Progressive Multifocal Leukoencephalopathy (PML) in a Patient with Sarcoidosis - PowerPoint Presentation

Progressive Multifocal Leukoencephalopathy (PML) in a Patient with Sarcoidosis Challenges in Diagnosis and Management Anny Wu, D.O.¹, Miles Bogner OMS-IV², Nisha Dsilva D.O.², Julie Jones D.O.³, Peter Pytel M.D.⁴, Emilie Morphew M.D.⁵ and Keith Reich D.O.¹ Department of Rheumatology, Franciscan Alliance, Munster, IN Midwestern University Chicago College of Osteopathic Medicine, Chicago, IL Department of Rheumatology, HealthPartners Specialty Center, St. Paul, MN Department of Pathology, University of Chicago, Chicago, IL Department of Pathology, Franciscan Health, Dyer, IN

Introduction

Progressive Multifocal Leukoencephalopathy (PML) Rare demyelinating infection of CNS caused by JC polyomavirus reactivation Occurs with defective cellular immunity Traditionally seen with: advanced HIV infectionhematologic and solid-tissues cancers hematopoietic stem-cell transplantation certain immunosuppressive meds biologics such as natalizumab (used in multiple sclerosis) Classically described as bilateral asymmetric lesions of the white matter but this is a notion that is increasingly challenged Symptoms include altered mental status, motor defects, ataxia and visual symptomsTypically progressive and fatal Muftuoglu M et al. N Engl J Med 2018;379:1443-51

JC virus Also called the John Cunningham virus Type of polyomavirusAccording to Miskin et al., 50 to 85% of healthy individuals are infected without sign of diseaseFirst visualized via electron microscopy by Zu Rhein and Chou in 1965 in the brain tissue of a deceased patient with PMLClassic cell type infected are the astrocytes and oligodendrocytes in the white matterThe oligodendrocytes are eventually destroyed, causing demyelination, leading to fatal disease Miskin DP et al. Curr Opin Neurol. 2015;28(3):288-94 Zu Rhein G et al. Science 11 Jun 1965; 148.3676: 1477-1479

Case

HPI A 48 year-old African American woman with a known history of sarcoidosis involving her lungs, skin, breast and related uveitis who presents with chief complaint of lower extremity swelling Secondary complaint is progressive lower extremity weakness for the past several weeks and eventual development of R arm weakness with loss of fine motor skillsNo fevers, chills, chest pain, abdominal pain, or worsening of skin nodules on her arms + dyspnea with exertion which is at her baseline + increased bladder urgency as well as bowel slowing without incontinence

HPI (con’t) Sarcoidosis was diagnosed over four years ago by an outside rheumatologist Home medications include azathioprine 50 mg BID mycophenolate 500 mg BID oral prednisone 10mg daily dapsone 100 mg daily for PJP prophylaxis Has had nonadherence with her medication regimen over the past few months but reported being on this regimen since time of diagnosis

Pertinent physical exam HEENT: Normocephalic, atraumatic, + chronic R eye peripheral vision deficit Lungs: CTABL, no w/r/r Heart: regular rate and rhythm, +S1 and S2 normal, no murmur, b/l LE +1 pitting edemaAbdomen/GI: soft, non-tender. Bowel sounds Skin: + nodules on b/l arms and elbows , +very dry and scaly skin of b/l LE , +erythema and calor extending up to knees Neurological: CN exam with XI weakness on R. DTRs intact bilateral upper and lower extremities. + R arm pronator drift . +Romberg's and deficient finger to nose test. Grip strength 2/5 R hand and 4/5 L hand. Bicep strength 4/5 L and 3/5 R . 5/5 strength b/l LE. Rectal tone intact on exam MSK: No evidence of Heberden’s or Bouchard’s nodes of any of the fingers. No joint effusion, swelling, tenderness, redness or restriction of motion

Admission workup Labs: normal CBC, BMP, B type natriuretic peptide and lactic acid Head CT w/o contrast: small high L parietal subcortical white matter lucency and subcentimeter L basal ganglia lucency read as ischemic change of uncertain ageMRI brain: multifocal signal abnormalities involving the bilateral cerebral hemispheres, the splenium of corpus callosum and the left basal ganglia and thalamus exhibiting high T2 and FLAIR signal and post-infusion enhancement

MRI brain

MRI brain (con’t)

Head and neck CT angiogram negative for an intracranial or carotid stenosis Whole spine MRI showed mild multilevel cervical and lumbar spondylosis worst at L4-5 Home meds have been continued and ASA started per stroke pathway Differential diagnosis of her brain imaging findings include neurosarcoidosis, atypical infection or malignancy Expanded workup including infectious and non-infectious etiologies performed (next slide)

Serum and urine laboratory results

CSF analysis Patient subsequently underwent lumbar puncture with grossly unrevealing results Of note, JC Virus PCR is negative

Decision making Cervical, thoracic and lumbar spinal MRIs showed mild multilevel cervical and lumbar spondylosis worst at L4-L5Incidentally findings of mediastinal and retroperitoneal lymphadenopathy. CT of chest, abdomen and pelvis ordered. Compared to 2014, increased thoracic abdominal and pelvic lymphadenopathy possible liver lesion Ultimate diagnosis would require tissue biopsy Liver biopsy preferable to brain biopsy no liver lesion was seen on abdominal ultrasound After some delay secondary to patient hesitancy as well as a required transfer to another hospital, a brain biopsy of the L occipital lobe was performed

Brain biopsy

PML pathology In a consensus statement from American Academy of Neurology in 2013 Definitive diagnosis of PML requires demonstration of Demyelination (seen on MRI)Bizarre astrocytesEnlarged oligodendroglial nuclei And other techniques to show the presence of JC virus Berger JR et al. Neurology 2013; 80:1430-1438

H&E stain at 10x shows an inflammatory lesion demonstrated by brain parenchyma with patchy inflammatory cell infiltrates that focally exhibit perivascular accentuation. Image courtesy of Peter Pytel, M.D.

Macrophages make up a prominent component of the inflammatory cell infiltrates and are highlighted by labeling for CD68 which appears brown. The stain shows the large number of macrophages that are easily underestimated based on the H&E. Image courtesy of Peter Pytel, M.D.

H&E stain at 40x shows enlarged oligodendrocytes with large nucleus (arrows). Image courtesy of Peter Pytel, M.D.

H&E stain shows a viral inclusion within an astrocyte (arrow) described as smudgy vaguely plum colored inclusions. Image courtesy of Emilie Morphew, M.D.

Immunohistochemistry staining for SV40 (dark brown/black) confirms the presence of JC virions in nuclei of infected oligodendrocytes. Image courtesy of Peter Pytel, M.D.

Pathology report No features of a neoplastic process No population of large CD20 positive cells suggestive of lymphoma was seenNoncaseating granulomas consistent with sarcoidosis were not reported IHC staining for SV40 was ultimately diagnostic of the presence of JC virus as well as progressive multifocal leukoencephalopathy (PML) SV40 cross-reacts with both JC and BK virus. However, BK virus has not been seen in human brain tissue

Treatment Immunosuppressive medications were held except for prednisone 15mg daily As of her last visit approximately one year laterPatient’s MRI brain lesions have slightly improved and remained stable Sarcoidosis remains at baseline However, she has since developed simple partial seizures requiring multiple antiepileptic drugs

Discussion

PML and sarcoidosis PML is rare in sarcoidosis patients and when it occurs, it is often misdiagnosed In 2014, Jamilloux et al.Documented 10 cases of PML in sarcoidosis patients and reviewed 20 previous published cases Patients were misdiagnosed as neurosarcoidosis in 8 out of the 10 cases An average of 4.5 (+/-3.9) months passed before a correct diagnosis was reached All 8 of the misdiagnosed patients experienced worsening neurological symptoms during the delay Jamilloux Y et al. Neurology 82.15 (2014): 1307-1313

Neurosarcoidosis vs. PML When a patient with sarcoidosis develops neurosarcoidosis, immunosuppressant therapy is often intensified Conversely, in PML, treatment focuses on strengthening the immune systemIntensifying treatment for misdiagnosed neurosarcoidosis when a patient actually has PML can lead to PML escalation This may be one of the reasons that the survival rate of PML in sarcoidosis is only 43% compared to 56-71% in HIV patients (Jamilloux et al.) Correct diagnosis is crucial Jamilloux Y et al. Neurology 82.15 (2014): 1307-1313

MRI T2 enhancing lesions Most common presentation of PML on MRI brain The small islands of demyelination coalesce overtime to produce large areas sometimes described as “ground glass” bright appearance on T2-weighted MRI Smith J et al. American Journal of Roentgenology 182.2 (2004): 289-295 Berger JR et al. Neurology 2013; 80:1430-1438Hodel J et al. Neurology 2016;86:1516-1523 In Hodel et al., the punctate pattern (PP) was felt to be a differentiating and specific finding of natalizumab-associated PML in patients who have pre-existing MS lesions PP was also found in patients with other conditions such as neurosarcoidosis and CNS vasculitis In our case, PP would not be a reliable diagnosis feature since neurosarcoidosis was a part of our differential diagnosis

JC virus PCR CSF PCR is not sufficiently sensitive enough to rule out JCV and this was indeed negative in our patient The sensitivity of this test has varied in studies from 56% to 92% (Aksamit et al. and Berger et al.) In the study by Jamiloux et al., 38% (11/29) of sarcoidosis patients eventually diagnosed with PML had a negative PCR result Aksamit et al. Neurologist 2006;12: 293–298 Berger et al. J Neurovirol 1998;4:59–68Jamilloux Y et al. Neurology 82.15 (2014): 1307-1313

JC virus PCR (con’t) However, repeat LP may be considered if clinically indicated In a 2016 review by Maas et al., one of seven patients were found to convert from PCR negative to positive later on Maas et al. J Neurol 2016; 263:2004-2021 Babi M et al. Hindawi Case Reports in Neurological Medicine 2015;article 643216Ultrasensitive TaqMan real-time PCR assay Alternative option Available at NIH Detects viral loads >10 DNA copies/mL vs. other tests with higher (>50 DNA copies/mL) thresholds

Immunosuppression differences Our patient was on multiple DMARDs (azathioprine and mycophenolate) that typically serve as alternatives to each other Although both were given at medium doses, being on two meds that overlap in function may have broadly immunosuppressed her in a way that predisposed her in the development of PML Maas et al. J Neurol 2016; 263:2004-2021 In Maas et al., there were survival differences found in patients with varying degrees of generalized immunosuppression It seems the more specific the immunosuppression is, the lower rate of PML mortality

PML in the absence of external immunosuppression The history of our patient challenges the idea that PML is largely due to immunosuppressant medication Although our patient was on multiple immunosuppressant medications, she had poor compliance in the months leading up to her neurological symptomsIn the Jamiloux et al. review, two patients were diagnosed with PML at the same time as sarcoidosis and, therefore, have not received prior immunosuppressant medication → possibility of underlying immunological dysfunction that predisposes patients with sarcoidosis to develop PML Jamilloux Y et al. Neurology 82.15 (2014): 1307-1313

Treatment

Specific PML treatments Cidofivir First nucleotide analogue medication approved for clinical use Used to treat cytomegalovirus retinitis in patients with (AIDS) In De Luca et al., it has not been found to be effective in AIDS related PML in addition to antiretroviral treatment Mefloquine Anti-parasite medication used to prevent or treat malaria No effect on JC viral load compared to control in Clifford et al. In the study by Jamiloux et al. of PML in sarcoidosis, patients treated with these agents did not have an increased rate of survival De Luca A et al. AIDS 2008;22:1759–1767 Clifford D et al. Journal of neurovirology 19.4 (2013): 351-358 Jamilloux Y et al. Neurology 82.15 (2014): 1307-1313

Specific PML treatments (con’t) Mirtazapine Tetracycline antidepressant and a 5-HT2a antagonistJC virus enters cells through the 5-HT2a receptor Treatment with mirtazapine was the only factor associated with decreased mortality in the study by Jamiloux et al. of PML in sarcoidosis patients However, a larger study of 74 PML patients treated with mirtazapine published by Jamiloux et al. 2 years later failed to find a statistically significant effect Assetta et al. Biological Chemistry (2017) Jamiloux et al. Clinical drug investigation 36.10 (2016): 783-789

Cytokines (IL-2 and 7) and vaccines have been tried as well Limitations include Efficacy dependence on precursor JC virus-specific T cellsTime required to produce a T cell response Muftuoglu M, et al. N Engl J Med 2018;379:1443-51

Emerging treatment modality In a 2018 paper by Muftuoglu et al., allogeneic BK Virus-Specific T cells were investigated in the treatment of PML Three immunocompromised patients with PML were treated with ex vivo-expanded, partially HLA matched BK virus specific T cellsThe BK virus is similar to the JC virus and part of the same familyIn two patients, improvement was seen in clinical features and imaging as well as clearance of JC virus One patient had a reduction of JC viral load Two developed immune reconstitution syndrome which may be a limitation to the approach Muftuoglu M, et al. N Engl J Med 2018;379:1443-51

Conclusion

This rare case of PML in a patient with sarcoidosis offers insight into the differentiation and management of these two diseases Her underlying diagnosis of sarcoidosis itself may have played a role in the development of PML In this patient’s case, early biopsy and quick diagnosis likely provided her a better chance against this lethal disease At this time, PML can only be reliably ruled out through a brain biopsy, which is challenging to obtain due to its invasive nature leading to patient reluctance as well as limited resources in the community hospital setting

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Acknowledgements Sheila Donnelly, M.L.S. Research & Instruction LibrarianMidwestern University LibraryGlendale, Arizona

Thank you! Questions? Contact:anny.wu@franciscanalliance.org