Central Nervous System–Immune Reconstitution Inflammatory Syndrome

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Central Nervous System–Immune Reconstitution Inflammatory Syndrome Aaron B. Paul

INTRODUCTION Central nervous system–immune reconstitution inflammatory syndrome (CNS-IRIS) represents a diverse group of disorders, all of which are characterized by an exaggerated inflammatory response to either a dead or dying opportunistic infection, viable pathogen from a persistent infection, or a self-antigen.1 First described in 1992 and most commonly seen in patients with HIV immunosuppression,2 CNS-IRIS has also been reported in patients following discontinuation of corticosteroids, anti-TNF-α therapy, or immunosuppression, as well as during the recovery of cell counts following cytotoxic chemotherapy, following engraftment of stem cell transplantation, and following plasma exchange or immunoabsorption in natalizumab-treated patients with multiple sclerosis diagnosed with progressive multifocal leukoencephalopathy (PML).3–6 CNS-IRIS is due to an abnormally regulated CD8+/CD4+ ratio resulting in excessive tissue inflammation.7 Histopathology demonstrates CD8+ lymphocytosis with CD8+ cells in both perivascular and parenchymal distributions.7 No universally accepted diagnostic criteria for CNS-IRIS have been developed. Rather, the diagnosis is suggested when the patient’s clinical status worsens despite immune reconstitution and without evidence of drug toxicity, opportunistic infection, medical noncompliance, or allergic reaction.9 Patients with life-threatening IRIS may need to have their antiretroviral therapy (ART) discontinued with initiation of treatment of their underlying infection and corticosteroids.10 Prophylactic antiepileptic therapy may also be considered.11 CNS-IRIS remains a significant public health issue affecting the morbidity of the world’s HIV-positive population.12 The incidence, severity, and mortality of CNS-IRIS varies with respect to patient population, type of AIDS-defining illness, and geography.1 In one meta-analysis, out of 13,103 patients started on ART from 54 cohort studies, 12.97% developed IRIS. More specifically, IRIS developed in 37.7% of patients with cytomegalovirus (CMV) retinitis, 19.5% with cryptococcal meningitis (CM), 16.7% with PML, 15.7% with tuberculosis (TB), 12.2% with herpes zoster, and 6.4% with Kaposi sarcoma.12 Risk factors in patients with HIV immunosuppression include ART naivety, severe immunosuppression at ART initiation (CD4+ < 50), rapid fall in HIV-1 RNA levels within 90 days of ART

initiation, rising CD4+ count with ART initiation, opportunistic infection at ART initiation, ART resumption after an interruption, young age, and male gender.1

CENTRAL NERVOUS SYSTEM–IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IMAGING SPECTRUM

Diagnosing CNS-IRIS can be challenging and should only be entertained in the appropriate clinical context with restoration of immune function leading to a worsening inflammatory response at sites of preexisting infection. Timely and accurate diagnosis also requires an understanding of the disease’s imaging spectrum. CM-IRIS is suspected clinically by the development of headache, fever, malaise, altered mental status, raised intracranial pressure, and cranial nerve palsies with lymphadenopathy or pulmonary infiltrates (Fig. 13.1).13 Imaging findings include leptomeningeal and perivascular enhancement, as well as enhancement of the gelatinous pseudocysts positioned within the perivascular spaces. Secondary involvement of the brain parenchyma accompanied by a communicating hydrocephalus can also be seen (Fig. 13.2).1 PML-IRIS is most commonly seen at 3 months after ART initiation but may occur anytime between 1 week and 26 months (Fig. 13.3). Imaging findings include increased FLAIR/T2 hyperintensity and enhancement of white matter lesions (WMLs) with worsening mass effect. Interestingly, enhancement is associated with increased survival. In one study, 87.5% of patients with a good outcome demonstrated enhancement on MRI, whereas 80% of patients with a poor outcome did not demonstrate enhancement.14 The ADC values and JC virus titers may also provide insight into the temporal evolution of the disease, both being higher in patients with rapid progression.15 Imaging findings are more severe in the setting of natalizumab-induced PML, due to prompt restoration of immune surveillance with plasma exchange or immunoabsorption.16 TB-IRIS and toxoplasma encephalitis-IRIS (TE-IRIS) can be difficult to differentiate from HIV-negative patients with TB and toxoplasma or from HIV-positive patients with TB and toxoplasma but without IRIS. Imaging findings in TB-IRIS include leptomeningeal enhancement, enhancing tuberculomas, and a communicating

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Figure 13.1. Central nervous system–immune reconstitution inflammatory syndrome conceptualization. Immune restoration results in a worsening inflammatory response at sites of preexisting infection.

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Figure 13.2. Cryptococcal meningitis–immune reconstitution inflammatory syndrome case example. HIV positive with remote history of cryptococcal meningitis presenting with seizures after starting antiretroviral therapy. Axial FLAIR (A–C) and postcontrast T1-weighted (D–F) images demonstrate leptomeningeal enhancement (green arrows) with secondary involvement of the brain parenchyma (orange arrow). There is enhancement (red arrows) of gelatinous pseudocysts within perivascular spaces with surrounding edema (blue arrow) as well. There is also vasogenic edema centered in the bilateral parietal white matter with extension into the occipital and posterior frontal lobes (black arrows). These findings progressed over several months despite negative cerebrospinal fluid studies.

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Figure 13.3. Progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome case example. HIV-positive male with recent diagnosis of progressive multifocal leukoencephalopathy (cerebrospinal fluid: JC virus DNA positive) presenting with neurologic decline since restarting antiretroviral therapy. Axial FLAIR (A and B) and axial and sagittal postcontrast T1-weighted (C–E) images demonstrate multifocal linear and nodular enhancement (red arrows) in the pons and right cerebellum with surrounding edema (blue arrows) and mild mass effect. There are also scattered foci of bilateral cerebellar leptomeningeal enhancement.

hydrocephalus (Fig. 13.4).17 Imaging findings in TE-IRIS include multiple enhancing nodules throughout the brain parenchyma, with one study suggesting a speckled enhancement pattern in addition to the more typical ring enhancement.18

RARE FORMS OF CENTRAL NERVOUS SYSTEM–IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME

CMV-IRIS commonly affects the eye, and 63% of patients with CMV retinitis who start ART develop a vitritis.17 However, in rare instances, CMV-IRIS may also affect the brain and spinal cord. In one study, imaging findings included FLAIR/T2 hyperintensity and restricted diffusion involving the internal capsules, basal ganglia, periventricular WM, and brainstem.19 The authors attributed the etiology to a vasculitis, with subsequent enhancement felt to represent subacute infarcts. This hypothesis has been supported by post mortem studies demonstrating CMV inclusions within capillary endothelial cells, astrocytes, and neurons.20 A radiculitis has also been reported within the setting of CMV infection, HIV, and ART.17 Varicella-zoster virus-IRIS (VZV-IRIS) manifests as a rare vasculopathy. Interestingly, a dermatomal rash may be absent.

Imaging findings include leptomeningeal enhancement throughout the brain and spinal cord, vascular beading, and infarcts.17 Due to its potential involvement of small vessels in addition to large vessels, negative findings on MRA or catheter angiography do not exclude the diagnosis.21 There have even been reports of CNS-IRIS occurring without coinfection due to an abnormally regulated immune system. Two such entities that have been described include neuro-IRIS without coinfection and tumefactive inflammatory demyelinating disease and fulminating leukoencephalopathy. The imaging findings in neuro-IRIS without coinfection include leptomeningeal enhancement, worsening WMLs, and mass effect.22 The authors attribute the etiology to the periodic leakage of viruses (i.e., HIV and Epstein-Barr virus [EBV]) into the cerebrospinal fluid (CSF) resulting in antigenic stimulation and subsequent inflammation resulting in a chronic, relapsing-remitting meningitis. The imaging findings reported in tumefactive inflammatory demyelinating disease and fulminating leukoencephalopathy include prominent perivascular enhancement and FLAIR/T2 hyperintensity involving the parietal and occipital WM.23 Post-mortem examination revealed infiltration of CD8+ cells into the perivascular spaces. A GuillainBarré syndrome occurring after ART initiation has also been reported.24

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Figure 13.4. Toxoplasma encephalitis–immune reconstitution inflammatory syndrome case example. HIV-positive male diagnosed with toxoplasmosis (CSF: toxoplasmosis antibody positive) who developed neurologic decline 1 month after restarting antiretroviral therapy. Axial FLAIR (A and B) and postcontrast T1-weighted (C and D) images before antiretroviral therapy demonstrate multifocal ring enhancing lesions involving the left lentiform nucleus, bilateral corona radiata, left frontal lobe, right thalamus (red arrow), and white matter adjacent to the posterior body of the right lateral ventricle (blue arrow) with surrounding edema. Continued

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Figure 13.4., cont’d Axial FLAIR (E and F) and postcontrast T1-weighted (G and H) images 1 month after starting antiretroviral therapy demonstrate worsening enhancement (black arrow) and edema (orange arrow) in the right posterior corona radiata and worsening edema in the left frontal lobe (green arrow).

TABLE 13.1  Summary of Central Nervous System-Immune Reconstitution Inflammatory Syndrome (CNS-IRIS) Imaging Spectrum CM-IRIS

PML-IRIS

TB-IRIS

TE-IRIS

CMV-IRIS

VZV-IRIS

Enhancement

Leptomeningeal/parenchymal/ perivascular/VR spaces

Parenchymal WMLs

Leptomeningeal/ parenchymal

Parenchymal

Leptomeningeal, subacute infarcts

Vasculitis Hydrocephalus Cord involvement

No Yes No

No No Rare

No Yes Rare

No No No

Deep WM/deep grey nuclei/brainstem, subacute infarcts Yes No Yes

Yes No Yes

CM-IRIS, Cryptococcal meningitis-immune reconstitution inflammatory syndrome; CMV-IRIS, cytomegalovirus-immune reconstitution inflammatory syndrome; PML-IRIS, progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome; TB-IRIS, tuberculosis-immune reconstitution inflammatory syndrome; TE-IRIS, toxoplasma encephalitis-immune reconstitution inflammatory syndrome; VZV-IRIS, varicella-zoster virus-immune reconstitution inflammatory syndrome; WML, white matter lesion.

Table 13.1 presents a summary of the CNS-IRIS imaging spectrum.

DIFFERENTIAL DIAGNOSIS The most important differential diagnoses for CNS-IRIS include CNS lymphoma, toxoplasmosis, and TB. The imaging findings in lymphoma consist of T2 hyperintensity within the

periventricular WM extending to the ependymal surface of the ventricles with associated enhancement and diminished diffusivity (Fig. 13.5).25 The imaging findings in toxoplasmosis consist of multifocal enhancing lesions involving the basal ganglia, thalami, and cerebellum with associated enhancement (ring or eccentric target sign) (Fig. 13.6).26 The imaging findings in TB consist of basilar meningitis with tuberculomas and associated enhancement (Fig. 13.7).27

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Figure 13.5. Central nervous system lymphoma case example. Male patient presenting with left arm weakness (brain biopsy: B-cell non-Hodgkin lymphoma). Axial FLAIR (A and B) and postcontrast T1-weighted (C) images demonstrate characteristic T2 hyperintensity involving the periventricular white matter (blue arrows), right thalamus, septum pellucidum, and corpus callosum with extension to the ependymal surface of the lateral ventricles. There is associated relatively confluent enhancement (red arrow). Diffusion tensor imaging (D—DTI map, E—ADC Map) demonstrates associated diminished diffusivity in the splenium of the corpus callosum (green arrows).

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Figure 13.6. Toxoplasmosis case example. Male patient presenting with neurologic decline in the setting of newly diagnosed HIV/AIDS (CSF: toxoplasmosis antibody positive). Axial flair (A and B) and postcontrast T1-weighted (C) images demonstrate multifocal lesions involving both cerebral hemispheres and basal ganglia (blue arrows) with a “target” enhancing pattern (red arrow) and surrounding edema.

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Figure 13.7. Tuberculosis case example. Female patient presenting with seizures in the setting of newly diagnosed HIV/AIDS (subdural collection biopsy: AFB positive). Axial FLAIR (A and B) and postcontrast T1-weighted (C and D) images demonstrate both intraparenchymal and subdural tuberculomas (blue arrows) with associated meningitis (red arrows). The tuberculoma in the left parietal lobe has rim enhancement. The left temporal subdural tuberculoma has associated leptomeningeal and pachymeningeal enhancement. There is also associated edema in the left temporal and parietal lobes.

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