Tuberculosis Meningitis in an Immunocompetent Patient

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Final diagnosis
Tuberculosis meningitis in an immuno-competent White man without epidemiologic risk factors for tuberculosis.

History of present illness
A 71-year-old man was admitted after presenting with cold-like symptoms for the past 3 weeks. He experienced rhinorrhea, congestion, cough, and a mild headache that had worsened over the past 1 week and was associated with light sensitivity.

His wife also reported worsening confusion, babbling speech, and lethargy over the past few days, as well as fevers at home.

Medical history
The patient’s history was notable for hypertension, aortic stenosis, and atrial flutter.

Key medications
Prior to hospitalization, he was taking amiodarone and apixaban.

Epidemiological history
He works as a masonry contractor and has been exposed to various environmental elements, although he has had no specific recent exposures. He was born in the suburbs of Philadelphia, Pennsylvania, and has lived his entire life there. He denies having lived or worked in rural areas. He has traveled internationally to Western Europe but has never lived abroad. He traveled to Ohio 1 month prior but otherwise has not traveled outside the Philadelphia area. He has had no significant contact with animals.

Physical examination
On admission, the patient was confused and disoriented. He was unable to answer questions or contribute to the history. His temperature was 101.9 °F. His heart rate was 61 beats per minute, blood pressure was 145/72 mm Hg, respiration rate was 18 breaths per minute, and oxygen saturation level was 100% on room air. Upon examination, he had no nuchal rigidity. Overall, he appeared ill. He had an audible systolic murmur and clear lung fields bilaterally. There were no notable rashes. He was confused and lethargic, opening his eyes to verbal stimuli but otherwise not interactive.

Studies
He had an HIV screen and a syphilis antibodies screen, both of which had negative results. Blood cultures collected were also negative. The results from his comprehensive metabolic panel and complete blood cell count with differential diagnosis were normal. Findings of a CT angiography of the head and neck were unremarkable. A chest, abdomen, and pelvis CT showed a punctate 4-mm left upper lobe pulmonary nodule. An MRI of the brain showed no intracranial mass, infarction, or hemorrhage. His respiratory panel was positive for parainfluenza. A CT of the sinuses showed right maxillary sinus disease. Results from a lumbar puncture showed a white blood cell (WBC) count of 563/ μL (normal range, 0-5 cells/uL), with 27% neutrophils, 72% lymphocytes, and 1% monocytes; a red blood cell count (RBC) of 158/μL; a glucose level of 10 mg/dL (normal range, 40-70 mg/dL); and a protein level of 237 mg/dL (normal range, 0-45 mg/dL); no opening pressure was recorded. Results from a meningitis-encephalitis panel were negative. Other pertinent negative testing results included cerebrospinal fluid (CSF), herpes simplex virus 1 and 2, cryptococcal antigen, Venereal Disease Research Laboratory test, JC polyoma virus, varicella-zoster virus, and West Nile virus immunoglobulin G antibodies. Results from a cytology of CSF were negative for malignant cells. Findings from a repeat lumbar puncture showed a WBC of 2/μL, RBC of 50/μL, glucose level of 50 mg/dL, and protein level of 33 mg/dL.

Clinical course
Upon his initial presentation, the patient was started on intravenous vancomycin, ceftriaxone, ampicillin, and acyclovir. He was also started on doxycycline for possible tick-borne illness. His fevers waxed and waned, and his mental status progressively worsened; this prompted a repeat CT of the head, which showed enlarging ventricles. He underwent an external ventricular drain placement. He had a positive result on his QuantiFERON-TB Gold In-Tube test despite having no epidemiologic history or known tuberculosis exposures. His antibiotics were discontinued after results for CSF cultures and a tick-borne illness workup came back negative.

Diagnostic procedures and results
Results from the patient’s CSF acid-fast bacteria (AFB) stain were negative. A Cepheid GeneXpert MTB/RIF polymerase chain reaction (PCR) assay run on CSF detected Mycobacterium tuberculosis (MTB) DNA. He underwent bronchoalveolar lavage with AFB cultures that were positive and MTB-PCR positive. His CSF fluid cultures grew AFB, identified as an MTB complex.

Treatment and follow-up
The patient was started on rifampin, isoniazid, pyrazinamide, ethambutol, and dexamethasone. His mental status remained unchanged, and his treatment team held goals-of-care discussions with his family. His family decided to transition him to comfort-directed care, and he died.

Discussion
Tuberculous meningitis (TBM) is a severe and potentially life-threatening form of meningitis caused by the bacterium MTB. TBM is particularly prevalent in regions with high rates of tuberculosis, such as parts of sub-Saharan Africa and Southeast Asia, but it can also occur in individuals with compromised immune systems or those who are not adequately treated for pulmonary tuberculosis. Cases in immunocompetent individuals without appropriate risk factors are exceedingly rare.¹ The onset of TBM is often insidious, with symptoms gradually worsening over weeks to months; neck stiffness is typically absent, which contributes to difficulty in diagnosing the disease.² Early initiation of antitubercular treatment is a strong predictor of survival from TBM, making early diagnosis crucial in these patients.

Diagnosis of TBM typically involves a combination of clinical evaluation, imaging studies, CSF analysis, and microbiological tests to identify MTB. Although an AFB culture remains the gold standard, testing is often timely and requires more than 2 weeks for results. Ziehl- Neelsen staining can provide rapid results but has a low sensitivity of 10% to 20%.²

The World Health Organization has endorsed the GeneXpert MTB/RIF PCR testing for diagnosis of extrapulmonary tuberculosis.² This modality allows the detection of MTB DNA and rifampin resistance in various bodily fluids, including CSF, within 2 hours. Although the GeneXpert MTB/RIF PCR test is significantly better than AFB staining, sensitivity remains imperfect and false negatives can occur. Research into more effective diagnostic tools and treatment regimens is an important area of focus in the fight against this challenging disease. Additionally, TBM should remain on the differential diagnosis for patients who present with subacute meningitis and a negative infectious workup despite lacking appropriate risk factors or an immunocompetent state.

References

1.Khanna SR, Kralovic SM, Prakash R. Tuberculous meningitis in an immunocompetent host: a case report. Am J Case Rep. 2016;17:977-981. https://doi.org/10.12659/ajcr.900762

2.Méchaï F, Bouchaud O. Tuberculous meningitis: challenges in diagnosis and management. Revue Neurologique. 2019;175(7):451-457.
doi:10.1016/j.neurol.2019.07.007