Progressive Multifocal Leukoencephalopathy: Cavitary White Matter Lesions

Abstract

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disorder of the central nervous system caused by the opportunistic neurotropic Polyomavirus JCV. PML typically presents in immunocom-promised individuals; is considered an AIDS defining condition; and is clinically characterized by cognitive defects, coordination problems, limb paresis, and speech disturbances. MRI can identify the characteristic bilaterally asymmetrical lesions that favor the subcortical frontal and parietal lobes as hypo-intensities on T1-weighted images and as hyper-intensities on T2-weighted images. Grossly, these areas appear discolored by a dusky, yellow-brown hue with the rare appearance of cavitation. No known therapeutic agent can specifically halt the progression of PML, and survival time after diagnosis averages less than two years. In this submission, we present a photo depicting striking lesions of severe PML of the cavitary type.

CASE PRESENTATION

A 47-year-old female with a past medical history of HIV+ and hypertension presented with acute shortness of breath, progressive neurologic decline including dysarthria and difficulty ambulating, a CD4 count of 33 cells/μL, and a total WBC count of 400 cells/μL. A CT of the head was normal, and a chest CT revealed diffuse ground-glass opacities. The patient was admitted to the hospital and diagnosed with Pneumocystis jirovecii pneumonia. Despite appropriate antibiotic treatment, neurological function rapidly deteriorated, and the patient expired two days after admission. Neuropathologic examination of the brain at autopsy revealed diffuse cerebral atrophy with a brain weight of 960 g (expected weight: 1290 g + 20).¹ A coronal section of the frontal lobe at the level of the caudate nucleus is shown below.

DISCUSSION

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disorder of the central nervous system caused by the reactivation of the human neurotropic virus JCV. This opportunistic agent, a member of the Polyomaviridiae family, is endemic in the worldwide population. With nearly 50% of children exhibiting anti-JCV antibodies, primary infection is presumed to occur in early childhood.² JCV remains in a latent state within renal tubular epithelial cells until an im-munosuppressive condition arises, and its reactivation results in lysis of oligodendrocytes, development of demyelinated plaques, and leukoencephalopathic destruction. While 80% of PML cases occur in HIV positive individuals, the disease may also manifest in those with hematologic malignancies, solid cancers, autoimmune diseases treated with immuno-modulators, and following post-organ transplant.^3,4 Since the advent of highly active antiretroviral therapy (HAART), the incidence of PML in the AIDS population has dropped to 5%, but survival time after diagnosis remains dismal at 1.8 years.^5,6 While no known therapeutic agent has been identified that can specifically halt the progression of JC viral infection, reversal of the immunosuppression, which normally allows viral activation, may benefit the patient.^6–8 Despite the discovery of several drugs targeting JCV infection and replication, clinical trials have yet to confirm advantages beyond those conferred by HAART in AIDS-associated PML.⁹

The clinical presentation of PML, as seen in this patient, is often insidious and is the initial AIDS defining illness in close to one-third of cases.^10,11 The most common neurologic signs include coordination problems, cognitive defects, limb paresis, and speech disturbances.⁶ As tracked by MRI, PML lesions typically first appear subcortically in the frontal and parietal lobes; however, demyelinated plaques can also be observed in deep gray structures, the cerebellum, brainstem, and even the spinal cord.^10,12 Lesions are identified as multiple, bilateral, asymmetrical, hypointensities on T1-weighted images and as hyperintensities on T2-weighted images.^10–12 In advanced cases, the lesions may enlarge, coalesce into larger areas of cellular injury and/or cystic cavities, and may be accompanied by atrophy.¹⁰ Histologically, PML demyelin-ated plaques are rimmed by oligodendrocytes containing prominent intranuclear eosinophilic inclusion bodies, as well as bizarre, hyperchromatic, multilobulated, and sometimes multinucleated astrocytes.¹³ By electron microscopy, JC vi-rions can present as filamentous, or most commonly, round structures of approximately 35–40 nanometers in diameter. Occasionally, round virions appear in a perfectly aligned pattern called crystalloid array.¹⁴ Lesions may contain foamy myelin-filled macrophages with or without axonal sparing. As the disease progresses, microscopic areas of demyelination within these plaques can coalesce to become macroscopic cystic cavities or plaque lesions with a dusky grey-brown appearance and areas of tissue softening on sagittal sectioning of autopsy brain specimens.¹³

Figure 1.

Coronal section of the brain at the level of the caudate nucleus, showing small cavitary lesions in the subcortical white matter at the junction of the corpus callosum and the left cingulate gyrus.

Figure 2.

A special stain for myelin reveals extensive areas of demyelination in the subcortical white matter (Panel A, Luxol Fast Blue). Within these areas of myelin loss, bizarre astrocytes can be observed (Panel B, H&E). Immunohistochemistry for VP1, the capsid protein of JCV, is positive in infected oligodendrocytes in the borders of the demyelinated plaques (Panel C). Original magnification for Panel A is 100× and 400× for Panels B and C.