Can pulmonary sarcoidosis trigger a progressive multifocal leukoencephalopathy? Considerations from a case series and a review of literature

Gamperl, Irene; Enzinger, Christian; Pichler, Alexander; Feichtinger, Michael; Schlager, Thomas; Fertl, Elisabeth

doi:10.1002/ccr3.1816

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…Associated with sarcoidosis, in which PML is a very exceptional manifestation itself, IRIS has been described only very few times. 18,38 In the present study, cranial MRIs revealed signs of IRIS in precisely those patients with an unfavourable outcome. The absolute JC virus count in the CSF did not correlate with the respective patient’s symptom severity, but its trend did coincide with the individual disease course.…”

Section: Discussionsupporting

confidence: 61%

Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome in seven patients with sarcoidosis: a critical discussion of treatment and prognosis

Dohrn

Ellrichmann

Pjontek

et al. 2021

Ther Adv Neurol Disord

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Progressive multifocal leukoencephalopathy (PML) is a subacute brain infection by the opportunistic John Cunningham (JC) virus. Herein, we describe seven patients with PML, lymphopenia, and sarcoidosis, in three of whom PML was the first manifestation of sarcoidosis. At onset, the clinical picture comprised rapidly progressive spastic hemi- or limb pareses as well as disturbances of vision, speech, and orientation. Cerebral magnetic resonance imaging showed T2-hyperintense, confluent, mainly supratentorial lesions. Four patients developed punctate contrast enhancement as a radiological sign of an immune reconstitution inflammatory syndrome (IRIS), three of them having a fatal course. In the cerebrospinal fluid, the initial JC virus load (8–25,787 copies/ml) did not correlate with interindividual severity; however, virus load corresponded to clinical dynamics. Brain biopsies ( n = 2), performed 2 months after symptom onset, showed spotted demyelination and microglial activation. All patients had lymphopenia in the range of 270–1150/µl. To control JC virus, three patients received a combination of mirtazapine and mefloquine, another two patients additionally took cidofovir. One patient was treated with cidofovir only, and one patient had a combined regimen with mirtazapine, mefloquine, cidofovir, intravenous interleukin 2, and JC capsid vaccination. To treat sarcoidosis, the four previously untreated patients received prednisolone. Three patients had taken immunosuppressants prior to PML onset, which were subsequently stopped as a potential accelerator of opportunistic infections. After 6–54 months of follow up, three patients reached an incomplete recovery, one patient progressed, but survived so far, and two patients died. One further patient was additionally diagnosed with lung cancer, which he died from after 24 months. We conclude that the combination of PML and sarcoidosis is a diagnostic and therapeutic challenge. PML can occur as the first sign of sarcoidosis without preceding immunosuppressive treatment. The development of IRIS might be an indicator of poor outcome.

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Section: Discussionsupporting

confidence: 61%

Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome in seven patients with sarcoidosis: a critical discussion of treatment and prognosis

Dohrn

Ellrichmann

Pjontek

et al. 2021

Ther Adv Neurol Disord

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“…Often this was accompanied by immunosuppressive therapy, but several case reports of PML in untreated sarcoidosis patients can be found. 5 , 7 , 8 It was also shown that the CD4 + T cell count was reduced in these patients. 5 , 8 In our cohort, four from six PML patients with sarcoidosis were not under immunosuppressive therapy at the time of developing first PML symptoms.…”

Section: Discussionmentioning

confidence: 79%

“… 4 Associations of PML and sarcoidosis are described 5 , 6 ; however, most patients were taking immunosuppressive drugs like steroids and steroid-sparing agents. Yet, PML has also been observed to develop in treatment-naive sarcoidosis patients 5 , 7 , 8 and even led to the discovery of underlying occult sarcoidosis. 9–11 …”

Section: Introductionmentioning

confidence: 99%

Treating sarcoidosis-associated progressive multifocal leukoencephalopathy with infliximab

Rosenkranz

Häußler

Kolster

et al. 2021

Brain Communications

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Although most of the progressive multifocal leukoencephalopathy (PML) cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, PML is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for PML. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell (Treg) frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of PML, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study we included, characterized and followed-up six patients with bioptically confirmed definite PML and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first PML symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4+ T cell and regulatory T cell frequencies. Due to progression of PML in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving PML. Notably, by treatment with infliximab, an antibody directed against tumor necrosis factor-α, three patients continously improved clinically, JC-virus was no longer detectable in the cerebrospinal fluid and Treg frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died nine weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to PML. Although immunosuppressive drugs should be avoided in PML, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt PML progression.

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“…Sarcoidosis associated with a PML-like disease was described in 1955, although in this report, 1 of the defining histopathologic features of the disease (enlarged oligodendrocyte nuclei) was not described. In the intervening 7 decades, the occurrence of PML associated with systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression has been described in 37 patients . Recent research for possible PML treatment includes infusion of interleukin (IL) 2 and IL-7, checkpoint inhibitors, polyoma virus-specific T-cell therapy (PyVST), and infliximab, the last of which was used for patients with sarcoidosis specifically .…”

Section: Introductionmentioning

confidence: 99%

Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression

et al. 2023

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ImportanceProgressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease.ObjectiveTo describe characteristics of patients with S-PML.Design, Setting, and ParticipantsFor this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023.ExposuresSarcoidosis without active therapeutic immune suppression.Main Outcomes and MeasuresClinical, laboratory, and radiographic features of patients with S-PML.ResultsTwenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/μL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not.Conclusions and RelevanceIn this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.

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Can pulmonary sarcoidosis trigger a progressive multifocal leukoencephalopathy? Considerations from a case series and a review of literature

Cited by 7 publications

References 11 publications

Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome in seven patients with sarcoidosis: a critical discussion of treatment and prognosis

Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome in seven patients with sarcoidosis: a critical discussion of treatment and prognosis

Treating sarcoidosis-associated progressive multifocal leukoencephalopathy with infliximab

Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression

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