Progressive multifocal leukoencephalopathy, the role of the susceptibility-weighted imaging sequence in a case of immunosuppression of an initially unknown cause
Article information
Abstract
We describe the case of a 47-year-old woman who was confused and complained about left-sided weakness when she presented to our institution. The patient underwent a head computed tomography that raised the suspicion of a recent-onset ischemic episode (subacute phase). The patient was admitted to the neurology department and underwent a magnetic resonance imaging (MRI) with contrast medium administration. The clinical and laboratory findings and the MRI features, particularly the presence of a hypointense rim in the susceptibility-weighted imaging (SWI) sequences, were consistent with a diagnosis of progressive multifocal leukoencephalopathy (PML). Immunosuppression was observed as a result of lymphopenia, and the patient was subsequently diagnosed with previously undocumented AIDS. Our aim is to present this rare case of PML in an immunocompromised patient with AIDS, describing the main MRI features and the possible role of SWI sequences.
Introduction
Progressive multifocal leukoencephalopathy (PML) is a rare neurological disease affecting the central nervous system. The incidence in the general population is estimated at 4.4 cases/100,000, and this incidence has dramatically increased secondary to the human immunodeficiency virus (HIV)/AIDS epidemic that began in the mid-1980s. This incidence has been exacerbated by the widespread use of highly active antiretroviral therapy (HAART) [1,2]. PML is caused by the John Cunningham virus (JCV), a DNA virus of the polyomavirus family, that usually remains latent in immunocompetent hosts. Typically, JCV causes symptomatic disease in severely immunocompromised patients such as those with AIDS and a CD4+ count less than 100. However, PML has occurred in patients with high CD4+ counts. Transplant patients are at an increased risk for PML as are patients with impaired cellular-mediated immune responses due to lymphoproliferative diseases and those under monoclonal or polyclonal antibody therapy. Occasionally, PML is related to immune reconstitution inflammatory syndrome caused by HAART. Patients with this condition experience an increase in CD4+ count followed by a paradoxical worsening of symptoms [3-5]. PML usually presents as a progressive neurological decline, and symptoms vary depending on the site of demyelination. PML is induced by replication of JCV within oligodendrocytes, astrocytes, and occasionally neurons. These cells are consequently destroyed by the JCV and CD8+ cytotoxic lymphocytes [6]. Mortality is 30% to 50%, and early diagnosis and initiation of appropriate therapy are of paramount importance. Diagnosis requires anamnestic data, cerebrospinal fluid (CSF) polymerase chain reaction (PCR) analysis, and imaging. Magnetic resonance imaging (MRI) is the preferred imaging technique; early changes and signs of progression are more likely to be identified on MRI. Typically, PML is characterized by a single or, more commonly, multiple white matter (WM) lesion(s) viewed on T2-weighted or fluid-attenuated inversion recovery (FLAIR) sequences. This appearance is occasionally associated with signs of active demyelination that can be viewed as restriction areas on diffusion-weighted imaging (DWI). Contrast enhancement is possible but rare. Susceptibility-weighted imaging (SWI) has provided a new perspective. On SWI, PML is associated with a hypointense signal that may be the result of iron deposits [7,8]. The cause, however, has not been fully clarified. We report the case of a young woman with neurological symptoms initially thought to be the result of an ischemic stroke. MRI and, specifically, SWI sequences were instrumental in reaching a definitive diagnosis of PML that was due to a previously undiagnosed case of AIDS.
Case Report
A 47-year-old woman with no relevant medical history was referred to our institution for a progressive cognitive decline associated with episodic confusion of 6-week duration. She had difficulty naming objects and people and was unable to concentrate. She also manifested a progressive left-sided weakness with a tingling sensation that was particularly prominent in her lower limb. Her condition deteriorated on the day prior to presentation; and the patient’s family knew of no comorbidities, particularly none that could be responsible for her immunosuppression. She was awake alert and partially oriented to her surroundings. Neurological examination revealed clear signs of cognitive impairment; her mini-mental state examination (MMSE) score was 21, indicating mild cognitive impairment, and confirmed left-sided weakness (strength of 4/5). There were no visual-spatial or cranial nerve functional deficits. An unusual leukopenia caused by lymphopenia was observed (white blood cells, 3.86 × 103/µL; lymphocytes, 0.73 × 103/µL [19%]; neutrophils, 2.54 × 103/µL [65.7%]; monocytes, 0.37 × 103/µL [9.6%]; eosinophils, 0.14 × 103/µL [3.6%]; and basophils, 0.02 × 103/µL [0.3%]). A stroke was suspected, and the patient was referred to the radiology department for an emergency computed tomography (CT) exam. CT demonstrated a subcortical focal area of low attenuation in the precentral gyrus (Figure 1). The patient was admitted to the neurology department with the misdiagnosis of subacute ischemic stroke.
Head computed tomography imaging
The sagittal (A), axial (B), and coronal plane (C) images showed a subcortical focal area of low attenuation (red arrows) in the right precentral gyrus compatible with ischemic stroke.
A brain MRI revealed an area of hyperintensity on the T2-weighted FLAIR sequences and a hypointense area on the T1-weighted sequence in the precentral gyrus. This area had a particular gyriform pattern and affected only the WM; the cortical gray matter (GM) was spared. No enhancement was observed after administration of contrast media. The DWI sequence demonstrated no significant restriction of diffusion but a rim of hypointensity on the cortical side of lesions (Figure 2). This was confirmed to involve the subcortical U-fibers and is better appreciated in the SWI sequence (Figure 3).
3-T magnetic resonance imaging sequences
The axial three-dimensional fluid-attenuated inversion recovery (A) showed an area of hyperintensity and axial diffusion-weighted imaging (DWI) with 1,000 b-value (B), and the relative apparent diffusion coefficient map (C) showed no significant restriction of diffusion. There is a T2 shine-through effect, but DWI showed a rim of hypointensity at the cortical side of lesions (red arrow) involving the subcortical U-fibers. Pre- (D) and post-gadolinium sequences (E, F) on sagittal and axial planes showed an area of hypointensity in the precentral gyrus on the T1-weighted sequence without significant enhancement after administration of contrast agent.
3-T magnetic resonance imaging
(A) The axial susceptibility-weighted imaging (SWI) sequence showed a hypointense subcortical linear alteration barely visible on the diffusion-weighted imaging sequence, involving the subcortical U-fibers. (B) The SWI phase image showed a hyperintense linear alteration in the same area. This indicated the presence of magnetic micro-susceptibility phenomena from deposits of material with paramagnetic properties.
The MRI results led us to discount the ischemic stroke diagnosis. These results indicated the presence of a pathological demyelinating condition. The subcortical U-fiber involvement with a well-demarcated peripheral border, the localization exclusively at the right precentral gyrus, and the presence of lymphopenia suggested that the patient might be suffering from PML caused by immunodeficiency. HIV tests showed a high viral load (6.75 × 105 HIV copies/mL) and a CD4+ count of less than 200 cells/mL, confirming a diagnosis of advanced AIDS. CSF analysis revealed a cell count of 17 cells/µL, protein level of 79 mg/dL, and glucose concentration of 56 mg/dL. CSF PCR demonstrated 5.73 × 104 JCV copies/mL. Appropriate therapy including HAART was initiated, and the brain MRI was repeated 2 months later. At that time, the patient’s neurological condition was in steady decline, and her MMSE was 17/30. The patient continued to experience progressive difficulty in speaking, with signs of aphasia and progressive lower limb weakness that had begun to also affect her right lower limb. On MRI, we observed massive progression of T2-weighted FLAIR areas of hyperintensity extending to the precentral gyrus, semioval center, and corona radiata and partially to the parietal lobes (Figure 4).
3-T magnetic resonance imaging
(A) The axial 3D-FLAIR sequence showed multiple hyperintense areas extending on the precentral gyrus, semioval center, right and left corona radiata, and right and left parietal lobes. (B) The axial SWI sequence showed a hypointense subcortical linear alteration involving the subcortical U-fibers. (C) Axial DWI (b-value, 1,000) and the relative ADC map showed faint restriction in the right precentral gyrus. The axial pre- (D) and post-gadolinium T1-weighted sequences (E) showed multiple confluent areas of hypointensity without significant enhancement after administration of the contrast agent.
3D FLAIR, three-dimensional fluid-attenuated inversion recovery; SWI, susceptibility-weighted imaging DWI, diffusion-weighted imaging; ADC, apparent diffusion coefficient.
The written informed consent was obtained for publication of this report and accompanying images.
Discussion
This case report describes a severely immunocompromised patient with AIDS and consequent PML that was initially misdiagnosed as ischemic stroke. Stroke on MRI is characterized by an immediately hyperintense area on DWI that correlates with a hypointensity on apparent diffusion coefficient (ADC) maps as the consequence of restricted diffusion of cellular edema. After hours of ischemia, a hyperintense area appears on T2-weighted and FLAIR with a pronounced cortical enhancement in the post-contrast sequences [9]. In contrast, PML lesions are found mainly in the subcortical and juxtacortical WM of supratentorial or infratentorial structures [10]. Typically, on MRI, a single or multiple focal area(s) of hyperintensity are observed on T2-weighted/FLAIR sequences and are associated with hypointensity on T1-weighted [11,12]. Usually, T1-weighted post-contrast sequences show only faint or null enhancement, and DWI/ADC maps are not specific, can be variable, and are usually negative for restriction. A rim of restricted diffusion in DWI/ADC maps may be observed, and this is interpreted as a sign of active demyelization. A particular feature due to the demyelization process associated with PML is the remarkable appearance of the lesion, sharply demarcated toward the GM, which is spared, and blurred toward the WM [13]. Another difference observed between stroke and PML imaging patterns is the presence of a curious dark rim adjacent to the cortical side of lesions on the SWI sequence. SWI is a new technique based on the magnetic properties of tissue and combines a T2*-weighted magnitude image with a high-pass filtered phase image and a gradient echo sequence. In this sequence, contrast information is derived from phase images used to differentiate diamagnetic tissue from paramagnetic tissue. This is important for the evaluation of heme products [14]. The rim visible on the SWI sequence is probably due to the involvement of U-fibers, but the etiology has not been fully explained. The execution of quantitative susceptibility mapping by Carra-Dalliere et al. [15] suggested the presence of paramagnetic material. Mahajan et al. [7], using in vivo and postmortem MRI and correlating these with anatomopathological examination, found a band of increased iron-rich macrophages at the GM-WM passage, compatible with the dark rim in SWI. The presence of macrophages could reflect the extensive inflammation process induced by JCV that is followed by oligodendroglial dysfunction, myelin degeneration, and axonal impairment. These are visible as hyperintense areas on T2-weighted or FLAIR sequences and lead to progressive brain damage. Another possible cause of the SWI dark rim is blood-brain barrier damage caused by the filtration of heme products into the perivascular space [7,8,15]. The specific position of iron deposits is caused by the cerebral microenvironment, with restricted passage of macrophages to the cortex. Another possible explanation is the high iron content of U-fibers and the presence of long arterioles and venules with a gyriform distribution [8,16,17]. The dark rim on the SWI sequence had been initially interpreted as a specific sign of PML, but recent studies have proposed that it is suggestive but nonspecific. Umino et al. [18] described the presence of a rim along the cerebral cortex in patients with infarcts and encephalitis, and Kesavadas et al. [19] described two cases of hypoxic ischemia. The dark rim’s interpretation as a specific sign of PML may assist in early diagnosis and, therefore, in the early initiation of appropriate therapy [20]. The rim has also been proposed to be a possible marker of the endpoint neuroinflammatory process and a possible outcome predictor by its presence only in long-survivor patients [8]. Future studies are necessary to elucidate the reason for its presence.
We presented a case of PML initially diagnosed as ischemic stroke. PML is rare and its pathological mechanism has not been totally revealed. Early diagnosis is important to prevent the progression of the disease, and early MRI PML pattern recognition is crucial for the initiation of appropriate treatment and disease progression containment. CSF PCR analysis for JCV with a sensitivity of 80% may be the gold standard for PML diagnosis, but neuroimaging is a useful option. In our case, the suspicion of PML was derived from the dark rim observed on the SWI sequence. While present in other pathologies, this SWI hypointense rim is highly suggestive of PML.
Notes
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization: Balzano RF, Guglielmi G; Data curation: D’Arma GMA, Balzano RF, Masino F; Formal analysis: D’Arma GMA; Methodology: D’Arma GMA, Balzano RF; Supervision: Guglielmi G; Writing–original draft: D’Arma GMA, Masino F; Writing–review & editing: Balzano RF, Masino F