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Show Progressive Multifocal Leukoencephalopathy: Recent Advances and a Neuro-Ophthalmological Review Padmaja Sudhakar, MBBS, David M. Bachman, MD, Alexander S. Mark, MD, Joseph R. Berger, MD, Sachin Kedar, MBBS, MD Background: Progressive multifocal leukoencephalop-athy (PML) is a severe often fatal opportunistic infection of the central nervous system caused by reactivation of a ubiquitous polyoma virus, JC virus. Although typically characterized by multifocal asymmetric subcortical white matter lesions, it may be monofocal and affect the cortical gray matter. Among the broad spectrum of clinical manifestations that occurs with PML, visual complaints are common. Evidence Acquisition: Combination of representative per-sonally observed cases of PML and comprehensive review of case series of PML from 1958 through 2014. Results: Neuro-ophthalmic signs and symptoms were reported in approximately 20%-50% of patients with PML and can be the presenting manifestation in half of these. A majority of these presentations occur from damage to cere-bral visual pathways resulting in visual field defects, cortical blindness, and other disorders of visual association. Given the decreased frequency of infratentorial and cerebellar involvement, ocular motility disorders are less common. Conclusions: Visual complaints occur in patients with PML and are often the presenting sign. Awareness of this condition is helpful in avoiding unnecessary delays in the diagnosis of PML and management of the underlying condition. Recent guidelines have established criteria for diagnosis of PML in the high-risk patient population and strategies to mitigate the risk in these populations. Journal of Neuro-Ophthalmology 2015;35:296-305 doi: 10.1097/WNO.0000000000000271 © 2015 by North American Neuro-Ophthalmology Society Progressive multifocal leukoencephalopathy (PML) was first described by Aström, Mancall, and Richardson in 1958 as a unique demyelinating disorder with characteristic histopathology in 3 patients with lymphoproliferative dis-orders (1). It is a severe often fatal demyelinating disease that results from lytic infection of oligodendrocytes by the JC virus, a ubiquitous human polyoma virus (2). PML usually occurs in the immunosuppressed patient and results in a dev-astating neurological illness which is fatal, unless the under-lying immunosuppressive cause is identified and treated. Despite the propensity of PML to produce visual symptoms, very few reports have addressed the neuro-ophthalmological features of this disease. The objective of this review is to provide a current understanding of the disease process includ-ing the varied neuro-ophthalmic presentations using illustra-tive cases. For purposes of this report, we reviewed medical literature on Medline and Google Scholar using the terms PML, progressive multifocal leukoencephalopathy and vision, diplopia, pupils, eye movements, and blindness. Where appropriate, we also used data gathered by Bachmann and Mark (coauthors of this article) reviewing 240 cases of PML published up to 1992. Epidemiology PML is almost always observed in association with an immunocompromised state, either from an underlying disease or associated treatment; however, in rare instance, it may be seen in the absence of apparent immunological abnormality (3,4). The PML era can be broadly divided Departments of Neurology (PS), University of Kentucky College of Medicine, Lexington, Kentucky; Departments of Ophthalmology (DMB), and Radiology (ASM), Washington Hospital Center, Washington, District of Columbia; Department of Neurology (JRB), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Department of Neurological Sci-ences and Ophthalmology (SK), University of Nebraska Medical Center, Omaha, Nebraska. Sachin Kedar has received royalty fees for editorial services from Elsevier Inc. Joseph Berger reports personal fees from Amgen, Astra Zeneca, Bristol Myers Squibb, Eisai, Janssen, Millenium, Parexel, Pfizer, Roche, Takeda, Genentech, Genzyme, Incyte, Inhibikase, Johnson and Johnson, Novartis, American Academy of Neurology, Consor-tium of MS Centers and grants from Biogen Idec, PML Consortium and Novartis. The other authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Padmaja Sudhakar, MBBS, Department of Neurology, University of Kentucky, 740 S Limestone, Suite L 445, Lexington, KY 40536, E-mail: psu224@uky.edu 296 Sudhakar et al: J Neuro-Ophthalmol 2015; 35: 296-305 State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. into 4 epochs: pre-HIV, HIV (pre-HAART), HIV (post- HAART), and modern era. Before HIV epidemic in the early 1980s, PML was rare and seen almost exclusively in patients with lymphoproliferative and myeloproliferative disorders (5-10). After the HIV pandemic, the incidence of PML increased by almost 50-fold making HIV the lead-ing cause of this disease (11-14). During this era (HIV pre-HAART), 5% of patients with HIV developed PML with a median survival of 6 months with fewer than 10% survival rate 1 year after symptom onset. With the advent of highly active antiretroviral therapy (HIV post-HAART era), there was a significant decline in the incidence (15). Mortality rates from PML improved from 90% in the 1980-1990 decade to 50% in the first decade of the 21st century (16). A new era of PML dawned in 2005 when PML was reported in association with treatment with natalizumab for Crohn's disease and multiple sclerosis (MS) (17-19). This resulted in a tempo-rary withdrawal of natalizumab, an anti-alpha-4 integrin, from the market in 2005. Of 99,517 patients treated with natalizumab until 2012, there were 212 confirmed cases of natalizumab-associated PML (20). Other than natalizumab and efalizumab, PML has also been reported with various monoclonal antibodies and immune-modifying therapies. Among other immunomodulatory agents that have impli-cated in predisposing to PML are the anti-TNF-alpha agents, infliximab, adalimumab, and etanercept, ruxolitinib (inhibitor of JAK 1 and 2), and oral agents used in treat-ment of MS, dimethyl fumarate (Tecfidera) (21,22). Cur-rently, several drugs carry an FDA-mandated black box warning for PML, including natalizumab, rituximab, brentuximab-vedotin, and mycophenolate mofetil. Pathogenesis Subclinical infection with JC virus generally occurs within the first decade of life and by adulthood; 50%-80% of the pop-ulation is seropositive for the virus (23,24). The virus remains latent in the kidney, bone marrow, and lymphoid organs (8). PML is caused by reactivation of the JC virus in the setting of immunosuppression with spread to the CNS leading to oli-godendrocyte infection and demyelination. JC virus infection of the brain typically causes a subacute progressive disorder with multifocal asymmetric subcortical white matter involve-ment from which the disease entity derives its name. Astro-cytes and neurons may also be infected but the virus does not complete its entire replicative cycle in the former. Instances of monofocal disease and gray matter involvement of cerebellar granular cells (25,26) and cerebral cortical neurons have been described (27). Isolated lesions of the cerebellum and brain-stem are rare [Joseph Berger, MD and 2013 personal obser-vation and Mossakowski and Zelman (28)] and may be higher in the HIV/AIDS population with PML (12) com-pared with other predisposing causes such as natalizumab-associated PML (29). Clinical Presentation Despite a propensity to affect the cerebral hemispheres, any part of the brain may be affected, which produces a variety of neurological manifestations. Behavioral and cognitive abnormalities are seen in one-third to half of all individuals (12,29). Common findings include motor weakness, gait abnormalities, visual field defects, language problems, and incoordination (12,30). Less common findings include headache, sensory loss, seizures and diplopia (12,30). Spinal cord involvement has only been reported in pathologic specimens; myelopathy has not been described clinically (31). There are no descriptions of optic nerve disease or peripheral nervous system involvement by PML. Despite significant overlap in clinical presentation, cognitive prob-lems more often herald natalizumab-related PML, whereas motor weakness is associated with HIV-related PML (29). Neuro-ophthalmology of PML Very few studies in literature have systematically described the neuro-ophthalmic features of PML (32,33). Brooks and Walker (30) reviewed 230 published and unpublished cases of PML and reported visual field deficits (34.7%), visual blurring (7.2%), diplopia (1.4%), optic atrophy (1.4%), and cortical blindness (2.9%). Only 45% of these were virologically or pathologically confirmed cases. Berger and Pall (12) reported visual field defects (19%) and diplopia (9%) in their series of 154 HIV-associated patients with PML at presentation. In their review of 240 published cases of PML, Bachman and Mark found 125 patients (52%) with neuro-ophthalmological findings (2-7,11,34-138). Of the 74 patients with AIDS, 40 (54%) had neuro-ophthalmological findings (See Supplemental Digital Con-tent, Table E1, http://links.lww.com/WNO/A163). Visual disorders can be the presenting features in approximately 20% of patients with both HIV-associated and non- HIV-associated cases of PML (10-12,41,120,139-142). In the following sections, we will describe the pertinent neuro-ophthalmological features using illustrative cases. Case 1 A 63-year-old woman with a history of Sjogren's syndrome and ovarian cancer developed difficulty reading a clock face and began bumping into objects in her left visual field. Her symptoms were initially attributed to "chemobrain"; but 3-4 months later, she developed stuttering, difficulty fold-ing clothes, tying her shoes, and dressing herself, followed a month later by left arm and leg weakness. Neurological examination showed dyscalculia, difficulty following three-step commands, dressing apraxia, dense left homonymous hemianopia, and mild left hemiparesis. Brain magnetic res-onance imaging (MRI) obtained 2 months later showed a large T2/fluid-attenuated inversion recovery image (FLAIR) hyperintense signal abnormality affecting the right parietal and occipital lobes with extension across splenium Sudhakar et al: J Neuro-Ophthalmol 2015; 35: 296-305 297 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. of the corpus callosum (Fig. 1). There also was involvement of the right thalamus, posterior limb of internal capsule, and right cerebral peduncle. The lesion was hypointense on T1 imaging, did not enhance with contrast, was subcortical in location, and did not demonstrate mass effect. CSF exam-ination showed JC virus DNA by polymerase chain reaction (PCR technique). She had an absolute CD4 count of 390 cells per microliter and CD4/8 ratio of 0.5. Homonymous Hemianopia Homonymous hemianopia (including quadrantanopia) is the most common ophthalmic manifestation of PML from involvement of optic radiations in both AIDS and non- AIDS series, seen in 25% of the 240 cases of PML reviewed by Bachman and Mark through 1992 (See Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A163). Other studies have reported higher figures (35%-45%) for homonymous hemianopia in reported cases of PML (30,32). Unilateral and bilateral homonymous hemianopia and quad-rantanopia may be the presenting symptom of PML in AIDS (33,142,143). Reversal of both vision and other neurological deficits 8 months after resumption of highly active antiretro-viral therapy (HAART) was reported in patients with HIV-associated PML (144,145). Homonymous hemianopia also has been reported in cases of PML from natalizumab. In a series of 28 patients with natalizumab-associated PML, 5 had homonymous hemianopia and 3 reported diminished vision as a presenting manifestation (29). Homonymous hemianopia in patients with MS on natalizumab should raise suspicion for PML. This has prompted recommendations for visual acuity and visual field testing every 3 months in patients with MS treated with natalizumab for 1 year or longer (146). Case 2 A 35-year-old man with a history of HIV and non-Hodgkin's lymphoma, in remission for 7 years after treatment, developed dizziness, confusion, and blurred vision. He discontinued HAART 3 years earlier and was lost to follow-up. For the last 3 months, he had difficulty driving and had sideswiped cars on his right side. Neurological examination performed 1 month later was remarkable for cortical blindness, visual agno-sia, pure word deafness, and right hemiparesis. MRI brain showed T2/FLAIR hyperintense signal in the left parietal and occipital lobes and splenium of corpus callosum (Fig. 2). There was extension into the left posterior frontal lobe, external capsule, and posterior limb of the internal cap-sule, thalamus, mid-brain, pons, and contralateral occipital lobe. Most recent CD4 count was 26 cells per microliter, CD4:CD8 ratio was 0.18, and HIV viral load was 74,800 copies per mL. CSF examination confirmed JC virus DNA by PCR technique. Biopsy of the occipital lesion showed features that were consistent with PML (Fig. 3). Abnormalities of Visual Association A large spectrum of disorders of visual association has been observed with PML including visual neglect (12), visual hal-lucinations (147), prosopagnosia, and impaired spatial percep-tion (12,139). Balint syndrome (148-151) has been reported in patients with PML. These patients frequently complain of visual distortion, difficulty reading, "fragmented" environ-ment, difficulty driving, and other visuospatial abnormalities. In those instances in which Balint syndrome has been attrib-uted to HIV encephalopathy, it is far more likely to have been caused by unrecognized coexisting PML (152,153). Bachman and Mark have seen 2 patients with optic aphasia in FIG. 1. Case 1. Magnetic resonance imaging of progressive multifocal leukoencephalopathy. On axial fluid-attenuated inversion recovery image image (A), there is a hyperintense lesion (arrow), which appears hypointense and does not enhance (arrow) on postcontrast T1 axial scan (B). 298 Sudhakar et al: J Neuro-Ophthalmol 2015; 35: 296-305 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. association with alexia and homonymous hemianopia. Both had involvement of the dominant parietal lobe and corpus callosum producing the "disconnection syndrome." These pa-tients had presented with difficulty reading and naming letters on the Snellen chart despite 20/20 visual acuity. Cortical blindness in PML results from bilateral involve-ment of the retrogeniculate visual pathways, typically the optic radiations or the primary visual cortex and may be seen in 6%-8% patients (30,41). These cases may start with visual blurring and progress to visual field loss and cortical blindness, as unchecked PML progresses to bilateral occipital involve-ment often accompanied by neurological deficits such as pro-sopagnosia and alexia with agraphia (139). Unless there is a high degree of suspicion, presentation of PML as visual loss may be mistakenly attributed to ophthalmic causes such as cataract or postoperative inflammation after eye surgery lead-ing to unnecessary procedures and diagnostic delay (154,155). Case 3 A 34-year-old homosexual man with a 12-year history of AIDS and no previous opportunistic infection reported a 2-week history of right face and arm paresthesia, numbness, and weakness. One week before presentation, he developed blurred vision and binocular vertical diplopia. He had discontinued HAART 1 year ago due to intolerance to medications. On examination, he had right hemiparesis, right central facial palsy, and left hypertropia (consistent with skew deviation). Visual acuity, visual fields, pupillary reflexes, and retinal examination were normal. Brain MRI showed a T2 hyperintense lesion in the left pons extending to the left cerebral peduncle (Fig. 4). There also was involvement of the centrum semiovale bilaterally. Lumbar puncture demon-strated 5 white blood cells per mL, 1093 red blood cells per mL (traumatic tap), protein of 86 mg/dL (normal: 15-60 mg/ dL), glucose of 58 mg/dL (normal: 15-45 mg/dL), and 120 FIG. 2. Case 2. Magnetic resonance imaging of progressive multifocal leukoencephalopathy. A. On axial fluid-attenuated inversion recovery image scan, there is a hyperintense lesion with extension through the splenium of the corpus callosum. B. The postcontrast T1 sagittal image shows the affected area (enclosed between the arrows) to be hypointense without evidence of enhancement. FIG. 3. Case 2. Histopathology of the left parieto-occipital lesion. A. There is infiltration with macrophages, scattered bizarre astrocytes (black arrow), and oligodendrocytes with "glassy" nuclei (white arrow) (hematoxylin & eosin, ·400). B. There is loss of myelination with ingestion of myelin by macrophages (arrow) (Luxol fast blue, ·400). C. JC viral particles are present in atypical astrocytes and oligodendrocytes (arrows) (SV40T immunostain, ·600). Courtesy of Craig Horbinski, MD, PhD, University of Kentucky, Lexington, KY. Sudhakar et al: J Neuro-Ophthalmol 2015; 35: 296-305 299 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. copies per mL of JC virus DNA by PCR. In his blood, he had 120,000 copies per mL of HIV-1 RNA. Infratentorial PML Infratentorial demyelinating lesions may occur in isolation or with supratentorial lesions (12,109,156-158). The cere-bellum is more commonly involved than the brainstem probably as a consequence of greater volume and due to a unique cerebellar syndrome from the causative virus referred to as JC virus granule call neuronopathy (159). Patients with brainstem findings may have concurrent involvement of the cerebellum seen on imaging or on path-ological investigations (157). Infratentorial (cerebellar and brainstem) abnormalities were noted on neuroimaging stud-ies in 48% (20% isolated infratentorial lesions) of 154 PML cases in a large series (12). Infratentorial involvement on imaging studies does not necessarily translate to clinical abnormalities in as many as 50% of cases. This poor cor-relation could be artifactual (retrospective studies, brainstem signs either not elicited or recorded) or related to the natural history of the disease with chances of brainstem involve-ment being less when duration of PML is less than 2 and half months (109). Brainstem involvement may cause nuclear, internuclear, and supranuclear palsies producing diplopia, facial weakness, and numbness, hypoacusis, dysarthria, dysphagia, and nys-tagmus. PML may cause isolated or multiple ocular motor cranial neuropathies, multiple cranial neuropathy (sixth and seventh), internuclear ophthalmoplegia (160), or abnormali-ties of ocular smooth pursuit, saccades, and nystagmus (12,161). PML with cerebellar JC viral granular neuronopathy may present with a combination of cerebellar and brainstem signs such as ataxia, nystagmus, diplopia, dysarthria, dyspha-gia, and vertigo (51,65,77,88,136,157,162,163). PML caus-ing progressive brainstem disorder was reported in a patient with systemic lupus erythematosus being treated with etaner-cept and prednisone after she presented with diplopia, right face hypoesthesia, vertigo, dysarthria, right hemiparesis, hemi-ataxia, and gait problems. Brain MRI demonstrated lesions of bilateral pons and medulla, right middle cerebellar peduncle extending into the right cerebellar hemisphere, and left para-median cerebellum (164). Optic Nerve Primary involvement of the optic nerve has not been reported in PML, which is surprising because the JC virus targets the oligodendroglia, which produces optic nerve myelin. Optic atrophy is usually secondary to underlying cause such as MS (5). The latter is particularly true in the patients with MS who have developed natalizumab-associated PML. Curiously, Brooks and Walker (30) in their review of 230 cases of PML, which predated the use of natalizumab for MS found optic atrophy in 1.4% of cases at the time of diagnosis. DIAGNOSTIC CONSIDERATIONS Demonstration of the JC virus in brain tissue or CSF is insufficient for diagnosis of PML because the virus may be found in these locations of normal individuals. Diagnostic criteria for PML have been published as a consensus statement from the American Academy of Neurology's Neuroinfectious Disease Section (See Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A164) (165). The 2 FIG. 4. Case 3: Magnetic resonance imaging of progressive multifocal leukoencephalopathy. A. Top panel, Axial fluid-attenuated inversion recovery images reveal hyperintensive lesion in left pons extending into left cerebral peduncle (arrows). Bottom panel, Postcontrast T1 axial scans show the lesion to be hypointensive with enhancement. B. Top panel, Axial diffusion-weighted imaging shows the lesion to be hyperintense. Bottom panel, apparent diffusion coefficient (ADC) images fail to show evidence of restricted diffusion. 300 Sudhakar et al: J Neuro-Ophthalmol 2015; 35: 296-305 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. diagnostic approaches used include demonstration of typical histopathological findings and JC virus in tissue specimen or a demonstration of JC virus in the CSF of patients who fulfill clinical and radiographic criteria. The characteristic histopath-ologic features of PML include multifocal demyelination, enlarged bizarre astrocytes with lobulated hyperchromatic nuclei, and enlarged oligodendroglial nuclei. The presence of JC virus in the specimen can be confirmed by electron micros-copy, immunohistochemistry, or PCR techniques. The imaging characteristics of PML are not diagnostic. Hypodense white matter lesions without mass effect or contrast enhancement are seen on computed tomography. Brain MRIs show hyperintense white matter lesions on T2 and FLAIR images, which are hypointense on T1 images. Gadolinium enhancement is seen in 15% of HIV-associated PML and 40% of natalizumab-associated PML (166). TREATMENT Although there is no definitive pharmacological treatment for PML, management is aimed at reversal of the underlying immunosuppressive state, which includes treatment with HAART in patients with HIV/AIDS and removing offend-ing immunosuppressive agents, such as natalizumab. Risk mitigation strategies used to prevent the development of PML include monitoring patients on natalizumab for JC virus antibody, limiting the cumulative total dose in those that are JC virus antibody positive and serial brain MRI scans to detect PML early (167). In JC virus antibody- positive individuals, the risk of PML after 24 months of treatment with natalizumab is as follows: in those without previous immunosuppressant use, the risk is estimated at 3 per 1000 and in those with previous immunosuppressant use, it is 13 per 1000 (https://medinfo.biogenidec.com). Discontinuing natalizumab in these circumstances requires an informed discussion with the patient. Although increas-ing the time interval between doses of natalizumab has been suggested to decrease the occurrence of PML, there are no well-controlled trials to demonstrate the efficacy of this strategy. There is no consensus about the drug of choice after natalizumab discontinuation. A patient with PML after dimethyl fumarate (Tecfidera) treatment has been re-ported in the absence of other prior or concomitant immu-nomodulatory therapy (Tecfidera product label, December 2014). A combination of lymphopenia and reduced leuko-cyte binding to VCAM by 33% induced by dimethyl fuma-rate (168) may underlie an increased risk for PML. These observations coupled with reports of PML with fumaric acid esters in the treatment of psoriasis raise concerns about its use in this population (21,22). CONCLUSIONS The neuro-ophthalmic manifestations of PML are protean and depend on the parts of the nervous system affected. Impaired vision from lesions of retrogeniculate visual pathway and association cortices appears to be one of the most common manifestations of PML. Ocular motility disorders result from involvement of the brainstem and cerebellum. Without awareness of these presentations, the diagnosis of PML may be missed in those patients who initially are seen by an ophthalmologist or neurologist with visual complaints. Approximately one-third of patients with PML present with visual disturbances. Homonymous hemianopia is the most common neuro-ophthalmological manifestation; however, a wide variety of abnormalities of afferent and efferent visual systems are observed. Visual complaints may not only herald PML but are frequently the most debilitating symptom. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: P. Sudhakar, D. M. Bachman, J. R. Berger, S. Kedar; b. Acquisition of data: P. Sudhakar, D. M. Bachman, A. S. Mark, J. R. Berger, S. Kedar; c. Analysis and interpretation of data: P. Sudhakar, D. M. Bachman, A. S. Mark, J. R. Berger, S. Kedar. Category 2: a. Drafting the manuscript: P. Sudhakar, D. M. Bachman, J. R. Berger, S. Kedar; b. Revising it for intellectual content: P. Sudhakar, J. R. Berger, S. Kedar. 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