The decedent was a 54-year-old white man who presented in March 1997 with right retro-orbital headache, followed by multiple skin lesions over the anterior aspect of his lower extremities. Multiple skin biopsies from the right lower leg revealed acute and chronic inflammation with necrotizing vasculitis. In addition, a nasal mucosal biopsy performed in November 1997 suggested changes that were compatible with Wegener granulomatosis. During this period of approximately 8 months, he was treated with multiple immunosuppressive agents, including cyclosporin, cyclophosphamide, methotrexate, prednisone, and azathioprine on an inconsistent basis. The pattern of intermittent headaches and skin lesions continued until March 2001, when he was noted to have difficulty walking, and was staggering, withdrawn, and then confused. In May 2001, he was found to have left-sided hemiparesis and visual field deficiency. Magnetic resonance imaging at a local hospital showed increased signal on T2 that was primarily subcortical, mainly located in the right anterior temporal lobe, and that extended to the midbrain, pons, and basal ganglion. This magnetic resonance imaging study was followed by lumber puncture, which showed an elevated protein level (0.072 g/dL; reference range, 0.015–0.045 g/dL) and a normal glucose level (520 mg/dL; reference range, 500–890 mg/dL) with no white blood cells or red blood cells. Polymerase chain reaction of cerebrospinal fluid for John Cunningham virus (JCV) was positive. Results of extensive laboratory workup, including fluorescence-activated cell sorting of peripheral blood and hematologic and immunologic analysis of total and subclasses of immunoglobins, were all within normal limits. Results of the patient's human immunodeficiency virus serology were negative. Angiography showed no evidence of vasculitis in the central nervous system. Comfort care for the patient at home was elected, and he died in August 2001, 4 years and 5 months after initial presentation. An autopsy was performed at the request of the family. The patient's past medical history included rheumatoid fever as a child and right orchiectomy for testicular histoplasmosis in 1973.

Relevant positive autopsy findings were as follows. (1) Multiple hyperpigmented macules, up to 3.0 cm in greatest diameter, were noted in the abdomen and bilateral mid-thigh. Microscopic examination revealed inflammatory cells (mainly lymphocytes) infiltrating the deep dermis, superficial subcutaneous adipose tissues, and around the perivascular spaces, some even within the vessel walls. No thrombi, fibroid necrosis, or giant cells were present. (2) No evidence of vasculitis or any changes suggestive of Wegener granulomatosis were identified in the lungs. However, a single remote left lung granuloma with Cryptococcus was identified. (3) The brain weighed 1600 g, and its surface was smooth. Serial coronal sectioning of the brain at approximately 1.0-cm intervals revealed severe to complete liquidation of the white matter with sparing of the gray matter. The liquidation mainly involved the right side, ranging from the frontal, parietal, and temporal lobes to the middle part of the occipital lobe. In contrast, similar changes of the left side were mainly confined to the frontal and anterior half of the temporal lobes (Figure 1). Focal areas of mild liquidation of the substantia nigra of the right side were also noted. The spinal cord was grossly normal, although focal areas of softening were noted. Microscopic examination of sections from the right temporal lobe revealed that the subcortical white matter was totally destroyed and replaced by numerous foamy macrophages and reactive astrocytes, some of which were large and bizarre looking. A number of oligodendrocytes were noted, the majority of which were large with dark, deep-stained nuclei with homogenous nuclear inclusions (Figure 2). The histologic changes of the left temporal lobe were similar to, but less pronounced than, those found on the right side. Immunohistochemical stains with antibody against polyomavirus demonstrated strong nuclear staining of the oligodendrocytes (Figure 3). Glial fibrillary acidic protein and histocytic marker (CD68) stains confirmed the presence of reactive astrocytes and macrophages. Microscopic examination of the hippocampus, substantia nigra, cerebellum from the right side, and spinal cord specimens from cervical, thoracic, and sacral regions revealed similar morphologic changes. Electron microscopic examination of tissue samples from the right temporal lobe revealed numerous particles, which were spherical and approximately 35 to 45 nm, within the nuclei of oligodendrocytes (Figure 4). (4) In the cardiovascular system, sterile vegetations of the right atrial valves were found. (5) Two small foci of splenic coagulation necrosis were found within the reticuloendothelial system.

What is your diagnosis?

Progressive multifocal leukoencephalopathy (PML), which was first reported by Astrom et al in 1958,1 is a fatal subacute demyelinating disease of the central nervous system caused by member(s) of the Polyomavirinae subfamily, including JCV. It has been estimated that serologic positivity for JCV in the normal US population is 68% to 80%.2 However, most infected people are asymptomatic, and PML only develops in JC/BK (majority are caused by JC) virus–infected immunocompromised patients, such as those with acquired immunodeficiency syndrome, non-Hodgkin lymphomas, leukemias, and organ transplant receipts. The clinical presentation of PML includes progressive dementia, motor dysfunction, and vision loss with death within a short period of time. The pathogenesis of PML by JCV is complex and not well understood. However, it has been shown that the major target cells of JCV infection in the central nervous system are oligodendrocytes, and the initial interaction between JCV and glial cells involves virus binding to N-linked glycoproteins containing terminal α–(2,6)–linked sialic acids; JCV subsequently enters glial cells by receptor-mediated, clathrin-dependent endocytosis.3 

Documented cases in which PML developed in patients treated with immunosuppressant agents for Wegener granulomatosis4,5 and systemic lupus erythematosus6 have been published. In this case, the direct cause-effect relationship between the use of a particular immunosuppressant agent and the development of PML is difficult to establish. We can only speculate that 1 or a combination of 2 or more immunosuppressant agents may be responsible for the development of PML.

The diagnosis of PML in this case was suspected based on the findings of magnetic resonance imaging and was further confirmed by molecular (positive polymerase chain reaction analysis for cerebrospinal fluid JC virus) and morphologic (light and electron microscopy, as well as immunohistochemistry) studies. From a diagnosis point of view, PML has 3 main pathologic features, including demyelination without evidence of inflammation; frequent abnormal oligodendrocytes with large nuclei with ground-glass appearance; and many large, unusual, bizarre-looking astrocytes. The nuclei of oligodendrocytes and astrocytes containing viral inclusion bodies are characteristic, which can be well demonstrated by in situ hybridization, immunohistochemistry, and electron microscopy.7 The sensitivity and specificity values for polymerase chain reaction analysis of cerebrospinal fluid for JCV can reach 75% and higher than 90%, respectively.8 Differential diagnosis should include multiple sclerosis, other demyelinating disorders, and astrocytic neoplasia.

The prognosis for PML is dismal. The disease usually progresses rapidly, with death less than a year after diagnosis. However, patients surviving with PML for a longer period of time have been reported with the advent of highly active antiretroviral therapy.

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The author has no relevant financial interest in the products or companies described in this article.

Author notes

Corresponding author: Huan-You Wang, MD, PhD, Department of Pathology, PO Box 800214, The University of Virginia Health Sciences Center, 2200 Jefferson Park Ave, Charlottesville, VA 22908-0214 (hw3e@virginia.edu)