Chronic Meningitis

Epidemiology

Most cases of meningitis due to M. tuberculosis occur in children between 6 months and 4 years of age. ^, Risk factors include close contact with contagious cases, travel to or residence in tuberculosis (TB) endemic areas, human immunodeficiency virus (HIV) infection, other viral infections (i.e., measles), malnutrition, and immunosuppression. Close contact with an adult with pulmonary TB disease can be established in 45%–75% of children; however, the exposure history may not be initially apparent. ^, African Americans and immigrants or adoptees from countries where tuberculosis is endemic account for a disproportionate number of cases of tuberculous meningitis in the US. Large epidemiologic studies including children and adults find that about 1% of tuberculosis disease involves the central nervous system (CNS). ^, However, children are at higher risk for developing CNS tuberculosis. A review of pediatric tuberculosis cases in the US from 1993 to 2017 shows that meningeal infection accounted for 5.4% of all cases and depended on age: 11.2% in those younger than 1 year, 6.4% for 1- to 4-year-olds, 2.9% for 5- to 9-year-olds, and 2.6% for 10- to 14-year-olds.

Pathogenesis

Tubercle bacilli are inhaled, enter the lung alveoli, are filtered into draining lymph nodes, and then are spread lymphohematogenously throughout the body. Meningitis develops when caseous lesions in the brain cortex or leptomeninges rupture into the subarachnoid space. ^,

Clinical Manifestations

The clinical onset of CNS tuberculosis can be acute, but more often, there is a gradual progression of symptoms. CNS tuberculosis usually manifests as meningitis and less frequently as intracranial tuberculoma or a brain abscess. ^, Association with disseminated (miliary) tuberculosis is not uncommon. A compilation of 2,017 children from one large meta-analysis, one retrospective case series, and two prospective case series of CNS tuberculosis identifies common presenting symptoms to be fever (90%), altered mental status (59%), vomiting (64%), seizure (47%), and headache (37%). ^{, ,} Apathy is common, and about 31% of children develop cranial nerve paresis. ^, Death occurs in 19% of children, and 57% of survivors have neurologic sequelae. ^,

Laboratory Findings and Diagnosis

A careful history for tuberculosis risk factors in concert with clinical findings suggests the diagnosis. Abnormalities on chest radiograph consistent with TB are present in about 58% of cases, and tuberculin skin test (TST) or interferon-gamma release assay (IGRA) is positive in about 49% of children. ^, Cranial computed tomography (CT) frequently reveals hydrocephalus and basilar enhancement. ^, CSF abnormalities can be modest initially but become progressively more abnormal with increasing duration of symptoms. The CSF leukocyte count typically ranges from 10 to 500 cells/μL and can briefly show polymorphonuclear cell predominance, but usually, lymphocytes predominate. The CSF glucose level typically is low (frequently <20 mg/dL), and the protein level often is very elevated (>400 mg/dL). Reported positivity of acid-fast bacilli (AFB) stains of CSF range from 5% to 51%. The likelihood of detecting organisms on AFB stain depends on the volume of CSF sampled and the diligence of microscopic evaluations ^, ; large volumes (5−10 mL) of centrifuged CSF and ≥30 minutes of microscopic inspection yield better results. Growth of M. tuberculosis from CSF occurred in 300 of 1106 (27%) children with TB meningitis reported, and yields as high as 70% have been reported when up to 10 mL of CSF is sampled. ^, Gastric aspirate or sputum AFB smear and culture can increase the probability of diagnosis in children. Nucleic acid amplification (NAA) tests, such as polymerase chain reaction (PCR), are commercially available to detect mycobacterial DNA in CSF. A meta-analysis of the accuracy of NAA for diagnosing tuberculous meningitis revealed a sensitivity of 56% (negative predictive value, 44%) and a specificity of 98% (positive predictive value, 35.1%) among commercially available assays. Xpert MTB/RIF, an automated rapid test to detect TB and rifampicin resistance, may be helpful in the diagnosis of tuberculous meningitis, but it appears to be less sensitive than multiplex PCR. ^, The PCR test can remain positive for several weeks after treatment is initiated. Nonetheless, due to the modest sensitivity of Xpert MTB/RIF and PCR for tuberculous meningitis, one should use clinical judgment and not rely solely on the test result to determine if TB treatment should be started.

Epidemiology

Chronic syphilitic meningitis is rare and occurs in <1% of persons with syphilis; the incidence of meningitis is greatest in the first 2 years after T. pallidum infection. Incidence rates of syphilis have increased in the US in recent years, primarily among men who have sex with men. However, congenital syphilis in the US has also surged. Neurosyphilis rarely manifests as chronic meningitis, but partially treated neurosyphilis can imitate chronic meningitis.

Pathogenesis

Congenital syphilis usually occurs by transplacental transmission of T. pallidum into the fetal circulation. Postnatally acquired syphilis develops by penetration by T. pallidum through mucous membranes or abraded skin after direct contact with ulcerative lesions of infected people. The organism disseminates lymphohematogenously and can invade the CNS.

Clinical Manifestations

In children, syphilis usually is congenitally acquired. Most infants do not have symptoms at birth, although those with syphilitic meningitis are more likely to have symptoms than those without meningitis. Common clinical features of congenital infection include ≥1 of the following: hepatosplenomegaly, mucocutaneous lesions, lymphadenopathy, or osteochondritis. About 50% of infants with symptoms of congenital syphilis and 10% of asymptomatically infected infants have CSF abnormalities: a reactive Venereal Disease Research Laboratory (VDRL) test, elevated white blood cell (WBC) count, and/or elevated protein level. Despite CNS infection and abnormal CSF, neurologic signs or symptoms usually are not detectable. Without treatment, congenitally infected infants can develop acute leptomeningitis between 3 and 6 months of age with ≥1 of the following signs: stiff neck, vomiting, bulging fontanel, or hydrocephalus. If untreated, chronic meningovascular syphilis with progressive hydrocephalus, cranial nerve palsies, and/or intellectual deterioration develop by 12 months of age.

About one-third of patients with the early stage of postnatally acquired syphilis have CNS involvement, which may or may not lead to acute meningovascular neurosyphilis. If untreated, one-half of those with CNS infection develop symptomatic or asymptomatic late neurosyphilis. Features of symptomatic late neurosyphilis include dementia, tabes dorsalis, meningovascular disease, seizures, and optic atrophy.

Laboratory Findings and Diagnosis

The diagnosis of syphilitic meningitis can be difficult, as there is no single sensitive and specific diagnostic test. A serum treponemal-specific antibody test is positive in >95% of patients. If this test result is negative, the probability of syphilitic meningitis is very low (except in patients with poorly controlled HIV infection, who may fail to produce antibodies).

Useful tests for CSF samples include the VDRL test, treponemal-specific antibody tests, and PCR. The specificity of the VDRL test on CSF is high, but sensitivity is low (30%−70%). A nonreactive result does not exclude the diagnosis. A false-positive reaction can be due to blood contamination or high CSF protein. In contrast, a negative result of a treponemal-specific antibody test on CSF makes neurosyphilis unlikely, but a positive test does not confirm the diagnosis because false-positive results can occur as a result of CSF contamination with blood or small amounts of antibodies from the serum. The best indicator of CNS infection in neonates is an abnormal physical examination, anemia, thrombocytopenia, CSF abnormalities, and abnormal bone radiographs. Detection of T. pallidum DNA in the blood or CSF by PCR is highly predictive of CNS infection in congenital disease. PCR testing is sensitive for the diagnosis of acute neurosyphilis but is less useful in chronic cases. CSF chemokine CXCL13 level is elevated in neurosyphilis but can also be elevated in other conditions, so its diagnostic value remains to be determined.

Epidemiology

Brucellosis is a zoonotic disease, associated particularly with sheep, goats, swine, and cattle. Humans become infected by direct contact with infected animals or by ingestion of unpasteurized milk products. There does not appear to be an increased risk for patients with underlying diseases. Brucellosis is uncommon in the US, with about 100 cases annually and <10% occurring in children. Brucellosis is a common disease worldwide. A history of travel and consumption of unpasteurized dairy products is important, especially travel in the Mediterranean region, India, or Latin America. Meningitis occurs in fewer than 5% of brucellosis patients and is the first disease manifestation in about 1%. The incubation period varies from <1 week to several months, with an average of 3–4 weeks.

Pathogenesis

Brucella are facultative intracellular pathogens that can survive and multiply within phagocytes and other cells. It is postulated that infected leukocytes carry organisms into the CNS. Another hypothesis is that bacteria enter the CNS through direct endothelial cell invasion.

Clinical Manifestations

Meningitis is the most common presentation of neurobrucellosis. Symptoms are nonspecific and may include fever, headache, myalgia, sweating, vomiting, and meningeal irritation. ^, CSF findings include lymphocytic pleocytosis with a low to normal glucose concentration and high protein concentration. Systemic manifestations of brucellosis may be present. If treated, the prognosis usually is good; however, cases with serious neurologic sequelae are reported. ^,

Laboratory Findings and Diagnosis

Because neurobrucellosis has nonspecific symptoms, it is important to obtain a careful history regarding travel, diet, and animal exposures. CSF lymphocytic pleocytosis with low to normal glucose and elevated protein concentrations is typical. The CSF Gram stain usually is negative. CSF culture is positive in <25% of cases; cultures of blood and, especially, bone marrow increase the diagnostic yield. The laboratory should be advised to maintain the cultures for at least 4 weeks. The diagnosis can be confirmed by detection of specific Brucella antibodies in the CSF or serum by agglutination or enzyme immunoassay (EIA) or Western blot. ^, Promising diagnostic tools include PCR detection of Brucella DNA in the CSF or serum and next-generation sequencing of the CSF.