Aseptic meningitis has multiple etiologies with viral infection being the most common. Hospitalists should recognize atypical features suggestive of an alternative etiology. This case and literature review will focus on an atypical cause.
A 6-year-old previously healthy, fully immunized Hispanic American boy was admitted to the hospital during spring with a 2-week history of headache, vomiting, and fever. He was born in the United States and had never traveled. No one in his home was ill, but a classmate had viral meningitis.
One week into his illness, he was evaluated at an outside emergency department.The results of a noncontrasted cranial computed tomography scan, comprehensive metabolic panel, complete blood count, and C-reactive protein were normal. Lumbar puncture and cerebrospinal fluid (CSF) analysis were significant for lymphocytic pleocytosis with 376 white blood cells, low glucose, elevated protein, negative enterovirus and herpes simplex virus polymerase chain reaction, and subjective increased opening pressure. He was admitted to the outside hospital, treated with empirical parenteral antibiotics until CSF bacterial culture results were negative, and discharged from the hospital with a diagnosis of viral meningitis.
After discharge, his symptoms progressed with the development of diplopia from a new right sixth cranial nerve palsy. He was admitted to a pediatric children’s hospital after reevaluation in the emergency department with a normal findings on noncontrasted cranial computed tomography scan, laboratory tests, and analogous CSF analysis. His diagnosis at admission was viral meningitis.
The patient has aseptic meningitis, but is his clinical course most consistent with a viral etiology or are his progressive symptoms with new cranial nerve palsy suggestive of an alternative, less common cause?
Aseptic meningitis includes all causes of meningitis with negative results from bacterial CSF cultures. Viral infection, notably enteroviruses with late summer and fall seasonal outbreaks, is the most common cause.1,2 Symptom progression, seizures, neurologic deficits, and obtundation are rare other than in certain nonviral infectious causes.1 No single component of the CSF fluid analysis accurately discriminates between bacterial and viral meningitis.3 Hypoglycorrhachia, low CSF glucose, supports a bacterial etiology.2 An elevated serum procalcitonin level (>0.5 ng/mL) is most predictive of distinguishing between bacterial and viral etiologies, but is not universally available.4,5 Lymphocytic meningitis is seen with infectious and noninfectious processes. Infectious etiologies include viruses, Mycobacterium, spirochetes, rickettsia, and fungi as well as less common bacteria such as Listeria. Noninfectious etiologies include autoimmune diseases, malignancies, and medication side-effects.6 The progression and duration of symptoms, cranial nerve sixth palsy, nonenteroviral season presentation, and CSF analysis with lymphocytes, and low glucose and elevated protein concentrations suggested an alternative infectious etiology.
Upon admission, specific questioning disclosed an aunt who had a chronic cough of unknown etiology. Tuberculosis (TB) meningitis was suspected, and empirical therapy with isoniazid, rifampin, pyrazinamide, ethambutol, and prednisone was initiated. He underwent repeat lumbar puncture with a documented elevated opening pressure of 350 mmcH2O (normal, 50–200 mmcH2O) and a large-volume CSF collection of 20 mL (normal collection volume, 3–4 mL). A brain MRI with gadolinium contrast revealed basal enhancement supporting the diagnosis of Mycobacterium tuberculosis meningitis. The results of the tuberculin skin test (TST) were negative. The findings of the Serum QuantiFERON-TB Gold test and CSF M tuberculosis polymerase chain reaction were positive. CSF acid-fast bacilli culture grew pansensitive M tuberculosis after 4 weeks of incubation. Chest radiographic findings were unremarkable. The results of HIV testing were negative. His aunt who had multiple negative TST results before the patient’s presentation, but never had her sputum cultured, was identified as the index case. All immediate family members had latent tuberculosis infection. The patient successfully completed 12 months of treatment with no residual deficits.
Tuberculosis infection is caused by the acid-fast bacillus M tuberculosis. Clinical manifestations of M tuberculosis infection are dependent on the host’s immune response primarily mediated by T lymphocytes and macrophages ranging from asymptomatic infection to active disease. Latent TB infection (LTBI) is described by a positive TST without clinical symptoms, physical examination findings, or radiographic changes. Five to ten percent of cases of untreated LTBI progress to disease.7 TB disease is characterized by clinical or radiographic manifestations with or without a positive TST. Pulmonary disease is most common, but hematogenous dissemination may occur to almost any site. Risk factors for developing TB disease (especially extrapulmonary disease) include immunocompromised conditions, untreated HIV infection, recent LTBI, malnutrition, and age <2 years old.2 In the United States, immigrants of ethnic and racial minorities are disproportionately affected.8
Children acquire infection from contagious adults who are often household contacts. Transmission is via production of airborne respiratory droplets by a person with pulmonary tuberculosis. Contagiousness is directly related to the presence of organisms in expectorated sputum. Children rarely infect others because of low sputum inoculums and weak ineffective cough.9 Each adult with pulmonary TB infects ∼8 to 15 people before receiving a diagnosis and starting treatment.7
Central nervous system infection is the most serious complication of tuberculosis, and is uniformly fatal if not treated appropriately.8,10 Fifty to eighty percent of cases occur in children <5 years of age.11,12 Diagnosis is often delayed because of initial vague symptoms and low clinical suspicion. Clinical outcome is directly related to early diagnosis and treatment. Signs and symptoms are progressive and variable, including fever, headache, vomiting, nuchal rigidity, cranial nerve palsies, seizures, hemiplegia, and altered mental status. Based on a 2009 review of 554 patients, prolonged duration of symptoms and focal neurologic deficits were common with 58% of cases with symptoms present for >1 week, 37% with hemiplegia, and 27% with cranial nerve palsies.12 Imaging most commonly reveals hydrocephalus and basilar enhancement (Figs 1 and 2), but it also may show tuberculomas or vascular infarcts of the basal ganglia and midbrain.
The diagnosis of TB meningitis (TBM) is difficult because of its variable clinical presentation, inconsistent and nonspecific CSF and imaging results, and lack of a reliable rapid diagnostic test. CSF analysis usually reveals lymphocytic pleocytosis (usually <500 cells/mm3),13 low glucose concentration (CSF:plasma glucose <50%), and elevated protein. Elevated opening pressure is seen in 50% cases.10 TST results are negative in up to 50% of cases.11,12,14,15 Isolation of the bacillus in the CSF by culture or on smear remains the gold standard for diagnosis, but the results of CSF cultures are often negative and the cultures are slow growing. Various reviews have reported positive results on CSF smear or cultures in 33% to 64% of cases.11,12,15,16 Serial lumbar punctures to obtain large CSF volumes have been shown to increase the likelihood of recovering the bacteria.10 Nucleic acid amplification tests have demonstrated low sensitivity but high specificity.10 Interferon-γ release assays (IGRAs) such as QuantiFERON-TB Gold test detect M tuberculosis-specific interferon-γ–producing lymphocytes in the peripheral blood. IGRAs do not distinguish between latent infection and active disease, and a negative result does not rule out disease in a symptomatic patient. Currently, IGRAs are only licensed for diagnosing latent TB.10 IGRA data are lacking in children <5 years of age and in immunocompromised patients.17 Neuroimaging is a useful diagnostic modality and should be performed in every case of suspected TBM.10,13
Empirical treatment should include isoniazid, rifampin, pyrazinamide, and ethambutol.7,10,18 Adjunctive corticosteroids increase survival and are recommended in all patients with TBM.10,18,19 The treatment course is 9 to 12 months administered by direct observation therapy to ensure compliance and decrease emergence of antibiotic resistance.7,18 Hydrocephalus may require neurosurgical intervention or diuretic therapy depending on the severity and type, communicating versus noncommunicating.10,12,19 All household contacts should be tested with particular focus on finding the adult infectious case to prevent ongoing disease transmission.18
Morbidity and mortality remain high for TBM in children. Almost 50% of patients experience some permanent neurologic deficit.14,16 Prognosis is directly related to early diagnosis and treatment. Permanent neurologic deficits may include movement disorders, including hemiplegia and quadriplegia, seizure disorders, visual loss, hearing loss, and cognitive impairment.
TBM should be suspected in any child with meningitis associated with prolonged symptoms, cranial nerve palsies, ventriculomegaly, or basilar meningeal enhancement on imaging. A nonreactive TB skin test is common with TBM and should not dissuade the investigation and treatment.
The patient illustrated had a good outcome. In retrospect, good outpatient follow-up after initial hospital discharge may have resulted in a more timely referral and diagnosis.
Tuberculosis meningitis (TBM) commonly presents with lymphocytic pleocytosis, prolonged, progressive symptoms, and focal neurologic deficits. A high degree of suspicion is needed because of its initial vague presentation.
Empirical treatment should be initiated in all cases of suspected TBM, because prognosis is directly related to early treatment.
A brain MRI should be obtained in every case of suspected or confirmed TBM.
Treatment includes finding the adult infectious case to prevent ongoing disease transmission.
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- Copyright © 2012 by the American Academy of Pediatrics