Neuroradiological features of the tuberculosis-associated immune reconstitution inflammatory syndrome

Abstract

Setting: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important complication in human immunodeficiency virus type I (HIV-1) infected tuberculosis (TB) patients who start combination antiretroviral treatment (ART). Neurological manifestations occur in more than 10% of TB-IRIS cases. Apart from a few case reports, the radiological features of neurological TB-IRIS have not been described.

Objective: To describe the neuroradiological findings of patients with paradoxical neurological TB-IRIS.

Design: Computed tomography (CT; n = 13) and magnetic resonance imaging (n = 3) findings of 16 patients were reviewed.

Results: IRIS manifestations included meningitis (n = 4), intracranial space occupying lesions (SOLs, presumed tuberculomas; n = 5), meningitis and SOLs (n = 5), radiculomyelitis (n = 1) and spondylitis (n = 1). In patients with tuberculoma IRIS, we observed a high prevalence of 1) low density lesions on non-contrast-enhanced CT (all lesions), 2) multiple lesions (in 5/10 patients) and 3) perilesional oedema (17/22 lesions). In patients with meningitis, meningeal enhancement (n = 2) and hydrocephalus (n = 1) were infrequently observed.

Conclusion: This is the first substantial series to describe the radiological features of paradoxical neurological TB-IRIS. Compared to published radiological findings of tuberculomas in HIV-1-infected patients (not receiving ART), an increased inflammatory response is suggested in tuberculoma IRIS. However, this was not observed in patients with TB meningitis IRIS.

Figure 1. Illustrative case of paradoxical tuberculoma IRIS (Patient 9).

A 43-year-old HIV-1-infected male was diagnosed with AFB smear-positive lymph node TB. His CD4+ T-lymphocyte count was 89 cells/μl, and he was receiving trimethoprims ulfamethoxazole (160/800 mg daily) as primary prophylaxis. He showed clinical improvement on anti-tuberculosis treatment and was started on combination ART (stavudine, lamivudine, efavirenz) 50 days after anti-tuberculosis treatment was initiated. Fourteen days after starting ART, he developed headache, cognitive impairment and left upper limb weakness. One month later, he also developed an enlarged, fluctuant left supraclavicular lymph node. Fine-needle aspiration of lymph node revealed AFB, but TB culture was negative. Axial images of contrast enhanced computed tomography of the brain performed 56 days after neurological symptom onset showed generalised cerebral atrophy and communicating hydrocephalus. A 12 mm mixed hypodense and hyperdense lesion with surrounding oedema was present in the right thalamus. Lumbar puncture was deferred because of intracerebral mass effect. He was continued on ART, anti-tuberculosis treatment and prophylactic trimethoprim-sulfamethoxazole. Prednisone, which he received for a total duration of 69 days, was started at a dose of 1.5 mg/kg. His weakness resolved, and he was alive after 180 days of starting ART. Six months after ART was commenced his CD4+ T-lymphocyte count was 260 cells/μl and his HIV viral load was undetectable. IRIS = immune reconstitution inflammatory syndrome; HIV = human immunodeficiency virus; AFB = acid-fast bacilli; TB = tuberculosis; ART = antiretroviral treatment.

Figure 2. Illustrative case of paradoxical tuberculoma IRIS (Patient 6).

A 44-year-old HIV-1-infected male was diagnosed with pulmonary and culture-positive lymph node TB. His CD4+ T-lymphocyte count was 134 cells/μl, and he was receiving trimethoprim-sulfamethoxazole (160/800 mg daily) as primary prophylaxis. He improved on anti-tuberculosis treatment and was started on combination ART (stavudine, lamivudine, efavirenz) 27 days after commencing TB treatment. Two days after starting ART, he developed painful bilateral cervical lymphadenopathy. Lymph node aspirate cultured M. tuberculosis susceptible to rifampicin and isoniazid. Nineteen days after ART initiation the patient developed headache and focal seizures of his right arm. Neurological examination revealed an expressive aphasia which had been present since a left carotid injury resulting in a left MCA infarct several years before. Lumbar puncture performed was normal, and Toxoplasma gondii serum serology negative. Axial CECT (A) brain images performed 18 days after neurological symptom onset showed generalised cerebral atrophy, an old left MCA infarct, and multiple bilateral contrast enhancing lesions with surrounding oedema. The patient was diagnosed with neurological TB-IRIS and commenced on prednisone 1.5 mg/kg/day. Initially ART was continued. Serial brain imaging was performed over the next 11 months. Follow-up CECT performed 3 months later (B) showed progression in size, loculation and surrounding oedema of lesions. The patient was subsequently treated with therapeutic trimethoprim-sulfamethoxazole (320/1600 mg twice daily) for possible T. gondii encephalitis, with no radiological response 2 and 4 weeks later. ART was stopped at this time point but restarted 3 months later. Three repeat scans performed over the next 6 months showed radiological reduction in lesion size and surrounding oedema. (C shows the last CECT performed, 11 months after the first). The patient received prednisone for a total duration of 347 days. He was alive 180 days after starting ART, but subsequently died after defaulting from anti-tuberculosis treatment. His CD4+ T-lymphocyte count 7 months after starting ART was 502 cells/μl. IRIS = immune reconstitution inflammatory syndrome; HIV = human immunodeficiency virus; TB = tuberculosis; ART = antiretroviral treatment; MCA = middle cerebral artery; CECT = contrast-enhanced computed tomography.

Figure 3. Illustrative case of paradoxical TB radiculomyelitis IRIS (Patient 16).

A 26-year-old HIV-1-infected female was diagnosed with culture-positive pulmonary TB (susceptible to rifampicin and isoniazid) and TB meningitis. Her CD4+ T-lymphocyte count was 137 cells/μl. She showed clinical improvement on anti-tuberculosis treatment, and combination ART (stavudine, lamivudine, efavirenz) was commenced 43 days after starting anti-tuberculosis treatment. The patients developed headache, paraparesis, T10 spinal sensory level and urinary and faecal in-continence 7 days after starting ART. Lumbar puncture performed showed protein 72 g/l, glucose 2.3 mmol/l, lymphocytes 86/μl. TB, fungal and bacterial cultures were negative. T1, T2 and T1 gadolinium enhanced sagittal magnetic resonance images performed (A, B, C) 20 days after symptom onset showed abnormal spinal cord signal from craniocervical junction to conus medullaris with cord expansion between C2–C6 vertebral bodies. Cerebrospinal fluid revealed signal abnormalities on both T1 and T2 weighted images. The cauda equina appeared thickened. Post gadolinium enhancement of arachnoid mater and epidural soft tissue surrounding the spinal cord as well as basal leptomeninges of the brain were present. Lung nodules were also evident. Diagnosis of paradoxical TB radiculomyelitis IRIS was made, with anti-tuberculosis treatment and ART being continued. She also received 58 days of prednisone started at an initial dose of 1.5 mg/kg/day 5 days prior to scan. There was no documented clinical improvement, presumably due to irreversible cord damage, but the patient was alive 3 months after starting ART and was then lost to follow-up. TB = tuberculosis; IRIS = immune reconstitution inflammatory syndrome; HIV = human immunodeficiency virus; ART = antiretroviral treatment.