By Ulrike W. Kaunzner, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Authors of a recent study evaluated inflammatory activity in multiple sclerosis patients who developed natalizumab-associated progressive multifocal leukoencephalopathy (PML) using translocator protein positron emission tomography (TSPO PET) for imaging of microglia. They demonstrated that TSPO PET can monitor PML longitudinally.
SOURCE: Mahler C, Schumacher A-M, Unterrainer M, et al. TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy. Brain 2021;144:2683-2695.
Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system (CNS) infection caused by the polyomavirus, JC (JCV), which is carried by approximately 40% to 69% of the general population and is harmless except among those with impaired immune systems. PML can occur in multiple sclerosis (MS) patients being treated with certain disease-modifying treatments (DMT), and natalizumab has the highest incidence of DMT-associated PML (3.99/1,000 patients), with more than 800 cases identified worldwide. Clinical symptoms of PML include ataxia, vision changes, and cognitive symptoms, which make the differentiation from an MS relapse difficult. Diagnosis includes brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis. Clinical management of patients with natalizumab-associated PML is challenging, with a high fatality rate. Surviving patients often have lasting neurological disability. Monitoring surviving patients is further complicated by the reoccurrence of MS relapses after stopping natalizumab therapy. In addition, cessation of natalizumab causes recovery of the immune system, often leading to immune reconstitution inflammatory syndrome (IRIS), which worsens existing PML symptoms. Histopathological analysis showed that natalizumab-associated PML is associated with activation of the innate immune system.
Mitochondrial 18 kDa translocator protein (TSPO) is expressed by microglia and infiltrating macrophages and has been used to investigate the presence of immune cells in MS and other CNS diseases. A positron emission tomography (PET) radioligand that binds to TSPO was developed as a tool for monitoring micro-glial activity. Tools that allow specific monitoring of PML are lacking so far, and surveillance includes clinical observation, MRI, and repeated CSF analysis. A minimally invasive imaging technique, like TSPO PET, that can monitor the activity of PML lesions would be a significant improvement in the management of these patients.
Mahler et al first verified the expression of TSPO in patients with natalizumab-associated PML. They histologically explored TSPO-expressing cells in natalizumab-associated PML patients and showed the presence of predominantly microglia and blood-derived macrophages in PML lesions, thus confirming the use of TSPO PET for the investigation of PML-associated inflammation. Next, they followed a cohort of eight relapsing-remitting MS patients with natalizumab-associated PML and used serial PET imaging and the TSPO radioligand 18F-GE-180 alongside regular brain MRIs. MRI showed gadolinium enhancement in PML lesions predominantly during the IRIS stage, which returned to baseline levels within a few weeks. TSPO PET imaging also showed an enhanced tracer uptake during the IRIS phase of PML. However, this was followed by a slow one phase decay curve, and elevated uptake was present for more than four years after PML diagnosis. This indicates that TSPO PET can be used to follow longitudinal inflammation in PML lesions, beyond the PML-IRIS phase. In some cases, increased uptake was seen before PML lesions became clearly visible on MRI and before contrast enhancement became apparent as part of PML-IRIS. This indicates that TSPO PET might be able to detect PML lesions at very early stages prior to detection on MRI.
In addition, they assessed the differences of TSPO PET signals in PML lesions vs. MS lesions from patients without PML. They compared 89 MS lesions and 23 PML lesions and applied a set of criteria to distinguish these different lesion types. More than 96% of PML and MS lesions could be differentiated by using this specific diagnostic matrix. This is important, since patients can develop new clinical symptoms after initial PML symptoms, especially if treatment has been paused. These symptoms could be secondary to an MS relapse or due to further progression of PML; differentiation of these two etiologies is crucial because they require different management. In the study cohort, 13 new lesions occurred over the course of the study. The established diagnostic matrix was applied, and 92.3% of new lesions were identified as MS lesions. Initiation of B cell depleting treatments was started in three of the evaluated patients, and PET imaging showed a decrease of inflammation in new MS lesions, without affecting tracer uptake in the identified PML lesions.
COMMENTARY
This is an important study, which used TSPO PET for the first time to assess natalizumab-associated PML. TSPO PET could provide an imaging tool for longitudinal monitoring of inflammation associated with PML and could allow for differentiation of MS activity from PML. Moreover, it might be used for the early detection of PML, since activity can be discovered prior to clinical symptoms and prior to visibility on MRI.
The authors discussed some of the challenges of the study, particularly, the small sample size of eight patients. A larger cohort will be warranted to robustly establish early detection of inflammation and to follow inflammation longitudinally. Further exploration is needed to establish if TSPO PET can differentiate small PML lesions from MS lesions, particularly given the limited spatial resolution of PET. Also, the cost of PET imaging needs to be considered, as well as the feasibility and access to this type of imaging. PML is often fatal or leaves young patients disabled, so early detection is crucial. PML lesions can form months prior to development of clinical symptoms. Since PET might be used to detect inflammatory activity before detection on MRI, a poor outcome might be avoided and would argue for use of PET. In addition, PET imaging might offer a monitoring tool for other DMTs or could be translated for the monitoring of other inflammatory brain diseases and the use of new treatments. In conclusion, TSPO PET might expand our current imaging options for the early detection of PML and can be an important tool to longitudinally monitor inflammation associated with PML and other inflammatory diseases of the brain.
