Download Progressive Multifocal Leukoencephalopathy

Review Article
Address correspondence
to Dr Allen J. Aksamit Jr,
Mayo Clinic, Department of
Neurology, 200 First Street
SW, Rochester, MN 55905,
[email protected].
Relationship Disclosure:
Dr Aksamit reports
no disclosure.
Unlabeled Use of
Products/Investigational
Use Disclosure: Since there
are no US Food and Drug
Administration approved
treatments for progressive
multifocal leukoencephalopathy,
all treatments discussed by
Dr Aksamit are unlabeled.
* 2012, American Academy
of Neurology.
Progressive Multifocal
Leukoencephalopathy
Allen J. Aksamit Jr, MD, FAAN
ABSTRACT
Purpose of Review: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the human CNS that has gained new importance because of AIDS and newer immunosuppressive therapies. It destroys oligodendrocytes,
leading to neurologic deficits associated with demyelination.
Recent Findings: PML most commonly occurs in patients who are HIV infected, but
increasing numbers of patients are being recognized in the context of immunosuppressive therapies for autoimmune diseases. The precise pathogenesis of infection by
JC virus, the etiologic human papovavirus, remains elusive, but much has been learned
since the original description of the pathologic entity PML in 1958. Detection and
diagnosis of this disorder have become more sophisticated with MRI of the brain and
spinal fluid analysis using PCR detection. Immune reconstitution inflammatory syndrome complicates reversal of immunosuppression when PML has established a
foothold in the brain.
Summary: No effective therapy exists, but there is hope for better management
of patients by withdrawing exogenous immunosuppression and reconstituting the
immune system, with a projection of better long-term survival.
Continuum Lifelong Learning Neurol 2012;18(6):1374–1391.
INTRODUCTION
Progressive multifocal leukoencephalopathy (PML) is caused by JC virus infection of the oligodendrocytes in the
white matter of the brain, which leads
to neurologic deficits. JC virusYinduced
killing of oligodendrocytes leads to
myelin loss focally. This is manifest as
dysfunction of the cerebral hemispheres,
cerebellum, or brainstem. The optic
nerves and spinal cord are not clinically
affected in PML. This helps to distinguish it from multiple sclerosis (MS).
JC virusYinduced PML is regarded as
an opportunistic infection of the human
nervous system. AIDS is the most common associated immunocompromising
illness in recent years, but non-AIDS
immunosuppressive illnesses also
cause PML. In past years, lymphoretic-
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ular malignancy, such as chronic lymphocytic leukemia or non-Hodgkin
lymphoma, have caused PML. These
are considered B-cell neoplasms. The
importance of B cells in PML pathogenesis is not yet fully understood, but
some researchers have suggested B
cells carry JC virus into the brain. Other
diseases associated with immunosuppression, such as those related to organ
transplantation, and immunosuppression associated with rheumatoid arthritis,
sarcoidosis, systemic lupus erythematosus, and dermatomyositis, have all
caused PML. It is unclear whether these
disorders intrinsically lead to immunosuppression causing PML or whether
the treatments are required for PML to
occur. Immunosuppression prolonged for
6 months or more is associated with PML.
December 2012
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HISTORY
PML, first described as a neuropathologic entity in 1958,1 was noted to be a
microscopically multifocal demyelinating disease, with coalescence-forming
macroscopic lesions. Histologically, oligodendrocyte nuclear enlargement
and bizarre astrocyte formation established the disease as unique. Early on,
it was suspected to be a viral illness,
based on the pathologic appearance
of the inclusion-bearing oligodendrocytes
and its occurrence in immunosuppressed
populations.2 At the advent of electron
microscopic investigation, electron micrographs revealed polyomavirusYsize
particles in the nuclei of the infected
oligodendrocytes.3 However, it took
until 1971, when brain from a patient
with PML was cultured with human fetal
glial cells by Padgett and colleagues,4
to isolate a replicating human DNA
polyomavirus. The patient’s name from
whom this virus was identified was John
Cunningham, leading to the designation
as JC virus. Within 2 years, the group at
Wisconsin did further investigations to
show that much of the population carried antibodies to the newly described
JC virus.5 Early on, it was shown that
the virus exposure occurred as a consequence of adolescent or early adulthood exposure, and persistent serologic
reactivity was present in 60% to 70% of
the population. Other researchers isolated another polyomavirus, called SV40
virus, from another PML patient,6 but
all subsequent PML cases studied by
molecular means have been caused
by JC virus.
Part of the unique PML histopathology was the finding of bizarre astrocytes. These are cytologically bizarre
and have the appearance of tumorlike
astrocytic cells. A case of glioma in a
human PML patient was reported as
early as 1974.7 Subsequently, however,
gliomas have been extraordinarily rare,
and controversy about the association
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between the JC virus and human glioma remains.8Y10
By 1982, PML was reported to be
associated with AIDS.11,12 A review in
1984 showed only a few hundred cases
of known PML, some of which were
from the early aspects of the AIDS epidemic, although most had been associated with other immunosuppressive
illness.13
By 1984, the complete nucleotide
sequence of the double-stranded DNA
JC virus was published.14 It was found to
be closely linked to the SV40 virus and
another human polyomavirus, designated BK virus. By 1985, nonradioactive
means of in situ hybridization provided
evidence that oligodendrocytes and
bizarre astrocytes in the brain of patients with PML were infected by JC
virus.15 These tools became useful for
confirming the presence of JC virus in
cases of PML requiring pathologic confirmation by brain biopsy. Immunohistochemical staining for JC virus antigen
has also provided means for pathologic
confirmation of this infection.16
Although the pathogenesis of JC
virus entry into the brain remains somewhat unclear, in 1988 B cells were reported to contain JC virus in patients
with PML.17 Other authors subsequently
showed that JC virus was detected in
lymphocytes of PML and HIV-positive
patients by PCR.18
The PCR revolution in virology affected the diagnosis of PML. For the first
time, in 1992, JC virus was detected in
the spinal fluid of patients with PML.19,20
This has become the noninvasive standard for diagnosing PML and has now
become accepted as a surrogate marker
for histologic proof of JC virus replication in the brain.21
Despite the severe and usually fatal
nature of PML, no proven therapy has
been defined. A landmark article testing cytarabine in AIDS-related PML was
published and found to be ineffective
KEY POINT
h Progressive multifocal
leukoencephalopathy
is a reactivation,
opportunistic infection
by JC virus.
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Progressive Multifocal Leukoencephalopathy
KEY POINT
h Most people
(50% to 70%) are
latently infected
with JC virus.
in patients with AIDS.22 A variety of
agents have been tried, but none with
any reliable success.
More recently, PML has occurred in
patients with MS treated with natalizumab, an immunomodulatory monoclonal antibody. Natalizumab was removed
from the United States drug market for
a time because of its association with
PML infection23Y25 but later returned to
the market under stricter prescribing
guidelines.26 This, however, became a
harbinger of PML occurring with other
commonly used immunosuppressive
agents, including rituximab and mycophenolate mofetil.26,27 It is anticipated
that additional immunosuppressive
therapies may likewise continue to predispose to PML as an opportunistic
infection.
In opportunistic infections, particularly those associated with AIDS, immune reconstitution after initiation of
antiretroviral therapy can create a rebound inflammatory response that is
damaging to the infected organ. This
complication was named the immune
reconstitution inflammatory syndrome
(IRIS).28,29 IRIS may become manifest
in patients with AIDS-associated PML
treated with antiretroviral therapy and
was recognized in patients with MS in
whom natalizumab was stopped after
recognition of PML infection, leading to
an immune response that is damaging
to the brain. Treating PML in this
complex context of immunosuppressive
disease has created uncertainty about
treatment and challenges for the future.
PATHOGENESIS
The viral structure of JC virus demonstrates that it is double-stranded DNA
human polyomavirus. The virus is acquired in childhood or young adulthood.5 It is thought to enter the body
by a respiratory or oral route. Latency
is established in the body after infection. At least 50% of adults are sero-
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positive; recent interest in stratifying
patients with MS who are candidates
for natalizumab therapy reconfirmed a
seroprevalence in this patient population of adults as 50% to 60%.30 Seropositive individuals harbor latent virus
in the kidney, lymphoreticular tissue,
or brain. This occurs after primary
infection, but no illness is produced.
Periodic asymptomatic systemic reactivation also occurs without consequence,
principally detected as asymptomatic
shedding of virus in the urine. PML is
considered a JC virus reactivation infection in which a second event occurs.
When reactivation of viral replication
occurs systemically, immunosuppression
may cause dissemination to the brain.
However, it is also possible that latency
reactivation occurs in the brain and
causes PML (Figure 7-1).31
It is likely that JC virus is carried into
the brain via white blood cells. Clinically, this has been suspected because
the subcortical gray-white junction localization is typical of PML. Clinically and
pathologically this represents an end
arteriole location for hematogenously
disseminated cells, as occurs in brain
abscesses and metastatic brain carcinoma. The cell that carries JC virus into
the brain remains uncertain. B cells and
glia share a common DNA binding factor that may tie them in pathogenesis.32
One hypothesis suggests B cells carry
the virus. JC virus can sometimes be
found in B cells of the bone marrow,
and cells identified as B cells by flow
cytometry performed on blood of immunosuppressed patients can contain
JC virus.10 A study using double-labeling
techniques that evaluated lesions with
inflammation and identified B cells in
PML lesions did not demonstrate JC
virus.31 Other studies suggest that JC
virus can be present.10
The timing of JC virus entry into
the nervous system relative to the
development of PML is controversial
December 2012
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Pathogenesis of JC virus infection causing progressive multifocal
leukoencephalopathy. The virus is acquired in childhood or young adulthood
and becomes latent in lymphocytes, spleen, kidney, bone marrow, and
other lymphoid tissue. It also may establish latency in the brain. With immunosuppression,
JC virus replicates in oligodendrocytes; kills them, causing demyelination; and nonproductively
infects astrocytes, causing bizarre histologic changes.
FIGURE 7-1
Reprinted with permission from Aksamit AJ Jr, Microsc Res Tech.31 onlinelibrary.wiley.com/doi/10.1002/
jemt.1070320405/abstract.
and important in pathogenesis. One hypothesis suggests that JC virus reacts in
nonbrain organs, such as the spleen,
lymph node, or kidney, and then is
hematogenously disseminated during
immunosuppression to the nervous system, causing oligodendrocyte infection.
A second hypothesis suggests that JC
virus infection occurs in childhood or
adolescence, and dissemination occurs
via the bloodstream to the brain at the
time of primary infection. Latency is
established in the brain at this time
in this model. Then, with the onset
of immunosuppressive illness, the virus
is reactivated and causes PML. This pathogenesis is important to treatment
and immune surveillance of the brain.
This second hypothesis is suggested
in a study of natalizumab-treated cases
in which no JC virus was detected
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before PML developed in two of three
patients.24,25,33
JC virus produces different cellular
pathology in oligodendrocytes than in
astrocytes, but the mechanism for the
distinct pathology in the glial cells of
the same patient is unclear. In oligodendrocytes, JC virus infection is lytic.
The virus infects the cell and undergoes DNA replication and synthesis of
viral capsid proteins. The virus infects
adjacent cells from a central nidus of
infection, leading to a circumferential
expansion of demyelinated lesions.31
Astrocytes, on the other hand, take
on a bizarre morphologic appearance,
with marked enlargement of the cells
and distortion of the nuclei with enlargement or multiple nuclei. These cells
are similar to those seen in giant cell
astrocytomas unrelated to JC virus
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1377
Progressive Multifocal Leukoencephalopathy
KEY POINT
h Progressive multifocal
leukoencephalopathy
produces cerebral
focal syndromes
more commonly than
brainstem or cerebellar
syndromes, but either
can occur.
infection. Electron microscopic examination of these cells shows no virions
present. In situ hybridization and, to a
lesser extent, immunohistochemistry for
viral proteins show that these cells are
infected in a nonproductive fashion.16
They have a ‘‘transformed’’ appearance
in an oncogenic sense. The role of JC
virus in human astrocytomas is uncertain and controversial.8,9
CLINICAL
PML presents clinically as a focal or
multifocal neurologic disorder. The
disease, progressive multifocal leukoencephalopathy, was named for neuropathologic observation of microscopic
multifocal lesions involving the brain
white matter.1,31 However, clinically, a
more typical presentation is of a unifocal syndrome of cerebral or brainstem
dysfunction. The frequency of MRI focal
versus multifocal abnormalities at the
time of clinical presentation differs
among various authors. Some regard
PML to have typically multifocal changes
on MRI, even with unifocal clinical presentation. Others suggest that most
patients present with a unifocal MRI
scan and clinical unifocal syndrome simultaneously.31 Whichever is correct, a
multifocal or unifocal PML clinical presentation is possible.
The neurologic presentation of PML
reflects varying locations of the brain
affected. Motor system involvement
causes corticospinal tract findings. Cortical sensory loss, ataxic cerebellar deficits, and focal visual field defects
are common. ‘‘Cortical’’ deficits, such
as aphasia or visual-spatial disorientation, can occur because PML demyelination is often immediately subcortical,
undermining the cerebral cortex identified with the clinical syndrome.
Most patients with PML without AIDS
have neurologic focal deficits from cerebral hemisphere abnormalities. The
ratio of cerebral versus brainstem in-
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volvement is approximately 10:1. For
reasons that are unclear, brainstem involvement happens more commonly in
patients with PML who have AIDS, with
a cerebral to brainstem ratio of involvement approximating 4:1.
A patient with immunosuppression
characterized as a cell-mediated immunity defect who develops a subacute
focal progressive neurologic syndrome
should undergo a search for PML. Although JC virus infection has been
historically regarded as a ‘‘slow virus’’
infection, the illness of PML is subacute
in progression with focal worsening of
neurologic symptoms evolving over
days to weeks. Sometimes the focal
neurologic syndrome can seem acute
and be suggestive of a stroke mechanism.
Inevitably with PML, serial neurologic examinations demonstrate subacute neurologic worsening. The MRI of the
brain parallels the clinical changes over
time. Patients with more immunopreserved status may have a slower clinical
course, mimicking brain tumors such as
CNS lymphoma or glioma (Figure 7-2).
Weakness or paralysis occurs in 60%
of patients with PML.11Y13 Gait abnormalities are common and occur in up to
65% of patients at presentation, and
cognitive disorders are the presenting
manifestation in 30%. Presenting manifestations are most commonly memory
concerns or a behavioral disorder. Cognitive disturbances are present in most
cases with clinical progression in the
cerebral hemispheres. Aphasia occurs in
20%. Visual field defects are the presenting manifestation in 20%. Focal cortical
sensory loss (proprioception loss, astereognosis) is common but poorly quantitated as to frequency of occurrence.
Cortical limb monoparesis, limb apraxia,
unilateral ataxia, or focal brainstem signs
can all occur. Seizures are infrequent
but estimated to occur in 10% of patients. Illnesses associated with nonAIDS PML are shown in Table 7-1.
December 2012
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AIDS
AIDS is the most common mechanism
of immunosuppression leading to PML.
It is estimated that PML affects 1% to 4%
of symptomatic AIDS cases. PML can be
the presenting manifestation of AIDS.
However, more commonly, PML occurs
with low CD4 blood counts (less than
200 cells/2L) and occurs later in the
course of AIDS disease. As an opportunistic infection, PML incidence has
been less affected by combination antiretroviral therapy than other opportunistic infections of the nervous system,
such as toxoplasmosis or cryptococcal
meningitis (Case 7-1).
LYMPHORETICULAR
MALIGNANCY
The lymphoreticular malignancies are
the most common non-AIDS-related
cause of immunosuppression predisposing to PML. The most common disorders are chronic lymphocytic leukemia,
Hodgkin disease, and non-Hodgkin lymphoma. It is interesting that chronic
lymphocytic leukemia and most nonHodgkin lymphomas are generally regarded as neoplasms of B-cell lineage.
Yet all of these disorders are well known
to be associated with opportunistic infections that manifest as disorders of T-cell
immune deficiency, such as toxoplasmosis or cryptococcal meningitis. Therefore,
the precise immune defects that predispose to PML in these malignancies
remain ill defined.
RHEUMATOLOGIC DISORDERS
Virtually any form of rheumatologic disorder has been reported to be associated with PML. Since these autoimmune
disorders are commonly treated with
immunosuppressive agents, it is unclear
whether the underlying disease or the
treatment is primarily responsible for
the predisposition to PML. In a study
looking at underlying disorders in nonAIDS PML (Table 7-1), the frequency of
Continuum Lifelong Learning Neurol 2012;18(6):1374–1391
T2-weighted fluid-attenuated
inversion recovery brain MRI
scan of progressive multifocal
leukoencephalopathy (PML). Bifrontal PML
lesions including involvement of the corpus
callosum mimicking glioma or lymphoma.
FIGURE 7-2
connective tissue diseasesVrheumatoid
arthritis, systemic lupus erythematosus,
dermatomyositis, and vasculitis with methotrexate and cyclophosphamideVwas
16%. Estimates of PML incidence in patients with rheumatoid arthritis suggest
the frequency is low, approximately 0.4
per 100,000 discharges.35
KEY POINT
h Progressive multifocal
leukoencephalopathy
primarily occurs in
immunosuppressed
illnesses of T-cell
deficit, ie, AIDS or
lymphoreticular
malignancy.
TRANSPLANTATION
PML is an important but rare cause of
neurologic disease in transplant recipients. A recent study found the estimated incidence of PML in patients
receiving heart and/or lung transplant
occurring approximately 1.24 per
every 1000 transplant person-years.36
Mean onset of PML symptoms after
transplantation was 17 months. PML is
most often fatal (84% case fatality) in
this population but is compatible with
recipient survival measured in years
(3 of 50 patients). The risk of PML likely
exists throughout the entire posttransplant period and should be suspected
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Progressive Multifocal Leukoencephalopathy
TABLE 7-1 Progressive Multifocal Leukoencephalopathy Patients
at Mayo Clinic: Non-AIDS Progressive Multifocal
Leukoencephalopathy—Associated Diseases (n=58)
b Lymphoreticular Malignancy (n=32, 55%)
Chronic lymphocytic leukemia (n=14, 24%)
Hodgkin disease (n=6, 10%)
Non-Hodgkin lymphoma (n=12, 21%)
b Connective Tissue Diseases (n=9, 16%)
Rheumatoid arthritis (n=3, 5%)
Systemic lupus erythematosus (n=4, 7%)
Dermatomyositis (n=1, 2%)
Vasculitis with methotrexate and cyclophosphamide (n=1, 2%)
b Organ Transplantation (n=4, 7%)
Renal transplantation
Liver transplantation
Heart transplantation
b Granulomatous Disease (n=5, 9%)
Sarcoidosis
b Other (n=4, 7%)
Cirrhosis
Pulmonary fibrosis
Diabetes mellitus, pulmonary histoplasmosis, and prednisone
b ‘‘Normal Aged’’ Patients With No Immunosuppression (n=4, 7%)
Patients aged 66, 76, and 80 years
and quickly diagnosed because temporary reduction of immunosuppression
may be compatible with PML improvement and long-term patient survival.
The case fatality among patients
who develop PML posttransplantation
is high, with death occurring within
18 months in most cases. Exceptions
to this occur. In one series, three patients were still alive at 13, 44, and
155 months following PML symptom
onset.36 Among survivors, all patients
had their immunosuppressive drug regimen significantly reduced or withdrawn
at the time of diagnosis of PML. No
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patient survived without immunosuppressive medication reduction. Graft
rejection is of significant concern with
immunosuppressive drug reduction
but consistent with survival in some
cases of PML.
MULTIPLE SCLEROSIS TREATED
WITH NATALIZUMAB
Natalizumab, a monoclonal antibody directed against the !4 integrin molecule,
was approved by the US Food and
Drug Administration in November
2004 for treatment of patients with MS
after a controlled trial.37 By February
December 2012
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Case 7-1
A 55-year-old right-handed man had received a diagnosis of HIV disease 8 months earlier. He recently
went through a series of changes in his antiretroviral drug regimen and had persistent nausea despite
multiple changes of his medications. His CD4 count was 386 cells/2L, and HIV serum quantitation
was less than 400 copies of RNA/mL. For 2 months he had unsteadiness of gait and progressive decline
in balance, more prominent on the left side and affecting the left lower extremity. Change in
control of the left upper extremity with the unsteadiness also occurred. In the prior 1 month he also
noticed some diplopia.
His examination showed that his gait and station were impaired by marked ataxia. He could stand
independently only with support. Ataxia was present in the left upper and lower extremities.
Nystagmus occurred on lateral gaze and mild conjugate gaze paresis on the gaze to the left.
Extraocular movements were otherwise full, and pupils were normal. Diffuse hyperreflexia was
present, but plantar responses were flexor. The remainder of the neurologic examination
was unremarkable.
MRI scan of the head showed increased fluid-attenuated inversion recovery (FLAIR) signal involving
the cerebellar white matter of the left cerebellar hemisphere and extending into the pons through
the middle cerebellar peduncle (Figure 7-3). The
abnormality produced little mass effect. No contrast
enhancement was present on postgadolinium images.
Spinal fluid protein concentration was 104 mg/dL with
2 nucleated cells/2L. CSF Venereal Disease Research
Laboratory (VDRL) testing was nonreactive. Results from
the following tests were negative: cryptococcal antigen,
cytology, blood serology for toxoplasmosis, and PCR assays
for toxoplasmosis and Epstein-Barr virus in the spinal fluid.
PCR of spinal fluid for JC virus was ‘‘indeterminate’’
positive. Two of four specimens tested positive, with
one each of duplicate specimens run twice showing JC
virusYspecific PCR detection. The diagnosis was PML.
Comment. PML in AIDS typically occurs in patients
who have had HIV disease with more severe
immunosuppression. Usually CD4 counts are less than
200 cells/2L. However, immunosuppression does not
reliably predict pathology, and PML can occur with
normal CD4 counts. The presentation with cerebellar
or brainstem disease is more common in AIDS than
FIGURE 7-3 T2-weighted fluid-attenuated
inversion recovery brain MRI scan
non-AIDS cases. PCR testing for JC virus in the spinal
of progressive multifocal
leukoencephalopathy (PML). Left cerebellar and
fluid of patients with PML has 76% sensitivity,
pontine PML lesion.
combining a number of studies. A positive PCR finding
abolishes the need for brain biopsy. The indeterminate
result is a reflection of the assay operating at the limits
of detection and is a reason why not all patients with PML test positive by this method. The need for brain
biopsy in PCR-negative cases depends on clinical circumstances, including localization of the lesion, social
situation, and therapeutic options. This patient was treated with cidofovir and significantly improved.34
Whether the improvement was an effect of cidofovir, the immunologic restoration by the cART regimen
(which was stable throughout the PML course), or both is open to interpretation.
2005, two patients with MS who had
been treated with natalizumab therapy
were diagnosed with PML, leading to the
Continuum Lifelong Learning Neurol 2012;18(6):1374–1391
withdrawal of natalizumab from the market. One patient died.24 The second
patient, with PML proven by brain biopsy,
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Progressive Multifocal Leukoencephalopathy
KEY POINT
h Exogenous
immunosuppressive
treatments such as
natalizumab and
rituximab have
been linked to
progressive multifocal
leukoencephalopathy
occurrence.
had an unstable clinical course. He
developed severe clinical deficits and
IRIS when natalizumab was stopped.25
Another case of PML related to natalizumab was recognized in a patient
being treated for Crohn disease. He
died of a progressive syndrome, which
was initially diagnosed as astrocytoma.
A rereview of neuropathology revealed
PML.33 The long duration of therapy
and prior immunosuppressant exposure has been consistent with other
cases of PML. In transplantation, where
the date of immunosuppression can be
accurately determined, PML occurs late
(usually longer than 1 year) after immunosuppressants are introduced.
Since that time, natalizumab has been
reintroduced to the market with a close
monitoring system and a registry of
patients administered by Biogen Idec,
and with data available to physicians
online for assessment of risk to patients
(medinfo.biogenidec.com/medinfo).
Several aspects have emerged from the
data about these patients.23 The incidence of PML is dependent on the
duration of natalizumab use and substantially increased after 24 months
of use. Incidence of confirmed PML in
patients who have had 24 or more
infusions of natalizumab is now estimated to be one case of PML per 1000
patients.23 As of May 1, 2012, BiogenIdec reported 242 cases of natalizumabassociated PML. Of these, 20% have
died. Those who have survived experienced varying degrees of disability.
Seropositivity for JC virus in the blood
increases incidence of natalizumabassociated PML to as much as one
per 100 patients after 2 years of use.
Finally, prior exposure to other immunosuppressive drugs also increases the
risk of PML (Case 7-2).
OTHER DRUGS
Other specific immunosuppressant drugs
that can predispose to PML are predni-
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sone, methotrexate, cyclophosphamide,
and cyclosporine.26 It is also apparent
that newer immunosuppressives, such
as leflunomide, can predispose to developing PML.38 The exact risk with use
of these drugs, such as monoclonal antibodies targeting lymphocyte trafficking or
antagonizing specific cytokines, remains
to be defined on an individual basis.
Mycophenolate mofetil is used for
a variety of B- and T-cell disorders. It
was initially developed as a posttransplant antirejection drug. However, the
drug is used off-label for many other
autoimmune disorders because of its
favorable side-effect profile. The presence of PML in patients treated with
mycophenolate mofetil has been reported. Online resources may help with
risk assessment (www.gene.com/gene/
products/information/cellcept/), and this
subject has been covered in a recent
review.26
Rituximab is a therapeutic monoclonal anti-CD20 antibody that targets B
cells selectively and removes them from
the circulation. This monoclonal antibody has been used to treat a variety
of B-cell neoplasms (eg, chronic lymphocytic leukemia, lymphoma) and autoimmune diseases, specifically rheumatoid
arthritis, and off-label for systemic lupus
erythematosus. PML has been shown to
occur in rituximab-treated patients.27,39
It is estimated that the risk is approximately one per 25,000 patients with
rheumatoid arthritis treated with rituximab.27 Systemic lupus erythematosus
may have a higher propensity to PML.27
Another monoclonal anti-CD11a antibody named efalizumab was marketed
for the treatment of refractory psoriasis. It was withdrawn from the United
States market as of June 2009 because
of PML occurring in patients treated
with this drug. The frequency was
estimated to be four of 46,000 patients
treated.40 However, whether the rare
occurrence of a usually fatal neurologic
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Case 7-2
A 54-year-old right-handed woman was diagnosed with MS after experiencing diplopia. She had
an abnormal multifocal MRI scan reported by her local neurologist. Spinal fluid showed absent
oligoclonal banding, normal IgG index, normal protein concentration, and 3 white cells. Three
years later, natalizumab was started for treatment of multiple sclerosis. One year after starting her
natalizumab therapy, she developed progressive weakness of the left hand, which progressed and
spread during 1 month so that she essentially had left hemiplegia. Her treatment with natalizumab
had been discontinued at the beginning of her worsening symptoms.
MRI scan of the head showed an enlarging lesion
of T2 hyperintensity involving the white matter
in the right cerebral hemisphere, extending from
the deep white matter up to the superficial cortex,
and involving the precentral gyrus and premotor
subcortical white matter of the right hemisphere
(Figure 7-4). This worsened despite 4 days of IV
methylprednisone 1 g/d.
Spinal fluid testing was repeated and showed
glucose concentration of 71 mg/dL, protein
concentration of 48 mg/dL, and no white blood cells;
PCR was positive for JC virus.
Comment. The patient developed PML after starting
natalizumab therapy. A progressive neurologic deficit,
with subcortical white matter imaging abnormalities
that are worsening subacutely, would strongly suggest
a diagnosis of PML. PML needs to be considered with
high index of suspicion in patients on natalizumab
therapy. The patient received three plasma exchanges
to shorten the period in which natalizumab remained
T2-weighted
fluid-attenuated
FIGURE 7-4
inversion recovery brain MRI scan
active. She was at increased risk for developing IRIS,
of progressive multifocal
which subsequently needed treatment. IRIS is
leukoencephalopathy (PML). Right frontal large
more common and more severe in patients with
PML lesion with tiny left frontal lesions.
natalizumab-associated PML than in patients with
HIV-associated PML.
infection should prohibit drugs such
as this from use in all cases is uncertain.
Screening by serologic means allows one to determine whether a patient carries latent JC virus.30 Since
PML is regarded as a reactivation infection, this serologic testing has been
proposed as a screening tool so that
these immunosuppressives are used
only with great caution in seropositive
individuals. No reliable method is available to detect PML before symptoms.
A positive JC virus serology predicts
predisposition to infection. CSF PCR
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techniques or brain biopsy currently
are the only methods to confirm PML.
SARCOIDOSIS
Systemic sarcoidosis is associated with
defects in cell and humoral immunity,
with a granulomatous pathologic reaction. Many reports have been published
of PML occurring in patients with sarcoidosis. However, it is unclear whether
the predisposition to PML is part of the
primary disease or a result of the immunosuppressive treatment often used
chronically to treat the disease, such as
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1383
Progressive Multifocal Leukoencephalopathy
KEY POINTS
h Radiologic evaluation
should be done by MRI
scan in suspected cases.
h The principal MRI
finding is T2 or
fluid-attenuated
inversion recovery
subcortical white
matter demyelination.
h PCR for JC virus in
the spinal fluid is only
70% to 75% sensitive
in progressive multifocal
leukoencephalopathy
cases.
prednisone or methotrexate. Some patients with sarcoidosis who develop PML
are on no active treatment. In either
case, PML is an infrequent opportunistic
infection in patients with sarcoidosis,
although incidence data are lacking. In
a series of non-AIDS PML cases, sarcoidosis was present in 9% of the patients
(Table 7-1).
RADIOLOGIC FEATURES
An MRI scan of the head is more sensitive than a CT scan for detecting abnormalities related to PML (Table 7-2).41 A
normal MRI head scan would argue
against PML as the cause of neurologic
deficits. Rarely, patients with PML have
clinically detectable neurologic deficits
and no MRI abnormalities. MRI abnormalities are typically localized to the
subcortical white matter at the graywhite junction (Figure 7-2, Figure 7-4,
and Figure 7-5A, B, and C). The lesions
show increased T2 signal, no or little
mass effect, and minimal or no
enhancement after gadolinium administration (Figure 7-5C and D). These
characteristics have exceptions with
PML. Any cerebral lobe is potentially
vulnerable to disease. Some authors
have suggested that occipital PML is
more common.41 Presumably some of
the variability of the presenting syndrome represents the neurologic deficit
effect on the patient’s functions of daily
living. Any area of the white matter
areas of the brainstem can be affected.
More common is involvement of the
cerebellum. A focal abnormality on MRI
scan in the brainstem would suggest PML
when little mass effect and no contrast
enhancement are present.
DIAGNOSTIC TESTS
PCR has been used to amplify JC virus
DNA from the spinal fluid of patients
with PML. Current studies of JC virus
show that CSF detection is specific for
pathologically significant PML.19,20,42,43
All studies have been retrospective analyses of spinal fluid specimens of patients
with either pathologically confirmed or
clinically suspected PML, based on MRI
and coincident underlying immunosuppressive illness. Sensitivity of detection
is not 100%. Specifically, combined data
from published studies show that 76%
were correctly diagnosed by this assay.
It is unclear why false negatives occur.
The most likely explanation is low abundance of virus DNA in spinal fluid. Other
possible explanations include storage
TABLE 7-2 Brain MRI Findings
b MRI T2 and fluid-attenuated inversion recovery are most sensitive
b Lesions typically localize to subcortical white matter more commonly than
periventricular regions
b Gadolinium nonenhancing or minimally enhancing (unless immune
reconstitution inflammatory syndrome is present)
b Almost always abnormal
b Regional expression:
Frontal equals occipital
Unifocal greater than multifocal
Cerebral greater than brainstem
1384
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Brain MRI scan of progressive multifocal leukoencephalopathy (PML). All are
T2-weighted fluid-attenuated inversion recovery images except D, which is a
T1 postgadolinium image. A, Single superficial subcortical left frontal PML lesion.
B, Multifocal right-greater-than-left subcortical frontal PML lesions. C, D, Symmetric bioccipital
PML lesions that show trace enhancement after gadolinium.
FIGURE 7-5
and handling of specimens, small volume of spinal fluid assay, inhibitors in
the spinal fluid, and loss of DNA during CSF concentration. Combining data
from studies,19,43,44 the false-positive rate
identifying CSF specimens from AIDS
patients without PML or other controls
was only 2%. Sensitivity of 75% has been
borne out in larger studies.42 If PML is
suspected and PCR for JC virus is negative, the recommendation is to repeat
Continuum Lifelong Learning Neurol 2012;18(6):1374–1391
the assay and consider a laboratory capable of detecting low copy numbers of
JC virus DNA.
The other spinal fluid chemistry and
cell count findings in patients with PML
are typically nonspecific. Minimal pleocytosis occurs, but the finding is usually less
than 20 cells/2L. More than 20 cells/2L
suggests the possibility of a different infection or restored immunity of the host
with reaction against JC virus. A spinal
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1385
Progressive Multifocal Leukoencephalopathy
KEY POINT
h In suspected
progressive multifocal
leukoencephalopathy
cases with negative
CSF PCR for JC virus, the
PCR should be repeated
with consideration of a
laboratory capable of
detecting low DNA copy
numbers, or the patient
should be taken to
brain biopsy.
fluid pleocytosis can be seen when contrast enhancement increases on the
brain MRI. Pleocytosis correlates with
the neuropathologic finding of perivascular lymphocytic cuffing in the brain.
Spinal fluid protein is only moderately
elevated, usually less than 100 mg/dL.
Culture for JC virus is unrevealing.
PATHOLOGY
When spinal fluid PCR is negative for JC
virus, a brain biopsy of suspected PML
lesions is advised in order to confirm
diagnosis. Immunohistochemistry or in
situ hybridization are the best techniques for confirming JC virus in a biopsy
specimen.15,16,45 Oligodendrocytes at the
gray-white matter junction are the most
common site for infection (Figure 7-6A).
The spectrum of neuropathology in
the brain of JC virus infection in patients with PML has been changed. JC
virus infects oligodendrocytes, astrocytes, and now granule cell neurons
of the cerebellum.
The demyelination of PML is secondary to oligodendrocyte infection and
death.1 Demyelination expands in a circumferential way to produce plaques
easily demonstrated on myelin stains
(Figure 7-6B). Histology of PML shows
nuclear enlargement of infected oligodendrocytes. Virion accumulations produce the ‘‘inclusion-bearing’’ nuclei
of oligodendrocytes. Oligodendrocyte
nuclei are enlarged, with ground-glass
appearance, and amphophilic, basophilic, or sometimes eosinophilic staining after hematoxylin and eosin. The
death of oligodendrocytes leads to
release of virus and infection of neighboring cells. Virus spreads circumferentially from a central nidus to neighboring
cells, leading to expansion of demyelination.31 The number of oligodendrocytes infected with JC virus by in situ
hybridization is more numerous than
would be suspected based on nuclear
enlargement.16
On electron microscopy, oligodendrocyte nuclei are filled with JC icosahedral
virions approximately 40 nm in size. The
size helps to identify JC virus. Accompanying tubular forms of immature
Pathology of progressive multifocal leukoencephalopathy (PML). Gross and
microscopic appearance of PML lesions affecting the superficial subcortical
gray-white matter junction in the cerebral hemisphere. A, This is a
coronal section of fixed PML brain. The subcortical white matter is undermined by multifocal
punctate coalescent demyelinating lesions (black arrows). B, Luxol fast blue stain shows a
microscopic demyelinated lesion (between opposing black arrows) in the white matter
immediately subcortical. The cortex and neuronal cell bodies are in the left of the picture
(original magnification 430).
FIGURE 7-6
1386
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capsid protein may assemble in the
nucleus.
Bizarre astrocytes are a nonlytic JC
virus infection of astrocytes. These cells
look bizarre with enlarged and multilobulated nuclei. They look like neoplastic cells but do not form frank tumors.
Rare reports of gliomas in PML lesions
have occurred.7 More commonly, the
PML can be misdiagnosed as glioma because of the cell atypia.33 Bizarre astrocytes have limited JC virus DNA
replication by in situ hybridization and
viral capsid immunohistochemistry.
They do not, however, produce significant virions based on electron microscopic analysis.31,45
Double-labeling techniques have
shown that granule cell neurons of the
cerebellum are infectible with JC virus.18,46 Granule cell neurons show lytic
infection and cell death with atrophy of
the granule cell layer of the cerebellum.46
The pathology is associated with limited or no inflammation. This is regarded
to be proportional to the immune state
of the host. More severe immunosuppression is associated with little or no inflammation. Patients have had immune
reconstitution and developed IRIS in the
nervous system in the context of AIDS.47
KEY POINT
h No satisfactory antiviral
therapy is available
for the treatment of
progressive multifocal
leukoencephalopathy.
TREATMENT
No treatments have proven to be effective for PML (Table 7-3). General
principles about treatment include
improvement in immune status. Antiviral therapy may promote survival.48
Therapies can be offered if the goal
of neurologic stabilization satisfies the
patient’s quality-of-life goals. Although
the prognosis of PML is generally
dismal, removal of the immunosuppression influence of an external drug
allows the patient’s own immune
system to clear JC virus from the brain.
This is an effective approach but can also
lead to IRIS, which, when it occurs in
the brain after immune restoration, may
need treatment. IRIS should be treated if
TABLE 7-3 Treatment Options
b Immune Reconstitution
Stop immunosuppressants
Optimize antiretroviral therapy (in AIDS)
b Nucleoside Analogs (Questionable Effectiveness)
Cytosine arabinoside 2 mg/kg/d for 5 days, single course
Cidofovir 5 mg/kg once weekly for 2 weeks, then every 2 weeks for 2 months
b Treatments Not Likely to Work
Interferon alpha
Topotecan
5-hydroxytryptamine antagonists
Chlorpromazine
Mirtazapine
Risperidone
Mefloquine
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1387
Progressive Multifocal Leukoencephalopathy
KEY POINTS
h Patients with
progressive multifocal
leukoencephalopathy
associated with
AIDS should have
optimization of
antiretroviral therapy.
h Immune reconstitution
inflammatory syndrome
should be treated if
it is associated with
significant neurologic
deterioration.
1388
accompanied by neurologic deterioration
with short-term corticosteroids.
In patients with AIDS, cART should
be initiated. If the patient with AIDS is
already receiving cART, therapy should
be changed to optimize immune restoration and normalization of the CD4
count. Cytosine arabinoside has failed
in patients with AIDS-related PML.22
For deteriorating patients with PML
with or without AIDS, cidofovir can be
considered,34,49 although several studies have suggested it is ineffective.50,51
For patients with PML without AIDS,
no effective therapy is available. If the
goal to stabilize neurologic deterioration is acceptable in the clinical context of the systemic disease, however,
one may consider IV cytosine arabinoside 2 mg/kg/d for 5 days. A single
nonblinded study showed an approximately 30% response rate in patients
in whom 85% mortality was expected
within 1 year.48
Mirtazapine or risperidone have also
been suggested as options for treatment, but their effectiveness is not
yet proven. The receptor for JC virus
entry into the cell is identified as a
subtype of the serotonin receptors 5hydroxytryptamine 2A (5-HT2A).52 This
is combined with a sialic acidYN-linked
glycoprotein on the cell membrane. This
report has led to treatment of PML with
psychotropic medications known to
block the 5-HT2A receptor. Mirtazapine
is an antidepressant, and risperidone
is an antipsychotic proposed to be specific for blockade of this receptor. Mirtazapine has been used anecdotally at
15 mg/d to 30 mg/d, in patients with
nonYAIDS-related PML. 53,54 These
patients also had alteration of their
immunosuppressive regimen and treatment with other agents, including cytosine arabinoside or cidofovir. Risperidone
has been suggested to be potentially
more potent.55 None of this form of therapy blocking the serotonin receptor has
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been successful, although no blinded prospective trials have been published.
Mefloquine has been suggested to
be potentially helpful based on in vitro
screening of compounds with activity
against JC virus. Mefloquine hydrochloride was used in several cases of rituximabassociated PML.27 However, a recent
clinical trial was stopped for lack of
demonstrable efficacy.56
Interferon alpha has been rarely reported to have some success in treating PML; however, the patients were
treated with multiple agents, making
these reports difficult to interpret.
Current consensus is that interferon
alpha is not helpful in the treatment of
PML.18 Interferon beta also seems to be
of no help.57 Camptothecin and topotecan, two DNA topoisomerase inhibitor drugs, have antiviral activity against
JC virus. These drugs are antineoplastic
agents. Few case reports of treating PML
have been published.58 No series of PML
patients treated suggest that these drugs
are successful.
IMMUNE RECONSTITUTION
INFLAMMATORY SYNDROME
IRIS can occur after withdrawal of the
immunosuppressive agent and after
PML diagnosis. The immune response
is important in clearing JC virus from
the brain. Therefore, at least limited
inflammation is probably important in
neurologic survival.28 IRIS, however, is
thought to be injurious to the brain,
and many patients need additional treatment. Treatment is typically a short
course of high-dose IV methylprednisolone, usually 1 g/d for 5 days.29 However, universal consensus is lacking on
route, type, dose, or duration of corticosteroid therapy. Despite treatment
success and survival, PML deficits can
be expected to be permanent.
In the circumstance of natalizumabassociated PML, management of the
PML has routinely used plasma exchange
December 2012
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or immunoabsorption to hasten clearance of the drug and shorten the period in which natalizumab remains
active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred
within a few days to a few weeks after
plasma exchange, indicative of IRIS.
This syndrome seems to be more
common and more severe in patients
with natalizumab-associated PML than
in patients with HIV-associated PML
treated with cART.
PROGNOSIS
In general, PML has been regarded as
nearly a universally fatal disease. However, more recent experience with PML
suggests that patients can survive. A preAIDS era study showed the 4-month survival rate to be 30%, and the 12-month
survival rate 15%.13 In the pre-cART era,
AIDS-related PML was fatal in 95% of
patients in 6 months.46 Institution of
optimized cART therapy has produced 50% survival at 1 year.50 Natalizumab-associated PML has had a
higher survival rate of 80% (medinfo.
biogenidec.com/medinfo), although PMLassociated deficits are expected to be
permanent. These patients usually also
require treatment of IRIS.
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