Henry Ford Health System Henry Ford Health System Scholarly Commons Pathology Articles Pathology 1-15-2021 Unusual Case of Progressive Multifocal Leukoencephalopathy in a Patient With Sjögren Syndrome Ifeoma Onwubiko Kanika Taneja Nilesh S. Gupta Abir Mukherjee Follow this and additional works at: https://scholarlycommons.henryford.com/pathology_articles CASE REPORT Unusual Case of Progressive Multifocal Leukoencephalopathy in a Patient With Sjögren Syndrome Ifeoma Ndidi Onwubiko, MD, MPH, Kanika Taneja, MD, Nilesh Gupta, MD, and Abir Mukherjee, MD 03/05/2021 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= by http://journals.lww.com/amjforensicmedicine from Downloaded 84% neutrophils; glucose, 71 mmol/L; protein, 183 g/dL with neg- Abstract: Progressive multifocal leukoencephalopathy (PML) is a rare Downloaded ative cultures and no malignant cells on cytology). Hepatitis C anti- demyelinating disease caused by reactivation of John Cunningham virus af- body screen was negative. Immunoglobin G antibodies to Sjögren fecting typically subcortical and periventricular white matter of immunocom- syndrome–related antigen A and anti–Sjögren syndrome-related from promised hosts (human immunodeficiency virus infection, hematologic antigen B were positive. Thyroglobulin antibodies and antinuclear http://journals.lww.com/amjforensicmedicine malignancies). Cerebral hemispheric white matter is most commonly affected antibodies were elevated. Autoimmune serological tests for other by lytic infections, leading to progressive damage to oligodendrocytes in the antibodies, including antineutrophil cytoplasmic antibodies, DNA, central nervous system. Neuroimaging usually highlights scattered foci of white Scl-70, perinuclear antineutrophil cytoplasmic antibodies, rheu- matter hypodensity not attributable to contrast enhancement or mass effect. In matoid factor, and Smith antigen, were negative. contrast, we present an unusual case of PML predominantly affecting cervical Initial computed tomography of the head without contrast spinal cord and brainstem in an immunocompetent host. This is a rare subset of showed no intracranial abnormality. Multiplanar multisequence PML case that can occur in association with connective tissue disorders magnetic resonance imaging (MRI) of the brain without contrast (Sjögren Syndrome in this case), systemic lupus erythematosus being the most showed no acute process. Magnetic resonance imaging of the by common. Progressive multifocal leukoencephalopathy should be considered in BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= spine without contrast showed T2 signal abnormality involving the differential diagnosis of spinal cord or brainstem lesions, particularly in the the medulla extending into the upper cervical cord to C2 to C3 patients with connective tissue disorders. level with C3 medullary lesions (Fig. 1). Differentials, including Key Words: progressive multifocal leukoencephalopathy, Sjögren low-grade neoplasm, such as astrocytoma, chronic demyelinating syndrome, John Cunningham virus, oligodendrocytes, connective tissue disease and infection, were considered. Follow-up imaging 3 days disorders later remained unchanged. Patient continued to clinically deterio- – rate. She was managed for sepsis, pancytopenia, ventilator depen- (Am J Forensic Med Pathol 2020;00: 00 00) dency, and progressive hepatic decompensation. Eight days later, she died. CASE PRESENTATION At autopsy, gross examination of the brain revealed unre- A 65-year-old woman with known history of Sjogren syn- markable cerebral hemispheres, midbrain, basal ganglia, cerebel- drome presented to the emergency department at Henry Ford Hos- lum, pons, medulla and spinal cord. Histological examination pital, Detroit, MI, with a broken ankle secondary to a 4-month-old revealed confluent, extensive multifocal white matter lesions in fall. She also reported a 4-week history of vertigo, hemiparesis, the medulla. The cervical spinal cord, pons, mid brain, cerebellum, and right-sided weakness. Her medical history was pertinent for and basal ganglia were affected to a lesser degree. These lesions were cryptogenic cirrhosis, ascites, obstructive sleep apnea on continu- characterized by pallor, edema, perivascular lymphocytic cuffing, ous airway positive pressure, and hypothyroidism on Synthroid. microglial nodules, influx of activated microglial, and numerous oli- On examination, she appeared ill, pale, minimally respon- godendroglial nuclei with ground glass inclusions (Figs. 2, 3, and 4). sive, falling back to sleep quickly after waking. She was obtunded, The inclusions were immunoreactive with simian virus-40 (SV-40) oriented to person and date, but not to place. She was minimally (Figs. 5, 6), highlighted by P53 and MIB-1 immunostains. Other verbally responsive. Her speech was slurred with monosyllabic re- areas showed moderate hypoxic ischemic changes in the neocortex sponses. Her pupils were equal and reactive to light with full and hippocampus. These findings supported a diagnosis of progres- extraocular movements. She appeared to have a right facial droop sive multifocal leukoencephalopathy (PML) with moderate hypoxic – with no cough and gag reflex. There was absent and reduced mus- ischemic changes (Figs. 7 14). cle tone in the right extremities and left upper extremity, respec- Autopsy findings of other organs were consistent with bilat- on eral pleural effusion secondary to acute bronchopneumonia, ascites 03/05/2021 tively. Sensation to light touch and pain was intact but the patient was dysmetric with bilateral Babinski sign. There were di- secondary to hepatic cirrhotic, splenomegaly, and cardiomegaly. minished breath sounds in bilateral lung bases. Laboratory test showed high ammonia levels (47 μmol/L), with abnormal liver enzyme (aspartate transaminase, 56 IU/L), el- DISCUSSION evated blood urea nitrogen at 37 mg/dL, and normal serum creat- inine levels at 1.16 mg/dL. Progressive multifocal leukoencephalopathy is an opportu- nistic demyelinating disease of the central nervous system caused Cerebrospinal analysis was suggestive of a traumatic tap (red 1 blood cell count, 89,559; white blood cell count, 104 Â 109/L with by reactivation of the DNA viruses of the polyoma group. It is caused by 1 of 2 polyomavirus, John Cunningham (JC) virus, named after the first patient whose brain the virus was first iso- Manuscript received July 11, 2020; accepted October 24, 2020. 2 From the Henry Ford Health System, Detroit, MI. lated from. Strains of the JC virus has been isolated in nearly The authors report no conflict of interest. all of the documented PML cases with rare cases linked to the Reprints: Ifeoma Ndidi Onwubiko, MD, MPH, Henry Ford Health System, nonhuman primate viruses, such as simian vacuolating virus Detroit, MI. E-mail: [email protected]. 3 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. 40. The disease predominantly affects immunocompromised ISSN: 0195-7910/20/0000–0000 hosts, including people with leukemia, human immunodeficiency DOI: 10.1097/PAF.0000000000000656 virus-1 infection, lymphomas, and renal transplant.4 Am J Forensic Med Pathol • Volume 00, Number 00, Month 2020 www.amjforensicmedicine.com 1 Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Onwubiko et al Am J Forensic Med Pathol • Volume 00, Number 00, Month 2020 FIGURE 3. CD45 immunostain Â40 highlighting perivascular lymphocytes. Patient with autoimmune conditions, such as systemic lupus erythematosus, sarcoidosis, rheumatoid arthritis, and connective tissue disease, such as Sjogren disease independent of immuno- FIGURE 1. MRI of the spine without contrast. Arrow shows T2 therapy could develop PML due to disease associated lymphope- abnormality involving the medulla extending into the upper 13 cervical. nia. In 1998, Smith et al described a syndrome characterized by T-lymphocytes less than 300/μL or a CD4+ cell count of less than 20% of the total T cells on 2 occasions, in the absence of any de- Since the isolation of JC virus from the human brain of a pa- fined immunodeficiency of therapy leading to low CD 4+ T-cell tient with PML in the 1970s, JC virus seropositivity has been levels. By this definition, Kirtava et al14 reported that 5.2% of demonstrated in approximately 33% to 90% of people, depending Sjorgren syndrome have CD4+ T-lymphocytopenia. In 2008, on the study and geographical location.5,6 Although a large num- Power et al12 reported a rare case of PML in a patient with ber of the population are infected with the virus, people remain CD4+ T-lymphocytopenia and Sjogren syndrome. The patho- asymptomatic until they develop defective long-standing cell- physiology could be attributed to leukocyte sequestration in en- mediated immunity.7 Reports have been made in patients with larged spleen arising from portal hypertension from hepatic chronic meningoencephalitis in a young patient8 with chronic cirrhosis leading to patients developing leucopenia. In addition, clinical course9 and in an immunocompetent patient with sepsis.10 hypogammoglobinemia sequel to liver cirrhosis contributes to de- The disease was initially recognized as a paraneoplastic con- creased immunity. Transient failure of cellular immunity as seen dition in patients with hematological malignancies.11,12 Inciting in renal failure, liver cirrhosis, pregnancy, hepatitis C infection, factors to the development