State-of-the-Art Review
Section Editors: Valérie Biousse, MD
Steven Galetta, MD

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 leukoencephalopathy (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 personally 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 cerebral 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
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 Sciences 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, Consortium 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

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

P

rogressive 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 disorders (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 devastating neurological illness which is fatal, unless the underlying 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 including the varied neuro-ophthalmic presentations using illustrative 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
Sudhakar et al: J Neuro-Ophthalmol 2015; 35: 296-305

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State-of-the-Art Review
into 4 epochs: pre-HIV, HIV (pre-HAART), HIV (postHAART), 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 leading 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 temporary 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 implicated 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 treatment of MS, dimethyl fumarate (Tecfidera) (21,22). Currently, 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 population 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 oligodendrocyte infection and demyelination. JC virus infection
of the brain typically causes a subacute progressive disorder
with multifocal asymmetric subcortical white matter involvement from which the disease entity derives its name. Astrocytes 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 brainstem are rare [Joseph Berger, MD and 2013 personal observation and Mossakowski and Zelman (28)] and may be
higher in the HIV/AIDS population with PML (12) compared with other predisposing causes such as natalizumabassociated PML (29).
Sudhakar et al: J Neuro-Ophthalmol 2015; 35: 296-305

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 problems 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 neuroophthalmological findings (See Supplemental Digital Content, 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 folding clothes, tying her shoes, and dressing herself, followed
a month later by left arm and leg weakness. Neurological
examination showed dyscalculia, difficulty following threestep commands, dressing apraxia, dense left homonymous
hemianopia, and mild left hemiparesis. Brain magnetic resonance 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
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State-of-the-Art Review

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).

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 examination 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 nonAIDS 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 quadrantanopia 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 antiretroviral therapy (HAART) was reported in patients with HIVassociated 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).
298

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 agnosia, 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 capsule, 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 hallucinations (147), prosopagnosia, and impaired spatial perception (12,139). Balint syndrome (148–151) has been reported
in patients with PML. These patients frequently complain of
visual distortion, difficulty reading, “fragmented” environment, difficulty driving, and other visuospatial abnormalities.
In those instances in which Balint syndrome has been attributed 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
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State-of-the-Art Review

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.

association with alexia and homonymous hemianopia. Both
had involvement of the dominant parietal lobe and corpus
callosum producing the “disconnection syndrome.” These patients had presented with difficulty reading and naming letters
on the Snellen chart despite 20/20 visual acuity.
Cortical blindness in PML results from bilateral involvement 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 involvement often accompanied by neurological deficits such as prosopagnosia 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 leading 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 demonstrated 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. 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

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State-of-the-Art Review

FIG. 4. Case 3: Magnetic resonance imaging of progressive multifocal leukoencephalopathy. A. Top panel, Axial fluidattenuated 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.

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 cerebellum 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 pathological investigations (157). Infratentorial (cerebellar and
brainstem) abnormalities were noted on neuroimaging studies 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 correlation 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 involvement 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 nystagmus. PML may cause isolated or multiple ocular motor
cranial neuropathies, multiple cranial neuropathy (sixth and
seventh), internuclear ophthalmoplegia (160), or abnormalities 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
300

signs such as ataxia, nystagmus, diplopia, dysarthria, dysphagia, and vertigo (51,65,77,88,136,157,162,163). PML causing progressive brainstem disorder was reported in a patient
with systemic lupus erythematosus being treated with etanercept and prednisone after she presented with diplopia, right
face hypoesthesia, vertigo, dysarthria, right hemiparesis, hemiataxia, and gait problems. Brain MRI demonstrated lesions of
bilateral pons and medulla, right middle cerebellar peduncle
extending into the right cerebellar hemisphere, and left paramedian 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 natalizumabassociated 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
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State-of-the-Art Review
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 histopathologic 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 microscopy, 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 offending 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 increasing 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 reported in the absence of other prior or concomitant immunomodulatory therapy (Tecfidera product label, December
2014). A combination of lymphopenia and reduced leukocyte binding to VCAM by 33% induced by dimethyl fumarate (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.
Sudhakar et al: J Neuro-Ophthalmol 2015; 35: 296-305

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. Category 3: a.
Final approval of the completed manuscript: P. Sudhakar, D. M.
Bachman, A. S. Mark, J. R. Berger, S. Kedar.

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