Meningitis and Encephalitis

Streptococcus pneumoniae

S. pneumoniae remains the leading cause of bacterial meningitis in the United States and in the Netherlands, accounting for 43% and 51% of cases, respectively. ^, S. pneumoniae is most commonly encountered at the extremes of age—that is, in patients younger than 2 years and older than 50 years. Other risk factors include immunocompromised states (drug-induced or related to HIV infection, splenectomy, or hypogammaglobulinemia), alcoholism, and chronic liver and kidney disease. ^, In addition, up to 60% of patients with the disease have a nidus of infection such as otitis, sinusitis, or endocarditis.

Clinically, 60% of patients with pneumococcal meningitis present with the triad consisting of fever, nuchal rigidity, and altered mental status. These patients may present with severe symptoms, including focal neurological deficits, seizures, and cranial nerve palsies, and reportedly one-fifth are admitted to the hospital in a comatose state. Half of patients surviving S. pneumoniae meningitis experience residual neurological complications such as hearing loss, seizures, and cognitive impairment. ^{, , ,}

Pneumococcal meningitis remains as one of the meningeal pathogens with the highest mortality rate. Systemic complications are typically the cause of death in patients older than 60 years, whereas neurological complications are more commonly the cause in pediatric patients. Independent predictors for an unfavorable outcome include low Glasgow Coma Scale score, cranial nerve palsy, raised erythrocyte sedimentation rate, CSF leukocyte count less than 1000 cells/mm ³ , and a high CSF protein concentration on admission.

The mortality of pneumococcal meningitis is 30%, but with the use of adjunctive dexamethasone in high-income countries it has been reduced to 20%. ^, Adjunctive dexamethasone improves outcomes by decreasing inflammation due to bacteriolytic antibiotic therapy and is recommended in adults by the Infectious Diseases Society of America (IDSA), European, and UK guidelines to be given prior to or concomitant with, or within 15 minutes, 4 hours, and 12 hours after the first dose of the antibiotic, respectively. ^{, ,} Because steroids have no proven efficacy in meningitis caused by most other pathogens, and can actually increase adverse outcomes in meningitis caused by Listeria monocytogenes and Cryptococcus neoformans, they should be stopped if the meningitis is not caused by S. pneumoniae in adults or by H. influenzae in children.

Since the emergence of pneumococcal strains with reduced susceptibility to penicillin, the treatment of pneumococcal meningitis has changed. In the United States the prevalence of penicillin-resistant S. pneumoniae ranges from 25% to 50%. For specific recommendations, see the treatment section later in this chapter.

Pneumococcal conjugate vaccines have been developed and proved to be very effective in the prevention of invasive pneumococcal disease, including meningitis. The efficacy of the heptavalent pneumococcal conjugate vaccine (approved in the United States in 2000) has been reported to be as high as 97%. An analysis of population-based surveillance data from eight US sites from 1998 through 2005 found that the incidence of pneumococcal meningitis declined from 1.13 cases per 100,000 in 1998–99 to 0.79 cases per 100,000 in 2004–05. Specifically, the incidence decreased by 64% for patients younger than 2 years, and by 54% for patients 65 years and older, during the study period.

Neisseria Meningitidis

N. meningitidis is a common cause of meningitis in young adults and children (after the neonatal period). The majority of cases are sporadic, and endemic disease in the United States is attributed mainly to serogroups B, C, and Y. Traditionally, individuals living in close quarters, such as military personnel and college students in dormitories, are considered at moderately higher risk for meningococcal meningitis. Meningococcal disease has also been associated with smoking and with deficiencies in the complement system, specifically the terminal components (C5 through C8 and possibly C9). ^{, ,} The use of eculizumab (a terminal complement inhibitor) is associated with a 1000-fold to 2000-fold increased incidence of meningococcal disease requiring meningococcal vaccination and penicillin prophylaxis.

Meningococci invade the subarachnoid space and cause meningitis in up to 50% to 70% of patients with meningococcal disease. The clinical presentation of N. meningitidis has a broad spectrum, ranging from fatigue and fever to frank septicemia. Four clinical syndromes have been described in meningococcal disease: (1) bacteremia without sepsis, (2) meningococcemia without meningitis, (3) meningitis with or without meningococcemia, and (4) meningoencephalitis. ^, An individual patient may progress through each of these syndromes during the disease course. The meningitis triad of fever, neck stiffness, and altered mental status is reportedly present in only 27% of patients with meningococcal meningitis. Prototypical skin lesions (purpura and petechiae) associated with meningococcal disease are found in approximately 60% of adults and 60% to 90% of children with meningococcal meningitis. ^{, ,} The presence of this hemorrhagic rash is classical for N. meningitidis and is considered a hallmark of invasive meningococcal disease.

The mortality of N. meningitidis is 4% to 8% in children and 7% in adults, with septicemia the most common cause of patient fatality. It has been reported that 8% to 20% of meningitis survivors develop neurological sequelae, including sensorineural deafness, mental retardation, and seizures. Additional severe complications of meningococcal disease are Waterhouse-Friderichsen syndrome (a massive hemorrhage into the adrenal glands) and disseminated intravascular coagulation. Current guidelines for meningococcal meningitis recommend the use of penicillin or ampicillin if the penicillin minimum inhibitory concentration (MIC) is <0.1 μg/mL and ceftriaxone or cefotaxime if the penicillin MIC is 0.1 to 1.0 μg/mL. ^,

The meningococcal conjugate vaccine (against serogroups A, C, W, and Y) was approved in 2005 for use in people aged 11 to 55 years, and its administration is recommended to adolescents and first-year college students. ^, A US population-based observational study on data from 1997 to 2010 reported that during that period there was an 83% reduction in the incidence rate for meningococcal meningitis in all age groups. The researchers attributed this sharp decline to widespread vaccination. Unfortunately, this quadrivalent conjugate valent vaccine does not include serogroup B, which now accounts for approximately 70% of all cases of invasive meningococcal disease in 16- to 23-year-olds in the United States. In 2015 the US Advisory Committee on Immunization Practices (ACIP) recommended to administer one of the newly US Food and Drug Administration (FDA)–approved serogroup B meningococcal vaccines in healthy individuals 16 to 23 years of age, but as of 2018 only 17% of 17-year-olds had been vaccinated with these new vaccines. Because meningococcal meningitis is associated with a high risk of secondary infection in close contacts of the affected individual, close contacts are advised to take chemoprophylaxis with rifampin (RMP), ciprofloxacin, or ceftriaxone.

Haemophilus Influenzae

Historically, H. influenzae accounted for approximately 45% of meningitis cases in the United States. ^, The most commonly affected groups were infants and young children (peak age of incidence, 6–12 months). The introduction and widespread implementation of a conjugate vaccine against H. influenzae type b has virtually eliminated cases of H. influenzae meningitis in the United States and Western Europe. ^, A European study reported that prior to introduction of the conjugated vaccine in 1992, the average annual incidence of H. influenzae bacteremia and meningitis was 34.4 cases per 100,000 in children from birth to 4 years, which fell to 3.5 per 100,000 after implementation of routine vaccination. Specifically, the number of meningitis cases was reduced by 92%. The previously mentioned US population-based observational study reported a decrease in the incidence of H. influenzae meningitis across the country from 0.1 per 100,000 people in 1997 to 0.058 per 100,000 in 2010. The profound impact of vaccination is based not only on vaccine-related immunity but also on a subsequent decrease in nasopharyngeal colonization and subsequent herd immunity in unvaccinated participants.

Currently, H. influenzae is isolated in 7% of patients with meningitis. ^, Infection by this bacterium may occur in older children and adults; however, typically it is caused by non–serotype b pathogens. Predisposing conditions for Haemophilus meningitis include diabetes mellitus, asplenic states, alcoholism, and immunodeficiency. ^, Patients may also have a focus of infection, such as otitis media, epiglottitis, sinusitis, or pneumonia. A study describing the characteristics of 4839 adult and pediatric patients with invasive H. influenzae found that underlying conditions were present in 20.7% of the children and 74.8% of the adults. The presence of a lung focus has specifically been reported as a prognostic factor for an unfavorable outcome of meningitis. The most common neurological complication of H. influenzae meningitis is hearing loss, which occurs in 16% of children and 10% to 25% of adults. ^,

Owing to the emergence of chloramphenicol-resistant and β-lactamase–producing H. influenzae strains, third-generation cephalosporins, such as cefotaxime and ceftriaxone, have become the agents of choice for treatment of H. influenzae meningitis.

Listeria monocytogenes

L. monocytogenes is responsible for 2% and 5% of bacterial meningitis cases in the United States and in the Netherlands, respectively. ^, Listeria meningitis predominantly affects neonates and adults older than 50 years. Other risk factors include pregnancy, impairment of cell-mediated immunity, alcoholism, chronic liver and kidney disease, iron overload, malignancy, and immunosuppression after transplantation.

With regard to neonatal meningitis, two forms have been described: (1) early-onset sepsis syndrome, mostly likely acquired in utero and associated with prematurity, and (2) late-onset meningitis, occurring at about 2 weeks of age in term neonates, who likely became infected from the vaginal canal during delivery. A study of 189 patients with neonatal listeriosis documented a reduction in mortality if the mothers were treated with antibiotics at least 1 day prior to delivery. Except for vertical transmission between mother and child and sporadic cross-contamination in neonatal nurseries, Listeria is most commonly transmitted via the ingestion of contaminated food. ^, Several foods have been reported to be contaminated with L. monocytogenes ; rates of recovery of the organism ranging from 15% to 70% have been found for raw vegetables, unpasteurized milk, fish, poultry, and meats.

Clinically, 43% of patients with Listeria meningitis present with classical fever, neck stiffness, and change in mental status. A new focal neurological deficit at presentation has been reported in 37% of patients. These patients have a longer duration of symptoms prior to presentation than those with meningitis due to other pathogens. In the largest prospective study to date, a total of 818 cases of listeriosis was analyzed. For bacteremia and neurolisteriosis, the strongest mortality predictors were ongoing cancer, multiorgan failure, aggravation of any preexisting organ dysfunction, and monocytopenia. Furthermore, in the subset of patients with neurolisteriosis, mortality was higher in bacteremic patients or those receiving adjunctive dexamethasone.

Complications associated with Listeria meningitis include persistent fever, seizures (20%), cardiorespiratory failure (33%), and sepsis (17%). Hyponatremia has been reported in up to 80% of affected patients. Mortality of Listeria meningitis ranges from 15% to 30% in adults. ^{, , ,} The standard approach to the treatment of meningitis due to Listeria is administration of ampicillin or penicillin G, often combined with an aminoglycoside for at least the first week of therapy in proven infection.

Streptococcus agalactiae (Group B Streptococcus )

Group B Streptococcus (GBS) is a common cause of neonatal meningitis. This bacterium has been isolated from vaginal and rectal cultures in 15% to 35% of asymptomatic pregnant women. The child of an infected mother is infected through vertical transmission during delivery. Transmission may also occur horizontally from caregivers and nursery personnel. Obstetric factors associated with neonatal infection include positive result of GBS vaginal culture, premature rupture of membranes, and intrapartum fever. ^, Neonates with GBS meningitis usually have nonspecific symptoms and may have signs of sepsis and meningitis. Respiratory symptoms are common. One large study reported a mortality rate in children of 14% for GBS meningitis, with prematurity, shock, leukopenia, seizures, and high CSF protein level among the predictors of a fatal outcome. Prophylactic treatment with ampicillin during labor for women with positive culture results has been an effective measure in preventing neonatal GBS colonization.

GBS can also cause meningitis in adults, albeit more rarely. Predisposing factors have been reported in 80% of patients. Such risk factors include advanced age (>60 years), diabetes, liver or kidney failure, pregnancy or postpartum condition, malignancy, and collagen vascular disease. The mortality of GBS meningitis is significantly higher in adults, ranging from 25% to 30%. ^{, ,} In a review of 141 adult cases, 30% of patients died, with advanced age and immunosuppressive conditions being the most important risk factors.

Cerebrospinal Fluid Studies

Rapid diagnosis and treatment of bacterial meningitis are critical and reduce patient morbidity and mortality. LP is an essential part of the work-up to enable diagnosis and determination of the responsible pathogen ( Table 57.2

). Antibiotics should be started as soon as possible after the LP is done but should not be delayed if a CT scan of the head is to be performed prior to LP (see Table 57.1 ). Patients with underlying bleeding disorders ideally should undergo hematologic correction of the coagulopathy before LP. Those with suspected increased ICP should undergo cranial imaging of the head before LP. It should be noted that a mass lesion such as epidural abscess, subdural empyema, intracranial abscess, or obstructive hydrocephalus might sometimes be a consequence of bacterial meningitis. The IDSA guidelines recommend that adult patients with a history of a mass lesion, new-onset seizures, focal neurological deficit, papilledema, and/or altered consciousness undergo cranial imaging prior to LP. ^, Obtaining cranial imaging without a clinical indication has no clinical utility, and furthermore 40% of patients with bacterial meningitis who develop cerebral herniation have normal head CT scans. Compliance with the stricter guidelines (UK, European, and Swedish) is approximately 50%. It is actually rare for tonsillar herniation to occur when small amounts of CSF are withdrawn from the lumbar cistern. In a prospective study of 1533 episodes of bacterial meningitis in adults, 47 (3.1%) had deterioration possibly caused by LP, with two patients deteriorating within 1 hour after LP (0.1%).

Characteristic CSF abnormalities include an elevated opening pressure (in 50%), severe hypoglycorrhachia, elevated WBC count, and high protein concentration. The CSF WBC count (typically >1000 cells/mm ³ ) is usually dominated by neutrophils. Lymphocytes predominate in up to 10% of cases. A low CSF WBC count has been associated with poor prognosis. A very high count (>50,000 cells/mm ³ ) should raise the possibility that a bacterial abscess has ruptured into the ventricles. Elevated protein concentrations (>50 mg/dL) are present in 90% of patients. The CSF glucose concentration is usually less than 2.5 mmol/L (normal, 2.5–4.4 mmol/L) or typically less than 40 mg/dL (normal, 40–85 mg/dL); the CSF glucose concentration should always be compared with a simultaneous serum glucose, and that ratio is ≤0.4 in the majority of patients with bacterial meningitis.

The CSF Gram stain procedure is a rapid, inexpensive, and useful diagnostic tool to identify the presence of bacteria in patients with suspected meningitis. It identifies the causative pathogen in 60% to 90% of cases. ^, A cohort study of 696 adults with confirmed meningitis reported the specificity of the Gram stain to be 97%. The higher the bacterial concentration in the CSF, the more likely it is that the procedure will detect the pathogen. The yield of the CSF Gram stain may be slightly reduced in patients previously treated with antibiotics. For example, a European study found that pretreatment with antibiotics reduced the yield of the Gram stain slightly, from 56% to 52%.

CSF culture is the “gold standard” for diagnosis of bacterial meningitis. Results are positive in 80% to 90% of patients with meningitis, depending on the pathogen. ^, As with the Gram stain, treatment with antibiotics reduces the yield of CSF culture. Therefore it is important that CSF be obtained for culture before antibiotics are given to any patient in whom meningitis is suspected.

An elevation in CSF lactate concentration (>35 mg/dL) is another potential aid in the diagnosis of bacterial meningitis. This rapid test has been shown to have high sensitivity (93%) and specificity (96%) for differentiating bacterial meningitis from aseptic meningitis. A systematic review and direct meta-analysis of 25 studies concluded that the diagnostic accuracy of CSF lactate concentration was superior to that of conventional markers, specifically CSF glucose concentration, CSF–to–plasma glucose ratio, CSF protein concentration, and CSF leukocyte number. CSF lactate measurement is limited by the fact that this component is raised in several other neurological conditions, including stroke and trauma. Also, prior treatment with antibiotics substantially reduces the clinical value of CSF lactate measurement, lowering its sensitivity from 98% to 49%.

Serum Inflammatory Markers

Elevation in serum markers of inflammation may also be useful in diagnosis. An elevated (>20 mg/L) C-reactive protein (CRP) value has been shown useful in discriminating meningitis due to bacteria from that of viral etiology. A retrospective study in pediatric patients investigated the value of CRP in distinguishing Gram stain–negative meningitis from viral meningitis. The researchers reported that elevated CRP carried a sensitivity and specificity of 96% and 93%, respectively.

Procalcitonin (PCT) is a precursor of the hormone calcitonin. Its level is typically below the limit of detection in healthy adults but rises in response to proinflammatory stimuli, particularly bacteria. ^, An analysis of retrospective multicenter hospital-based cohort studies involving 198 patients from six pediatric units in five European countries analyzed the utility of PCT as a marker for bacterial meningitis. With a 0.5 ng/mL threshold, the investigators found that the PCT value carries a sensitivity of 99% and a specificity of 83% for distinguishing between bacterial meningitis and aseptic meningitis. Even though these results are impressive, it is important to note that these serum markers are helpful adjuncts but are not diagnostic of bacterial meningitis.

Latex Agglutination Test

The latex agglutination test (LAT) uses latex beads coated with bacterial antibodies or antisera specifically directed against the capsular polysaccharides of causative bacteria. In the presence of the specific antigen, there is detectable agglutination of the latex beads. The LAT has shown high sensitivity in detecting the antigens of common pathogens, specifically 78% to 100% for H. influenzae type b, 59% to 100% for S. pneumoniae, and 22% to 93% for N. meningitidis.

Although the test is simple and rapid, its use in the diagnostic algorithm for bacterial meningitis is controversial owing to the reporting of false-positive results. ^, In addition, the usefulness of the LAT in cases with negative results of CSF Gram staining or culture is very questionable. For LAT to be clinically practical it should be highly sensitive in cases of suspected bacterial meningitis with negative Gram stain or culture results. However, one retrospective review of adult and pediatric patients at an acute-care US hospital showed that for culture-negative meningitis, LAT had a sensitivity of only 7%. Furthermore, the test is significantly hindered by previous antibiotic treatment.

Clinical Models

Several clinical models can help physicians stratify the risk of bacterial meningitis. In children, the Bacterial Meningitis Score identified predictors for a low risk of bacterial meningitis: negative CSF Gram stain, CSF absolute neutrophil count <1,000 cells/mm ³ , CSF protein <80 mg/dL, and peripheral absolute neutrophil count <10,000 cells/mm ³ . In adults, a risk score derived a “zero risk” subgroup for any urgent treatable etiology (e.g., bacterial meningitis, herpes simplex encephalitis, fungal etiology) with 100% sensitivity and was validated in 214 patients with bacterial meningitis. Even though these clinical models exist, the majority of patients with aseptic meningitis are still being admitted and started on empirical antibiotic therapy.

Blood Cultures

Blood cultures should routinely be done in cases of suspected bacterial meningitis. Overall, blood cultures are able to identify the causative pathogen in 50% to 80% of cases. The diagnostic yield of blood cultures is reduced by 20% after prior treatment with antibiotics. ^,

Polymerase Chain Reaction Analysis

Unfortunately, CSF or blood cultures do not always identify the responsible pathogen in meningitis; hence molecular methods are increasingly being used for rapid confirmation of diagnosis. Polymerase chain reaction (PCR) analysis is a nucleic acid amplification test proven to have some value. As a PCR result can be positive in the absence of a positive CSF Gram stain or culture, the UK guidelines recommend obtaining an S. pneumoniae and N. meningitidis PCR analyisis. A multiplex PCR assay with a 94.2% sensitivity and 99.8% specificity is now widely available and can identify 14 viral, bacterial, and fungal causes in 1 hour ( E. coli K1, H. influenzae, L. monocytogenes, N. meningitidis, S. agalactiae, S. pneumoniae, cytomegalovirus [CMV], enterovirus [EV], HSV-1, HSV-2), human herpesvirus type 6 [HHV-6], human parechovirus, varicella-zoster virus [VZV], and C. neoformans/Cryptococcus gattii ). Positive results from this multiplex PCR assay, however, should be interpreted in the setting of a compatible clinical illness.

Radiologic Studies

CT scans of the skull base may also be useful in showing predisposing conditions such as sinus infection, mastoiditis, skull fractures, and congenital anomalies. MRI is superior to CT in evaluation and may show leptomeningeal enhancement and distention of the subarachnoid space. It is important to note that the diagnosis of meningitis is not based on imaging findings. In straightforward cases of bacterial meningitis, early CT and MRI usually demonstrate normal findings, so LP is still the most important diagnostic study. Regarding the complications of severe meningitis, both CT and MRI allow diagnosis of hydrocephalus, infarct, brain abscess, and subdural empyema (or effusion), so one imaging modality should be performed at some point during the hospital stay of any patient being treated for bacterial meningitis ( Fig. 57.1 ).

FLOAT NOT FOUND

Microbiology of Health Care–Associated Ventriculitis and Meningitis

HCAVM is caused by a different spectrum of organisms from those in community-acquired meningitis, as a result of diverse pathogenic mechanisms. Approximately 50% of patients have gram-positive infections (especially Staphylococcus species) and 50% have gram-negative infections (e.g., Enterobacteriaceae, Pseudomonas species). Despite this, antibiotic prophylaxis and antimicrobial-impregnated and antimicrobial-coated shunt catheters (e.g., clindamycin or minocycline with RMP) target only gram-positive organisms. Even though patients with gram-negative HCAVM are generally more ill, there is no difference in clinical outcomes except in centers with a high proportion of multidrug-resistant Acinetobacter infections.