Tuberculous Meningitis or Neurosarcoidosis—a Diagnostic Quandary

Abstract

Distinguishing granulomatous diseases remains diagnostically challenging. Clinical phenotypes and neuroimaging findings resemble many infectious and noninfectious disorders. We describe a Hispanic/Latino man diagnosed with tuberculous meningitis who deteriorated neurologically after treatments. Additional workup revealed a pathology more consistent with neurosarcoidosis. Care access delays and social circumstances likely complicated his diagnosis.

Case Presentation

A 50-year-old Hispanic/Latino man with a medical history of depression presented with left lower extremity weakness 9 years ago and was diagnosed with right basal ganglia stroke. He presented 6 months later with worsening weakness, falls, and urinary incontinence. A nonobstructive hydrocephalus was found on brain MRI. Placement of ventriculoperitoneal shunt improved his ambulation. Two years later, he developed worsening balance and confusion. Repeat brain MRI showed a compressive brainstem mass with noncommunicating hydrocephalus. Pathology of the mass revealed caseating granulomatous inflammation. Acid-fast bacilli (AFB) stains on the brain biopsy were negative. Although the patient was asymptomatic for tuberculosis (TB), T-SPOT TB was positive. He was treated empirically for TB (isoniazid, rifampin, pyrazinamide, and levofloxacin) for 3 months. His confusion resolved and ambulation improved. At discharge, he was using a walker.

Two years later, he presented with 2-week confusion and paraplegia. New brain MRI showed diffuse pachymeningeal and leptomeningeal thickenings extending from basal cistern to midcervical cord (Figure 1, A–B). A longitudinally extensive panmedullary transverse myelitis (LETM) extending from cervicomedullary junction to T2 (Figure 1, C and F) was found on spine MRI. Multiple short-segmented pachymeningeal adhesions within the thoracic cord and clumping of cauda equina were noted (Figure 1, D–E). Infectious and autoimmune workup, including QuantiFERON-TB, mycobacterium tuberculosis (MTB), angiotensin-converting enzyme (ACE), and antineutrophilic cytoplasmic antibodies (ANCA), were unrevealing. A repeat brain biopsy showed fibrous tissues with few nonspecific inflammatory cells. Due to past TB positivity, second TB treatments (isoniazid, rifabutin, ethambutol, amikacin, linezolid, moxifloxacin, cycloserine, and para-aminosalicylic acid) were given. Minimal neurologic improvement was noted. Whole-body PET showed multiple hypermetabolic lymphadenopathies in the cervical, supraclavicular, mediastinal, juxtadiaphragmatic, retroperitoneal, pelvic, and bilateral inguinal chains. Planned admission to expedite workup including lymph node biopsy and treatment was offered, but he was lost to follow-up.

Figure 1. MRI of Brain and Spinal Cord.

(A) Axial T1 postgadolinium MRI of the brain demonstrates diffuse nodular dural thickening and enhancement, most prominent over the right frontal convexity measuring up to 16 mm in maximum thickness. (B) There is leptomeningeal enhancement involving the basal cistern. (C) Sagittal T2 MRI of cervical spine demonstrates longitudinally extensive transverse myelitis spanning from cervicomedullary junction to T2. (D) Sagittal T1 postgadolinium MRI of the thoracic spine demonstrates multifocal areas of contrast enhancement suggesting leptomeningeal infiltration. (E) Sagittal T1 postgadolinium MRI of the lumbar spine demonstrates clumping of the cauda equina with enhancement suggesting arachnoiditis of the cauda equina. (F) Axial T2 MRI of cervical spine demonstrates panmedullary cord involvement.

Four years later, the patient was readmitted to an outside community hospital with acute confusion and unresponsiveness. He was transferred to our center for high level of care. On examination, he was disoriented with time and situation and had global memory impairment. Cranial nerves were intact. He had severe weakness (1+) in the lower extremities. Vibration was reduced, whereas pinprick and light touch were intact. Deep tendon reflexes were diffusely brisk with bilateral Babinski signs.

Elevated ESR (34 mm/h, ref 0–17 mm/h), CRP (18.0 mg/L, ref 0–4.9 mg/L), and ANA (1:160, speckled) were found in the serum. Rheumatologic and autoimmune panels (NMO IgG, MOG IgG, ANCA, myeloperoxidase [MPO], and proteinase 3 [PR3]) were negative. ACE level was normal in the serum but elevated in the CSF (19 U/L; ref 0.1–2.0 U/L). QuantiFERON-TB was negative. CSF analysis showed xanthochromia, elevated protein (>600 mg/dL), low glucose (39 mg/dL; serum glucose 94 mg/dL), and normal white blood cell count. Serum and CSF oligoclonal bands were negative. AFB stains and culture and MTB complex by PCR were negative in the CSF. Cytology showed rare lymphocytes (eTable1, links.lww.com/NXI/A954).

Brain MRI showed interval progression of extensive multinodular leptomeningeal and pachymeningeal enhancement. Spine MRI showed LETM progression (cervicomedullary junction to T10) but unchanged nodular leptomeningeal enhancement and clumping of cauda equina. CT of chest was normal. Mild prominent retroperitoneal lymph nodes were seen on CT abdomen/pelvis but due to the location were not biopsied. Right frontal dura was biopsied instead. Histopathology showed granulomatous inflammation noting rare necrotizing granuloma. CD3⁺ T cells and CD68⁺ macrophages were abundant (Figure 2). Immunochemistry staining for bacterial, fungal, and mycobacterial infections was negative. Fresh-frozen specimen was not sent for MTB PCR or tissue culture.

Figure 2. Histology of Brain Biopsy.

Biopsy of right frontal dura of the patient demonstrates dense fibrous tissue (A) with scattered granulomata (arrowhead) with necrotizing (B) and non-necrotizing (C) centers. Immunohistochemical stains show that within the granuloma there are CD68⁺ macrophages (D) and CD3⁺ T lymphocytes (E).

Differential Diagnosis

This is a 50-year-old Hispanic/Latino man with LETM, subcortical encephalopathy, hydrocephalus, and ischemic stroke. His symptoms were relapsing and progressive in nature. Differential diagnoses include infections, granulomatous diseases, autoimmune disorders, vasculitis, neoplasms, environmental exposures, and genetic causes (Table).

Table.

Differential Diagnostic Considerations of Granulomatous Diseases

Disease classification	Diagnostic considerations
Infectious	Tuberculosis
	Nontuberculous mycobacteriosis
	Syphilis
	Cryptococcus
	Coccidioides
	Histoplasma
	Blastomyces
	Aspergillus
	Lyme disease
Inflammatory	Sarcoidosis
	Necrotizing sarcoid granulomatosis
Vasculitic	Granulomatosis with polyangiitis
	Eosinophilic granulomatosis with polyangiitis
	Polyarteritis nodosa
Autoimmune	Rheumatoid arthritis
	Sjogren syndrome
	Crohn's disease
	Systemic lupus erythematous
Neoplastic	Lymphoma
	Lymphomatoid granulomatosis
	Langerhans cell histiocytosis
Environmental	Hypersensitivity pneumonitis
	Berylliosis
	Silicosis
	Asbestosis
Genetic	Chronic granulomatous disease

Tuberculous involvement of the CNS is a serious manifestation of extrapulmonary TB. The bacilli invade the CNS by hematogenous dissemination, forming small granulomas known as Rich foci in the dura, meninges, brain parenchyma, or spinal cord¹ (Figure 3). Pachymeningitis is because of diffuse dural thickening and enhancement.^1,2 Rupture of a tuberculous focus produces tuberculous meningitis (TBM); leptomeningeal enhancement, particularly in the basal cisterns,¹ can be seen on MRI. Noncommunicating hydrocephalus is a direct complication of TBM with or without tuberculoma.^1,2 Spinal cord shows LETM with arachnoiditis.² Positive serum QuantiFERON-TB or T-SPOT is supportive of TB. Our patient had these features, making TB an attractive diagnostic consideration. Empiric treatment is warranted when clinical suspicion is high, and the patient's initial response to TB treatment supports the diagnosis. The low sensitivity of AFB smear (20%–40%) and prolonged incubation time of CSF culture can make diagnosis of TBM challenging.³ Detecting mycobacterial DNA through PCR improves sensitivity (56%) and specificity (98%).³ However, negative AFB or mycobacterial DNA in the CSF cannot rule out TBM. The imperfections of these diagnostics prompted repeat TB treatment without further improvement seen. This led to considerations of alternative etiologies.

Figure 3. Pathophysiology of Tuberculosis and Sarcoidosis.

Cross-sectional schematic drawing of granuloma formation and pathology in tuberculosis versus sarcoidosis across representative anatomical locations of the CNS. These locations include dura, meninges, brain parenchyma, and spinal cord. Involvement in the base of the skull can lead to hydrocephalus. Illustration by Jill K. Gregory, CMI, licensed under CC BY-NC-ND.

Sarcoidosis is an idiopathic multisystem granulomatous disorder. The nervous system is involved in 5%–10% of cases with sarcoidosis, but additional 10%–15% is discovered on autopsy.⁴ Isolated neurosarcoidosis (NS) is present in 10%–17% of NS without systemic disease.⁴ Like TB, NS favors the base of the skull (basilar meningitis).^4-6 Clinically, it overlaps with TBM and can account for a myriad of neurologic deficits, notably LETM, subcortical encephalopathy, hydrocephalus, and ischemic stroke; all were documented in our patient.^5,6 Panmedullary cord involvement can be seen on MRI.^5,7 LETM is common in many infectious and autoimmune diseases. Coexisting pachymeningitis is, however, more consistent with NS.^5,6

Granulomatosis with polyangiitis (GPA), a rare immune-mediated angiitis affecting small blood vessels, was considered.^8,9 GPA causes necrotizing granulomatous inflammations resulting in triad of systemic vasculitis, recurrent upper and lower airway diseases, and rapidly progressive crescentic glomerulonephritis.⁸ Pachymeningitis, cerebral vasculitis, and cranial neuropathies have been reported.¹⁰ Diagnostic investigation includes serum cytoplasmic ANCA (present in 80%–90% of patients), highly specific for GPA (98%).⁸ ANCA directed against PR3 is seen in 65%–75% of individuals; 8%–30% of these individuals have ANCA directed against MPO.¹⁰ ANCA, PR3, and MPO were negative in this patient. He had no systemic manifestations of GPA, making this diagnosis less likely.

In an older patient with progressive leg weakness, bladder dysfunction, and cognitive changes, primary CNS lymphoma (PCNSL) should be considered. Both pachymeningitis/leptomeningitis and the presence of solid-enhancing tumors or complete ring enhancement on MRI can further support a neoplastic process.¹¹ PCNSL is responsive to steroids, but survival without chemotherapy is only 1.5 months.¹¹ Eight years had passed from initial onset of symptoms. Moreover, pathology of the brain biopsies was not consistent with PCNSL.

Final Diagnosis

Dural biopsy and histology are most suggestive of NS—a primary noninfectious non-necrotizing disease with rare necrotizing granulomas (Figure 2).

After biopsy, the patient received 3 days of IV methylprednisolone with minimal improvement. IV infliximab (5 mg/kg) with prednisone taper was started. He remained nonambulatory (bedbound) and required home health care services. Follow-up with neurology and rheumatology was recommended. However, transportation challenge (30 miles away from the clinic) led to his preference for a local neurologist. During a courtesy call 3 months later, wife reported he had deceased. The cause was unknown, and autopsy was not performed.

Discussion

This case highlights diagnostic challenges of granulomatous disorders and overlapping conditions, possible consequence of diagnostic errors, and social determinants of health.

Clinical presentations of NS can mimic several infections, making the diagnosis challenging. This includes overlapping clinical and radiographic features with TBM: headache, confusion, seizures, and cranial palsies are notable signs of elevated intracranial pressure from hydrocephalus.^1,5,12,13 Subcortical ischemic strokes can occur in both diseases due to involvement of perforating arteries supplying the deep brain structures.¹⁴ LETM, pachymeningitis/leptomeningitis, or cauda equina syndrome is seen.^4-6,12,13 Patients may experience progressive flaccid paraparesis, paresthesia, pain, and bowel or bladder dysfunctions.^5,6,12

There are no sensitive or specific biomarkers for NS.^4-6,13 In the CSF, lymphocytic pleocytosis, elevated proteins, positive oligoclonal bands, and low glucose are reported.^4-6,13 CSF ACE has poor sensitivity and specificity (62% and 76%, respectively)^13,15 and increases in proportion to CSF protein.^6,13 Increased soluble interleukin 2 receptors (sIL-2R, serum and CSF) could potentially help.^15,16 However, TBM, PCNSL, and viral/bacterial meningitis too can have elevated sIL-2R levels.¹⁶ sIL-2R was not checked in the patient.

The 2018 NS diagnostic criteria use clinical, laboratory, and radiographic evaluations with/without biopsy to categorize possible, probable, or definite NS.⁶ The diagnostic certainty increases with tissue biopsy. A CNS biopsy confirmation establishes a definite diagnosis of NS.⁶ However, CNS biopsy is not always possible due to location and morbidity.⁶ In such cases, systemic proof of sarcoidosis with correct neurologic syndrome is enough to establish probable NS.⁶ When pathologic confirmation of granulomas disease is lacking, it is termed possible NS.⁶ While this case is most fitting with definite NS,⁶ varying biopsy results and the presence of necrotizing granuloma add to some uncertainty. Sarcoid granuloma is typically non-necrotizing but can have small-to-moderate amount of central necrosis.¹⁷ Rigorous screening of infectious and noninfectious granulomatous disorders is essential, so an alternative etiology is not missed.⁶ Extensive laboratory and histologic evaluations overtime have shown less supportive of TBM, GPA, or PCNSL.

Diagnostic errors, defined as missed or delayed diagnoses, have been reported in sarcoidosis.^16,18,19 In most, the diagnostic error derives from difficult diagnostic nature of CNS granulomatous disorders and the consideration of an alternative diagnosis based on disease progression and results from further testing. The absence of TB from brain tissue staining, the lack of response to repeat TB treatment, and the worsening neurologic progression prompted considerations of alternative diagnoses.

Adding to the diagnostic quandary is the patient's socioeconomic circumstances. The requirement of preauthorizations commonly encountered with health maintenance organizations (HMO) delayed obtaining specialized laboratory and radiologic (i.e., PET) tests. We were uncertain whether a more accurate diagnosis could have been made earlier, given the overlapping features between NS and TBM and the initial positive T-SPOT (sensitivity 83.0%, specificity 80.9%),²⁰ which can be seen in latent, active, and old TB infections.²⁰ Nevertheless, social history, including place of birth, visitors, and travel, revealed the patient to be low risk for TB.

Specific social conditions that could have affected his health outcome include Hispanic ethnicity, lower educational attainment (high school), lower health literary, spouse/caregiver with limited English fluency, occupation (utility worker), and limitations in access to health services and affordability of diagnostic tools and treatment (Figure 4). Structural racism and implicit bias are also possible.

Figure 4. Impact of Social Determinants of Health in Case Study.

Social determinants of health consists of neighborhood and physical environment, community and social context, economic stability, health system, and education. This case report highlights that distance to doctor's office, high psychosocial stress, low income, inadequate health coverage, limited access to outpatient specialty care, lower health literacy, and educational attainment contribute to the adverse health outcome of our patient. ED = emergency department; HMO = Health Maintenance Organization.

Low educational attainment and health literacy are associated with adverse behaviors and increased emergency department (ED) utilizations.^21,22 Our patient had multiple ED visits due to worsening symptoms without interval follow-ups. Low education, chronic pain, and depression in NS are linked to poor quality of life.²³ The patient had a long history of inadequately treated depression. We speculate his depression, low health literary, and ED overutilization complicated this case.

Ascertainment bias given the Hispanic/Latino background is also possible. TB incidence among Hispanic/Latino individuals is 9 times higher than that in White individuals (3.5 cases vs 0.4 cases per 100,000 persons, respectively).²⁴ By contrast, sarcoidosis is rare in Hispanic/Latino individuals compared with Black or White individuals (4.3 cases vs 17.8 cases vs 8.1 cases per 100,000 persons, respectively).²⁵ Ascertainment bias could have propagated the TB diagnosis despite failed treatment.

Hispanic/Latino individuals (20%) were more likely than Black (14%), White (9%), and Asian (9%) individuals to be uninsured.²⁶ Hispanic/Latino individuals in the workforce are less likely to have employer-sponsored insurance (ESI) coverage (40.3% Hispanic/Latino vs 49.5% Black vs 65.6% White).²⁷ Even if ESI is offered, high premiums and worker contributions are cost-prohibitive. Average premiums for family coverage have risen 54%, and worker contributions have increased 71% (2009–2019).²⁸ Among all major health plans, HMO remains an attractive option to many low-income workers due to affordability, despite restrictions and limited access to subspecialty care.

Conclusion

This case underlines the diagnostic complexity of CNS granulomatous diseases. Demonstration of CNS inflammation with neuroimaging and CSF is paramount. Using 2018 diagnostic criteria, we feel NS is most likely given the positive brain biopsy. However, the rare necrotizing granulomas cannot entirely exclude past TB infection. Negative social conditions contribute to diagnostic and treatment delay. Improving access to specialty care in uninsured or underinsured communities, expanding health literacy, and addressing systemic ascertainment biases are important steps to mitigate diagnostic delays and errors.

Glossary

ACE

angiotensin-converting enzyme

AFB

acid-fast bacilli

ANCA

antineutrophilic cytoplasmic antibodies

ED

emergency department

ESI

employer-sponsored insurance

GPA

granulomatosis with polyangiitis

HMO

health maintenance organizations

LETM

longitudinally extensive panmedullary transverse myelitis

NS

neurosarcoidosis

PCNSL

primary CNS lymphoma

TB

tuberculosis

TBM

tuberculous meningitis

Appendix. Authors

Name	Location	Contribution
Jia Lin, MD, MPH	Department of Neurology, University of Southern California, Keck School of Medicine	Drafting/revision of the article for content, including medical writing for content; major role in the acquisition of data; study concept or design; and analysis or interpretation of data
Johannes Pulst-Korenberg, MD	Department of Neurology, University of Southern California, Keck School of Medicine	Drafting/revision of the article for content, including medical writing for content
Scott S. Zamvil, MD, PhD	Department of Neurology, University of California San Francisco	Drafting/revision of the article for content, including medical writing for content
Jennifer Graves, MD, PhD	Department of Neurosciences, University of California San Diego	Drafting/revision of the article for content, including medical writing for content
Scott D. Newsome, DO	Department of Neurology and Neurosurgery, Johns Hopkins University	Drafting/revision of the article for content, including medical writing for content
Lilyana Amezcua, MD, MS	Department of Neurology, University of Southern California, Keck School of Medicine	Drafting/revision of the article for content, including medical writing for content; study concept or design; and analysis or interpretation of data

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/NN for full disclosures.