Clinical manifestations

Presentation and course

Acute bacterial meningitis is classically associated with a triad of clinical signs and symptoms, which include fever, stiff neck (meningismus), and headache. The likelihood of all three being present is only 50%, and an altered level of consciousness, either lethargy or stupor, should be added to the classic symptoms. At least two of the following symptoms and signs: fever, meningismus, headache, and an altered level of consciousness—will be present in 95% of bacterial meningitis patients (47). Of these, fever is the most sensitive measure, and a temperature greater than 37.7 C (100 F) occurs in nearly everyone within 24 hours of symptom onset (33). Other common complaints include photophobia, nausea, and vomiting, which are often due to increased intracranial pressure. The most common physical exam findings of elevated intracranial pressure are papilledema and an altered level of consciousness, which often advance to obtundation or coma.

On examination, meningismus is the pathognomonic sign of meningeal irritation and is defined as passive resistance to neck flexion. Kernig and Brudzinski signs are also classic signs of meningeal involvement. The Kernig sign is elicited when the patient is supine, the thigh is flexed at a right angle to the trunk, and the leg is extended at the knee. The sign is positive when resistance to leg extension occurs due to meningeal irritation. Brudzinski sign is positive when a patient in the supine position has spontaneous flexion of the hips and knees following passive neck flexion. Although highly specific, they both lack sensitivity, so their absence does not exclude the diagnosis. In a prospective study of 297 adults with suspected meningitis, these two signs had a sensitivity of only 5% (78).

Streptococcus pneumoniae is the meningeal pathogen in 50% to 70% of individuals with community-acquired bacterial meningitis, and as such Streptococcus pneumoniae is the most common etiological organism outside the neonatal period (16). The most vulnerable populations are young children and adults older than 65 years of age, when immunity is most likely to be reduced. Major risk factors for developing pneumococcal meningitis include sinusitis, otitis media, and pneumonia. Cough and dyspnea are common systemic complaints, and chest radiography will demonstrate consolidation in those with lobar pneumonia. Immunosuppression due to HIV, cancer, long-term use of immunosuppressive agents (eg, transplant recipients), and individuals with deficiencies of complement or immunoglobulin G (IgG) are high-risk populations for developing pneumococcal meningitis. It should be noted that the classic signs of bacterial meningitis, such as meningismus, may not be present in immunocompromised patients, older adults, or children. Recurrent bacterial meningitis occurs in 6% of episodes and is most commonly caused by Streptococcus pneumoniae and seen more commonly in patients with otitis, sinusitis, and CSF leakage (77).

The second most common organism associated with bacterial meningitis is Neisseria meningitidis. The classic triad of fever, meningismus, and headache is present in only one third of individuals with meningococcal meningitis compared to nearly 60% in pneumococcal meningitis (41). Distinguishing systemic features of meningococcal infections, including septic arthritis and meningococcemia, may be present but are certainly not universally present. Septic arthritis is seen in 7% of adults with bacterial meningitis, and the most common cause was meningococcus (91). It is important to diagnose concomitant septic arthritis as it requires surgical drainage and a longer course of antibiotic therapy. Disseminated intravascular coagulation may occur with the breakdown of blood vessel walls and the development of a classic petechial rash. In addition to a petechial rash, a maculopapular or purpuric rash may also develop. This distinguishes meningococcal meningitis from Streptococcus pneumoniae or Haemophilus influenzae meningitis, where rashes are rarely observed. The overall specificity of a rash, when present, for meningococcal meningitis is 80% to 90%, with false positives likely attributed to individuals with other infectious etiologies, such as enteroviral meningitis or spotted fever rickettsioses (40).

Listeria monocytogenes is a gram-positive bacillus that causes meningitis in infants, the elderly, and immunocompromised individuals. Neurolisteriosis occurs in immunosuppressed individuals in 86% of cases in the Monalisa study (26). Neonates comprise one third of all patients with meningitis due to Listeria monocytogenes (49). Infection typically occurs transplacentally from maternal bacteremia, although acquisition during vaginal delivery can also occur. Neonates present with sepsis on the first or second day of life, along with fever and irritability. After the neonatal period, listeriosis is rarely observed in children. Outbreaks of Listeria monocytogenes infection in adults are associated with consuming unpasteurized dairy products, soft cheeses, deli meat, and seafood. Classically, listeriosis will produce a prodromal diarrheal illness before the development of meningitis. Meningitis due to Listeria monocytogenes may have fewer classic signs or a subacute presentation than meningitis due to other pathogens. For example, patients may present with confusion earlier in the course but may have a much milder, or even absent, stiff neck (61). Additionally, movement disorders, such as myoclonus, tremor, or ataxia, are present in 15% to 20% of patients and can be a distinguishing diagnostic clue (54). Another differentiating feature is brainstem encephalitis (rhombencephalitis) with involvement of the pons and medulla, which occurs in 17% of nonpregnant patients with Listeria monocytogenes meningitis (26). Lower cranial neuropathies, particularly facial paresis, cerebellar signs, and decreased level of consciousness due to involvement of the reticular activating system, are common with rhombencephalitis. In a large multicenter French study, the presence of bacteremia and the use of adjunctive steroids were associated with higher mortality (26). A follow-up observational study from the Netherlands also showed bacteremia and age as a risk factor for adverse outcomes, but steroids were associated with decreased mortality (17).

Haemophilus influenzae is a gram-negative encapsulated organism that is spread via respiratory droplets. Symptoms initially begin with an upper or lower respiratory infection that spreads by bloodborne dissemination to the meninges. Meningitis due to Haemophilus influenzae type b is no longer a common cause of meningitis in children due to successful vaccinations but is a causative organism of bacterial meningitis in older adults.

Staphylococcus aureus is a gram-positive bacterium that is the etiological agent of meningitis related to recent neurosurgical procedures, head trauma, or central nervous system (CNS) shunt devices, and as a result of hematogenous dissemination from systemic infections such as pneumonia, endocarditis, urinary tract infections, or skin infections. S. aureus can present with community-acquired bacterial meningitis with concomitant endocarditis, endophthalmitis, or vertebral discitis and is associated with an inpatient mortality of 35% (88). Most patients who develop meningitis as a result of hematogenous dissemination have underlying conditions such as cardiovascular disease, cirrhosis, immunosuppression, or a history of intravenous drug abuse (31). Meningitis develops acutely and progresses rapidly with high fever and an altered level of consciousness. Focal neurologic signs are common.

Additional organisms that cause bacterial meningitis are uncommon and largely anaerobic species. This includes Fusobacterium, Bacteroides, Actinomyces, Peptostreptococcus, and Cutibacterium species. These organisms are found most commonly in children of mothers with amnionitis or in adults with infections of the ears, nose, or lungs or CNS shunt infections (11).

Prognosis and complications

Before the advent of antibiotics, mortality in bacterial meningitis often exceeded 90%. Today, mortality rates are much lower but overall remain high, signifying the seriousness of the condition. Mortality is highest in pneumococcal meningitis, where rates are at least 20% in high-income countries and as high as 50% in low-income countries (55). Comparatively, meningococcal meningitis has a much lower mortality rate, with rates less than 10%, regardless of socioeconomic status (71).

Despite the precipitous decline in mortality, sequelae occur in many survivors. Approximately 50% have neurologic deficits that exist on a spectrum of mild and transient to severe and permanent. Focal neurologic deficits most often occur with pneumococcal meningitis and are commonly associated with vascular abnormalities (eg, vasculitis, cerebral sinus venous thrombosis, delayed cerebral injury, mycotic aneurysm) (27; 35), ischemic infarction, subdural empyema, cerebral abscess, or intraparenchymal hemorrhage (72). Focal neurologic deficits such as aphasia, ataxia, or hemiparesis occur in up to 10% of survivors (55).

Sensorineural hearing loss is also common with bacterial meningitis, particularly in children with pneumococcal meningitis and coexisting otitis media. Hearing loss is often permanent and results from bacteria and inflammatory cytokines migrating from the meninges to the cochlea with the resultant destruction of hair cells (55). The use of adjunctive dexamethasone decreases this complication, particularly in children with pneumococcal meningitis.

Cognitive impairment occurs in up to one third of adult survivors with deficits in multiple domains, including attention, memory, and executive function (44). However, the largest contributor to cognitive impairment is decreased processing speed, which remains stable once the meningitis resolves. The likelihood of developing cognitive impairment does not differ between pneumococcal and meningococcal meningitis. In children, it is common for underachievement in school to occur, though a minority will demonstrate improvement over time.

Seizures occur in approximately 20% of patients, usually at the onset or within the first several days of the illness, and are considered a poor prognostic indicator (83). Survivors of meningitis develop epilepsy as a consequence of the illness 10% to 20% of the time, thus necessitating long-term antiepileptic drug therapy.

Clinical vignette

A 35-year-old man was under the care of a rheumatologist for 6 months of fever of unknown origin when he presented to the emergency room for evaluation of fever, headache, vomiting, and pain with passive flexion of his neck. On initial evaluation, he had a temperature of 38.50 C, meningismus, and photophobia, but his level of consciousness was normal. A CBC and blood cultures were obtained, and he was treated empirically for bacterial meningitis and herpes simplex virus encephalitis with dexamethasone, a third-generation cephalosporin, vancomycin, and acyclovir. Over the course of 2 hours, he became obtunded. Head CT demonstrated no evidence of cortical edema, and the fourth ventricle appeared normal. Spinal fluid analysis demonstrated an opening pressure of 450 mmH₂O, 612 WBCs/mm³ with a predominance of polymorphonuclear leukocytes, glucose concentration of 0 mg/dL, and a protein concentration of 286 mg/dL. Gram stain demonstrated gram-positive bacteria in pairs and culture grew Streptococcus pneumoniae. His hospitalization was complicated by a left temporal parietal intraparenchymal hemorrhage affecting language. Over the course of several years, he regained language such that he could communicate with his family but not to the degree where he could return to work.

Predisposing conditions must be sought in patients with no known predisposing or associated conditions for bacterial meningitis. This patient did not have pneumonia, sinusitis, or otitis media. He had not recently had a neurosurgical procedure. Immunoglobulins and complement levels were sent, and a deficiency of complement was detected, which explained his fever of unknown origin and was the predisposing condition that put him at risk for bacterial meningitis.

Biological basis

Etiology and pathogenesis

The initial step in the pathogenesis of bacterial meningitis is colonization, most often of the nasopharynx, followed by either contiguous spread of infection or bloodborne dissemination. Once the organism traverses the blood-brain or blood-choroid plexus barrier and establishes infection, the pathophysiological mechanisms that lead to the neurologic complications begin.

S pneumoniae is a gram-positive, catalase-negative, and alpha-hemolytic bacteria. As the bacterium initially colonizes the nasopharynx, antecedent illnesses with pneumonia, otitis media, and sinusitis are common in pneumococcal meningitis. In a study of 2,548 adults with bacterial meningitis, otitis was present in 27% of patients, with Streptococcus pneumoniae being the leading pathogen (88%) (27; 65). Colonization is mediated by hundreds of surface proteins that act as adherence factors (59). These proteins include pneumococcal surface adhesion A (PsaA) and choline-binding protein (CbpA), which allow the bacterium to adhere to cells in the nasopharynx (37). Other important factors for nasopharynx colonization include neuraminidase NanA, which decreases the viscosity of the mucus, thus exposing cell receptor targets, and immunoglobulin (Ig) A protease, which is necessary to diminish mucosal host cell defense (66; 79).

Once S pneumoniae is attached to nasopharynx receptors, pneumolysin is released by the bacterium and binds to nasopharynx membranes, creating transmembrane pores (43). In addition, pneumolysin interferes with cellular immunity by preventing chemotaxis of polymorphonuclear leukocytes that mediate local bactericidal activity (63). The organism can either directly invade the CNS via contiguous spread or enter the bloodstream and spread to the CNS hematogenously.

N meningitidis is a gram-negative diplococcus that can disseminate through the bloodstream and avoid immune surveillance through a combination of capsular polysaccharides, outer-membrane proteins, and endotoxins (73). The bacterium is found in the nasopharynx in up to 20% of healthy individuals (21). The likelihood of acquisition is determined by age, close contact with an infected individual, and lifestyle factors such as smoking (82). The bacterium is spread through inhalation of aerosolized droplets or saliva, and the organism attaches to nasopharynx epithelium before invading. Meningococcemia, where the bacterium enters the bloodstream, can occur with resultant vascular injury, endothelial necrosis, and disseminated intravascular coagulation.

L monocytogenes is a facultative intracellular gram-positive bacillus that has a predilection for neonates, pregnant women, and the immunocompromised. It is typically acquired by foodborne transmission (18). The neonate acquires the bacterium from the mother’s genitourinary tract during vaginal delivery or via transplacental transmission. Direct invasion of brain endothelial cells occurs during bacteremia.

Bacteria, such as pneumococcus and meningococcus, may reach the subarachnoid space either from a contiguous source (eg, otitis, sinusitis) or hematogenously. After nasopharyngeal colonization, bloodstream invasion is followed by crossing the blood-brain barrier at the choroid plexus of the lateral ventricles (83). Once access to the subarachnoid space occurs, there is bacterial multiplication. Antibiotic-induced lysis of bacteria causes the release of bacterial cell wall components. This includes peptidoglycan and lipopolysaccharide that stimulate the production of inflammatory cytokines by microglia, astrocytes, endothelial cells, and white blood cells in the CSF. The result is leptomeningeal inflammation.

The best-studied cytokines include interleukin-1 and tumor necrosis factor-alpha, which act together to increase the blood-brain barrier permeability. This subsequently results in vasogenic edema as well as leakage of plasma proteins into the CSF, forming a purulent exudate in the subarachnoid space. The exudate can both diminish the resorptive ability of arachnoid granulations and obstruct CSF flow through the ventricles, leading to communicating and obstructive hydrocephalus, respectively. The purulent exudate can also cause vasculitis, leading to cerebral ischemia. If cerebral ischemia results in infarction, then cytotoxic edema will occur. The combination of vasogenic and cytotoxic edema increases the likelihood of developing increased intracranial pressure. In addition, both the bacteria and cytokines cause the production of reactive oxygen and nitrogen species (ie, free radicals) that induce apoptosis in neurons. As a result, dexamethasone is utilized in the clinical setting, given its ability to inhibit tumor necrosis factor-alpha and interleukin-1, thus decreasing the inflammatory response and its subsequent complications. Even though the efficacy of adjunctive dexamethasone is clear in adults with pneumococcal meningitis, emerging data from the Netherlands also show a benefit in non-pneumococcal meningitis (84). A controversy exists in Listeria meningitis as a French study showed increased mortality with steroids, but a follow-up Dutch study showed a mortality benefit (26; 17).

Epidemiology

The etiological organism most likely to cause bacterial meningitis is highly dependent on age. In the neonatal period, Streptococcus agalactiae (group B streptococcus) and Escherichia coli are the most common meningeal pathogens worldwide, followed by Listeria (38). In children outside the neonatal period, S pneumoniae and N meningitidis predominate. In adults, pneumococcus and meningococcus cause approximately 85% of all bacterial meningitis, with pneumococcus causing up to 70% of community-acquired meningitis (87). Listeria monocytogenes is the third most common meningeal pathogen and is typically seen in the elderly, neonates, and immunocompromised patients.

Bacterial meningitis occurs in a higher frequency in patients with immunodeficiency, whether inborn or acquired, and those with anatomic defects affecting barriers to the CNS (01). Populations include children less than 2 years of age due to an immature immune system, elderly patients (greater than 65 years of age) due to immunosenescence, and conditions that reduce immunity such as asplenia (eg, sickle cell disease), diabetes mellitus, HIV, cancer, and the use of immunosuppressive agents in transplant recipients or in patients with autoimmune conditions (89). In addition, dural disruption with leakage of cerebrospinal fluid (CSF) following surgery or head trauma also greatly increases the risk of developing bacterial meningitis. If a patient develops recurrent meningitis, a search for anatomic defects causing CSF leaks should be undertaken with neuroimaging in conjunction with ear, nose, and throat consultation (77).

The epidemiology of bacterial meningitis has shifted significantly over the past several decades. This has partly occurred due to the effectiveness of vaccines against Haemophilus influenzae type b and, most recently, against Streptococcus pneumoniae and Neisseria meningitidis (38). A United States study of bacterial meningitis between 1997 and 2010 showed that S. pneumoniae and N. meningitidis are the most common causes, accounting for 43% and 25% of all cases, respectively (20). The incidence of both pneumococcal and meningococcal meningitis during the study period decreased most likely due to the introduction of the pneumococcal conjugate vaccine PCV-7 (2000) and by the quadrivalent meningococcal (A, C, Y, and W135) conjugate vaccine (2005). Another study of 1412 adults with bacterial meningitis in the Netherlands from 2006 until 2014 also documented that S. pneumoniae and N. meningitidis are the most common etiologies (51% and 37%, respectively) (08).

The highest incidence of bacterial meningitis remains in sub-Saharan Africa at 10 to 40 per 100,000 persons. In contrast, the incidence in the United States and Europe ranges from 1 to 7 per 100,000 persons (16). In sub-Saharan Africa, outbreaks of meningococcal meningitis are particularly common, where serotype A affects up to 1000 individuals per 100,000 population each year. With the introduction of meningococcal vaccination against serogroup A, the most common serogroup in Africa, the incidence of meningococcal meningitis dropped nearly 60%. However, this was followed by an increase in serogroup W and serogroup C with a current incidence of meningococcal meningitis that is similar to the incidence before serogroup A vaccine introduction (80).

The most common cause of meningococcal meningitis in Europe is serogroup B, whereas serogroup Y is the most common in the United States. Initially, a vaccination against serogroup C was developed in Europe following a significant increase in incidence in those countries. Although this resulted in a near disappearance of serogroup C meningitis, a surge in other serogroups occurred, most notably serogroup W (92). Shortly thereafter, a quadrivalent serogroup A, C, W, and Y vaccine was introduced, and the overall incidence of meningococcal meningitis again decreased (19).

Notable groups at risk for meningococcal meningitis include individuals with deficiencies in immunoglobulins, such as agammaglobulinemia or complement deficiency, along with young adults in close contact, such as those living on military or college campuses. Vaccine requirements at these institutions have greatly reduced the incidence of meningococcal meningitis outbreaks.

Prevention

There are vaccinations for the two most common causative organisms of bacterial meningitis, pneumococcus, and meningococcus. The Centers for Disease Control and Prevention recommends routine pneumococcal conjugate vaccine (PCV13) for all babies and children younger than 2 years of age. The pneumococcal polysaccharide vaccine (PPSV23) is recommended for all adults 65 years of age or older, persons aged 2 through 64 years of age with underlying chronic medical conditions, and adults 19 through 64 years of age who smoke cigarettes (24). Most recently, in June 2021, the pneumococcal 20-valent conjugate vaccine (PCV20) was approved to be used in adults 18 years and older. Chronic medical conditions with the highest risk for pneumococcal disease are cardiopulmonary diseases such as chronic obstructive pulmonary disease and congestive heart failure, renal disease, diabetes mellitus, splenectomy, and those with immunocompromised states such as those with hematological cancers, HIV, or on immunosuppressive drugs (64).

The meningococcal conjugate vaccine (MenACWY) is recommended on a routine basis for all preteens and teens at 11 to 12 years of age, with a booster dose at 16 years of age (23). This vaccine covers the four most common serotypes of meningococcus (A, C, W135, and Y) and is a requirement at most colleges and universities in the United States. Persons aged 10 years or older with an increased risk of meningococcal disease are also advised to receive routine vaccination. In addition, the CDC recommends two serogroup B meningococcal (MenB)vaccines for patients older than 10 years of age at risk for meningococcal disease. Lastly, a pentavalent vaccine (ABCWY) is now available and recommended as an option for patients older than 10 years who are getting both the MenACWY and the MenB vaccines.

As outbreaks of meningococcal meningitis often occur in close quarters such as dormitories and military barracks, individuals not previously vaccinated should be treated with chemoprophylaxis when in close contact with an individual with meningococcal meningitis. The recommended chemoprophylactic agent is rifampin 600 mg twice daily for 2 days. Children older than 2 years of age can be treated with rifampin 10 mg/kg twice daily for 2 days or a with a single intramuscular injection of ceftriaxone 125 mg. Rifampin should be avoided in pregnant women, given its teratogenic properties. Pregnant and lactating women, along with children under 2 years of age, should be given intravenous or intramuscular ceftriaxone in a single injection of 250 mg for adults and 125 mg for children.

Vaccination of infants for Haemophilus influenzae type b begins at 2 months of age.

Differential diagnosis

Associated or underlying disorders

Viral meningitis is the leading consideration in the differential diagnosis of bacterial meningitis. The clinical features of fever, headache, and meningismus occur in both conditions, prompting the need for empiric antimicrobial therapy and diagnostic work-up with lumbar puncture and CSF analysis. Once CSF studies have excluded bacterial meningitis, either by culture or potentially by risk score (see below), antibiotics can be discontinued. Classically, CSF studies in viral meningitis will demonstrate a lymphocytic pleocytosis (100 to 1000 cells/mm³) with normal or mildly elevated protein and normal glucose concentrations. The key clinical difference is the presence of an altered or decreased level of consciousness in bacterial meningitis, in addition to focal neurologic deficits and seizures, which are absent in viral meningitis. Furthermore, a risk score was derived and validated to differentiate bacterial meningitis from viral CNS infections. Patients were considered to be a low risk for bacterial meningitis if none of the following conditions were present: serum white blood cell (WBC) >10.0 x109/L, CSF WBC>2000 per mm3, CSF granulocyte count >1180 per mm3, CSF protein >220 mg/dl, CSF glucose <34 mg/dl, and fever on admission. This risk score had a 99.6% to 100% sensitivity in identifying low-risk subgroups for bacterial meningitis (88). Viral meningitis can be managed symptomatically, with the exception of meningitis due to herpes simplex virus or varicella-zoster virus. In those patients, acyclovir, valacyclovir, or famciclovir can be used. Given the benign and self-resolving nature of viral meningitis, the outcomes are typically excellent.

Another important consideration is herpes-simplex virus encephalitis, which will also present with headache, fever, and altered mentation. In addition, in herpes-simplex virus encephalitis, there can be behavioral abnormalities, seizures, and focal neurologic deficits such as aphasia or hemiparesis. The presentation is often less acute than bacterial meningitis and evolves over a period of several days to a week. Imaging is particularly useful in herpes-simplex virus encephalitis with MRI T2-FLAIR and DWI sequences demonstrating hyperintensities and diffusion restriction in the medial and inferior temporal lobe, inferior frontal lobe, thalamus, and insular cortex (07). These lesions typically begin unilaterally and remain asymmetric if contralateral involvement occurs.

CSF analysis with polymerase chain reaction (PCR) is considered the gold standard for diagnosing herpes-simplex virus encephalitis (76). CSF studies show a moderate lymphocytic pleocytosis (100-500 cells/mm³), although a neutrophilic pleocytosis early in the course can occur, with elevated protein and normal glucose concentrations. PCR is a highly reliable test with a sensitivity of 96% and specificity of 99%, although a negative result within the first 72 hours of symptom onset can occur, particularly in immunocompromised patients (10). If clinical suspicion remains high, repeat lumbar puncture with PCR testing 72 hours later should be performed (70) but, unfortunately, is done in only 14% of patients with encephalitis (69).

In the summer and early fall months, arthropod-borne virus (ie, arbovirus) encephalitis should be considered in the differential diagnosis of bacterial meningitis. Mosquitoes are the primary vector for arboviral infections, which are often preceded by a prodromal syndrome of fever, malaise, myalgias, and nausea and vomiting that is similar to infection with influenza. This is followed by headaches, confusion, decreasing levels of consciousness, and seizures. West Nile virus is the most common arbovirus in the United States and is ubiquitous (51). Unfortunately, West Nile virus is underdiagnosed as only one third of patients with meningitis or encephalitis get tested for it (90). Patients with West Nile virus may have conjunctivitis or a maculopapular rash. Neuroinvasive disease may also present with flaccid paralysis, similar to a polio-like syndrome, or movement disorders such as myoclonus, tremors, or parkinsonism from resultant basal ganglia involvement. Lastly, approximately 50% of patients with West Nile virus encephalitis have concomitant retinopathy (39).

In arthropod-borne flavivirus encephalitis, including West Nile virus, St. Louis encephalitis virus, and Japanese encephalitis virus, symmetric, bilateral T2 hyperintensities in the basal ganglia and thalami with extension into the brainstem or subcortical white matter may be seen on magnetic resonance imaging (75).

All arboviral infections are diagnosed by lumbar puncture with CSF analysis. CSF may show a neutrophilic pleocytosis very early in the course that will evolve into a moderate lymphocytic pleocytosis of several hundred cells, along with normal glucose and protein concentrations. Diagnosis is made by demonstration of IgM antibody to the particular arbovirus in the CSF or a four-fold or greater rise in antibody titers between acute and convalescent serum samples taken 4 weeks apart (22). In immunosuppressed individuals, such as those with a solid organ transplant, a CSF West Nile virus PCR can be used in the diagnosis (46).

Subarachnoid hemorrhage is a differential diagnosis of bacterial meningitis and will commonly present with meningismus, headache, altered mentation, and occasionally fever. However, the sudden onset with maximal severity of the headache (“thunderclap” headache) and the presence of blood in the subarachnoid spaces on head CT quickly distinguishes subarachnoid hemorrhage from infectious meningitis. If blood is not present on the initial head CT, a lumbar puncture should be performed to look for xanthochromia. The presence of xanthochromia, a yellowish supernatant due to red blood cell breakdown obtained from a centrifuged CSF sample 6 to 12 hours after a subarachnoid hemorrhage occurs, is diagnostic.

Additional differential diagnosis considerations include focal intracranial mass lesions such as a brain abscess, subdural empyema, or epidural abscess. In addition to fever, these will commonly present with focal neurologic deficits and seizures and will be visible on MRI. Fungal and tuberculosis meningitis present more insidiously than bacterial meningitis, with a CSF profile of lymphocytic pleocytosis with a decreased glucose concentration and elevated protein concentration. Neurosarcoidosis and leptomeningeal carcinomatous should also be considered as part of the differential diagnosis of bacterial meningitis.

Diagnostic workup

The mainstay for diagnosis of bacterial meningitis remains CSF analysis. An opening pressure should be obtained with the patient in the lateral recumbent position. Typical tests include CSF white blood cell count with differential, red blood cell count, protein and glucose concentrations, Gram stain and bacterial culture, and PCR assays. Head imaging is often obtained before lumbar puncture because of concern for cerebral herniation, although studies have shown lumbar puncture to be safe for most patients (29). Nonetheless, it is recommended to obtain a noncontrast head CT before lumbar puncture in patients with new-onset seizures, immunocompromised state, neurologic deficits on examination, papilledema, or a decreased level of consciousness (28). Once head imaging has excluded a space-occupying lesion, lumbar puncture can be safely pursued. Antimicrobial therapy and adjunctive dexamethasone should be given before the lumbar puncture if a CT scan is ordered.

CSF culture is the gold standard for diagnosing bacterial meningitis and providing susceptibilities to guide antimicrobial therapy. The specificity is nearly 100%, although sensitivities can vary broadly depending on the causative organism. For example, Listeria monocytogenes has a sensitivity as low as 40%, whereas Haemophilus influenzae has a sensitivity as high as 97% (09). Gram stain is positive in 50% to 75% of individuals with bacterial meningitis (31; 62).

The likelihood of obtaining a positive CSF culture depends on the timing of antibiotic initiation. Culture is positive in 85% before antibiotic administration, approximately 75% when obtained less than 4 hours after antibiotic administration, approximately 10% when obtained between 4 and 8 hours, and 0% after 8 hours (57). These values are highly influenced by the causative etiologic organism, as Streptococcus pneumoniae can grow in culture up to 8 hours after antibiotic initiation, whereas Neisseria meningitidis cultures are sterilized within 2 hours of antibiotic initiation. Despite the fact that antibiotics lower culture sensitivities, antibiotics should never be delayed, given the significant increase in mortality that can ensue with even a few hours of delay (50).

Blood cultures are also useful in identifying the meningeal pathogen. Most important is acquiring two sets of blood cultures before antibiotic initiation, as a positive result is obtained 50% to 80% of the time (14). C-reactive protein and procalcitonin should also be obtained as they have excellent positive predictive values in differentiating bacterial and viral meningitis (42). Brain MRI with and without gadolinium should be performed to demonstrate the complications of bacterial meningitis, such as ischemic infarction, cerebral edema, venous sinus thrombosis, and hydrocephalus, for these complications to be treated.

The CSF white blood cell count will demonstrate a significant pleocytosis with a predominance of polymorphonuclear cells (86). A lower-than-expected white blood cell count in the CSF can occur in immunosuppressed patients, particularly those on immunosuppressive agents or individuals who are neutropenic or septic (89). CSF white blood cell count and glucose concentration begin to normalize after 3 days of antibiotic therapy, with an 84% reduction in CSF pleocytosis between day 3 and 7 (30). A low glucose concentration (hypoglycorrhachia) is defined by a CSF glucose concentration of less than 40 mg/dL. This should be adjusted for the serum glucose concentration with a CSF to serum glucose ratio of 0.60 or greater being normal. A ratio of less than 0.40 is considered worrisome for bacterial meningitis, with a ratio less than 0.31 seen in approximately 70% of cases of bacterial meningitis (06). The CSF and serum glucose levels should be tested concomitantly or obtained within 60 minutes of each other to be reliable, but this only occurs in only 14% of patients (74). CSF protein concentrations are often elevated to greater than 100 mg/dL, although this is a nonspecific finding. The opening pressure is increased to greater than 18 cm of water in most patients.

Although the meningeal pathogen may not grow in culture, PCR assays are now available to detect bacterial nucleic acid in the CSF. The first bacterial PCR assay used a 16S rRNA conserved sequence that could detect small numbers of viable and nonviable organisms in the CSF. When this broad-based PCR was positive, a more specific PCR to detect the nucleic acids of S pneumoniae, N meningitidis, E coli, L monocytogenes, H influenzae, and S agalactiae was utilized.

Individual PCRs have been replaced in many hospitals by CSF pathogen panels that test for multiple organisms simultaneously. The most commonly used PCR panel is the FilmArray Meningitis/Encephalitis panel, which tests for 14 pathogens, including the six aforementioned bacterial meningeal pathogens. This PCR panel has a rapid turnaround time, often less than 1 hour. Importantly, antibiotics do not interfere with the results. Although fairly sensitive and highly specific in validation studies, further studies are still needed for verification as, in some studies, the meningitis/encephalitis panel can have a false-positive rate of up to 3%, particularly for Streptococcus pneumoniae (52; 53).

Metagenomic next-generation sequencing has emerged as an unbiased approach to detect potentially any pathogen with a singular method (93). With this technique, all the nucleic acid in a sample is simultaneously sequenced and then compared to a reference database to identify the organism. Metagenomic next-generation sequencing has the potential for diagnosing difficult cases with uncommon organisms and may also be useful for common organisms if initial culture and PCR assays are negative. Potential limitations include the length of time it takes until results are available and the possibility of false positives due to contamination from the patient’s skin or laboratory reagents (45). Importantly, molecular diagnostic tests do not provide information about bacterial sensitivity to antibiotics, and positive results should be confirmed by a second method, such as culture, singleplex PCR, or serology.

Management

As bacterial meningitis is a medical emergency, all patients with compatible signs and symptoms of bacterial meningitis should have two sets of blood cultures followed immediately by the initiation of empiric antimicrobial and adjunctive therapy. In children and adults up to age 50, empiric therapy should include a combination of a third-generation (ceftriaxone or cefotaxime) or fourth-generation (cefepime) cephalosporin plus vancomycin. Vancomycin is added to cover the possibility of a cephalosporin-resistant strain of Streptococcus pneumoniae. A combination of meropenem and vancomycin can also be recommended. Acyclovir is added to the empiric regimen if there are clinical findings of encephalitis. Ampicillin is added to cover Listeria monocytogenes in children less than 3 months of age, adults older than 50 years of age, and those with chronic illnesses or immunocompromised states. In patients with concomitant otitis media, sinusitis, or mastoiditis, metronidazole is added to cover gram-negative anaerobes. In patients with a recent neurosurgical procedure, cefepime or meropenem should be used in place of ceftriaxone or cefotaxime to adequately cover Pseudomonas aeruginosa. Appropriate dosing of antibiotics in pediatric and adult populations is listed in Table 1.

Table 1. Doses of Antibiotics in Bacterial Meningitis

	Antibiotic	Total daily pediatric dose (dosing interval)	Total daily adult dose (dosing interval)
	Ampicillin	300 mg/kg daily (every 6 hours)	12 g/day (every 4 to 6 hours)
	Cefepime	150 mg/kg daily (every 8 hours)	6 g/day (every 8 hours)
	Cefotaxime	225-300 mg/kg daily (every 6 to 8 hours)	8-12 g/day (every 4 to 6 hours)
	Ceftazidime	150-200 mg/kg daily (every 8 hours)	8 g/day (every 8 hours)
	Ceftriaxone	80-100 mg/kg daily (every 12 hours)	4 g/day (every 12 hours)
	Meropenem	120 mg/kg daily (every 8 hours)	6 g/day (every 8 hours)
	Metronidazole	30 mg/kg daily (every 6 hours)	2 g/day (every 6 hours)
	Vancomycin	60 mg/kg daily (every 6 hours)	45-60 mg/kg daily (every 6 to 12 hours)

Antibiotic therapy is tailored once the pathogen is identified and antimicrobial susceptibilities are determined. Pneumococcal meningitis is treated with 14 days of intravenous antibiotics, meningococcal meningitis with 7 days of intravenous third- or fourth-generation cephalosporin, and Listeria monocytogenes meningitis with 21 days of ampicillin with the addition of gentamicin for synergy as it was associated with decreased mortality in the Monalisa study (26). If no clinical improvement is seen after 48 hours of antibiotic therapy and if it is safe to perform a lumbar puncture, a repeat CSF analysis is indicated to ensure eradication of the organism (30). If a pathogen is not determined from bacterial culture or PCR assays, then empiric coverage should be continued for 14 days.

In addition to antibiotics, adjunctive therapy with dexamethasone should also be initiated empirically in patients suspected to have bacterial meningitis. Dexamethasone exerts its effect by inhibiting tumor necrosis factor-alpha and interleukin-1, thus decreasing the inflammatory response (34). Dexamethasone should be administered intravenously at a dose of 10 mg every 6 hours for 4 days. Ideally, the first dose should be administered before or with the first dose of antibiotics (81). Of note, a study of 80 adults with pneumococcal meningitis showed a mortality benefit if corticosteroids were administered up to 12 hours after antibiotic administration, prompting the United Kingdom guidelines to recommend considering this approach (56).

The benefits of dexamethasone have been well established. A randomized controlled trial in Europe demonstrated that adjunctive dexamethasone reduced the mortality risk in pneumococcal meningitis from 34% to 14% (32). Another study in the Netherlands showed that nationwide implementation of dexamethasone decreased mortality from 31% to 17% in pneumococcal meningitis (48). In addition, dexamethasone decreases rates of sensorineural hearing loss in children with meningitis, particularly from H influenzae (13). A favorable trend toward reduced mortality and decreased hearing loss was reported with the use of dexamethasone in patients with meningococcal meningitis (40). Furthermore, adult studies have shown a benefit in patients with non-pneumococcal and non-Haemophilus meningitis (84). One contested debate is Listeria monocytogenes. Although a French cohort study showed increased mortality in adults with neurolisteriosis treated with steroids, a follow-up Dutch study showed a reduction in mortality with adjunctive steroids (Brouwer and van de Beek 2017).

Special considerations

Pregnancy

Pregnant women are at significantly increased risk of infection with Listeria monocytogenes. This is attributed to a decline in cell-mediated immunity during the third trimester of the pregnancy, and the bacterium can replicate directly in the placenta. The result can be premature birth, amnionitis, or neonatal infection, although neonatal meningitis is rare (58). In women with confirmed listeriosis, ampicillin should be given with the addition of an aminoglycoside if amnionitis is present. Incidence among pregnant women and neonates has reduced significantly over the years, likely due to educational programs on food-borne infections (49).

As part of routine prenatal screening, vaginal and rectal swabs are tested for group B streptococcus at 36 to 38 weeks of pregnancy. If the culture is positive, intravenous antibiotics, typically penicillin, are given at the onset of labor. This greatly reduces the risk of the neonate developing group B streptococcus infection within the first week of life (early onset). However, it does not decrease the risk of group B streptococcus infection after the first week of life through the end of the neonatal period (late onset).

There are no recommendations for vaccination in pregnant women to prevent pneumococcal or meningococcal infections. It is unknown whether vaccines cause fetal harm, and there is no evidence that they reduce infant infections (04; 25). If a pregnant woman is exposed to an individual with meningococcal meningitis, prophylaxis with a single dose of intravenous or intramuscular ceftriaxone should be administered.