C5 inhibitors (eculizumab/ravulizumab)

Meningococcal vaccines (both ACYW and serogroup B) are given two weeks before administering the first case of the C5 inhibitor.

Avoidance of risk factors.

Post-Exposure:

Antimicrobial Prophylaxis:

Close contact is defined as individuals with more than eight hours of contact in less than three feet of proximity to patient or person directly exposed to patient’s secretions during seven days before the onset of symptoms and until 24 hours after initiation of antibiotic therapy.[20] Close contacts and healthcare workers who had contact with patient’s secretions should receive chemoprophylaxis with either ciprofloxacin, rifampin, or ceftriaxone.[39]

In rare cases of ciprofloxacin-resistant N. meningitidis, rifampin, and ceftriaxone are used as alternatives for prophylaxis. Patients under C5 inhibitors (eculizumab and ravulizumab) should receive antibiotic prophylaxis of penicillin or macrolide (penicillin allergy) in addition to vaccination for the entire duration of therapy. Close contacts receiving prophylaxis should be under surveillance for ten days following exposure. Surveillance and counseling about the sign-symptom of meningococcal infection would ensure prompt treatment of any secondary case.

Chemoprophylaxis should be given to patients with invasive meningococcal disease with nasopharyngeal carriage of N.meningitidis before discharge from the hospital to prevent transmission to close contacts.[40]

Differential Diagnosis

Differential diagnoses should include a myriad of neurologic diseases such as

• Encephalitis (bacterial/viral)
• Brain abscess
• Malignancy
• Intracranial bleed
• Cerebrovascular accident[41]

Other relevant differentials are

• Tetanus
• Rabies
• Medications causing serotonin syndrome/neuroleptic malignant syndrome
• Sinusitis

Meningococcal meningitidis progresses to meningococcemia with a purpuric rash which is difficult to differentiate from

• Sepsis
• Disseminated gonococcemia
• Rocky Mountain Spotted Fever
• Typhus(endemic or epidemic)
• Leukocytoclastic vasculitis
• Hemorrhagic dengue
• Ehrlichiosis
• Anaplasmosis
• Borreliosis(Lyme disease)
• Thrombotic thrombocytopenic purpura
• Idiopathic thrombocytopenic purpura

Prognosis

According to the CDC, current mortality rates of the patient with meningococcal meningitis in the United States are approximately 10% to 15 % with treatment [20] and up to 50% if left untreated. Prompt antibiotic administration, especially within one hour, has been proven to improve morbidity and mortality, as well as prevent complications such as increased intracranial pressure and septic shock.[42][43] 

The factors like shock, presence of focal deficits, mental obtundation or coma, purpuric or ecchymotic rash, absence of meningeal signs, low or normal blood leukocyte count, age of more than 60 years, presence of anemia, thrombocytopenia, low erythrocyte sedimentation rate (or C-reactive protein level), low blood concentrations of antithrombin or proteins S and C, high blood levels of plasminogen activator inhibitor 1 (PAI-1), malignancy, intracranial bleed, and cerebrovascular accident, are considered as a poor prognostic factor for meningococcal meningitides patients.[44] Female gender and cases in the outbreak have also been associated with high case- fatality rates among meningococcal disease patients.[45][46]

Complications

Complications of meningococcal meningitis can arise early or late in the disease course and can adversely impact morbidity and mortality. Intracranial complications include cerebral edema, vascular alterations, and hydrocephalus. Extracranial complications include septic shock, disseminated intravascular coagulation, multiorgan failure, including acute adrenal crisis due to adrenal hemorrhage (Waterhouse- Friderichsen syndrome), and electrolyte disturbances.[47] 

Late complications of meningococcal meningitis include chronic pain, skin scarring, and neurologic impairment. Other common complications include hearing impairment, visual impairment, and seizures. Hearing tests are recommended four weeks after hospital discharge. Post-traumatic stress disorder can also ensue; management may require psychiatric or psychological intervention.[42]

As with any critical illness, other complications could include prolonged ventilatory weaning, tracheostomy care, feeding tube care, prolonged physical and occupation rehabilitation, development of polyneuropathy, and polymyopathy of critical illness, as well as the development of secondary infections and wounds.