Progressive
Multifocal Leukoencephalopathy
by Mark Bowers
HIV is a member of a family of retroviruses that frequently
find their way into brain tissue. The spectrum of HIV-related
diseases in the brain is wide, caused either by the direct
or indirect effects of the growth of HIV in the brain, or
by various viruses, bacteria and fungi that cause opportunistic
infections and complications. AIDS dementia complex (ADC)
is the most widely recognized of these complications (see
“AIDS Dementia Complex” in the December 1996 BETA).
Another complication is progressive multifocal leukoencephalopathy
(PML).
PML is rarely found in early HIV disease; when it does occur,
it is almost always found in people with late-stage HIV
disease. More PML infections are found in people with AIDS
than in people with any other immunosuppressive disorder.
In March 1996, Joseph Berger, MD, reported on a retrospective
study of the incidence of PML in Americans with AIDS. For
the period 1981-1995, as many as 5% of people with AIDS
had PML either as their first AIDS-defining infection or
one that developed after an AIDS diagnosis. Fewer than 89%
survived more than 1 year after diagnosis, but 11% lived
longer than a year with either partial or complete remission.
PML is progressive in that there is continuous expansion
of brain lesions caused by the JC virus. Neurological abnormalities
increase over time, frequently caused by multifocal
(in several areas) lesions. However, it is common for a
person with PML to have only one brain lesion instead of
multifocal lesions. PML may cause dementia, but it is almost
always seen with other neurologic problems. A characteristic
finding is leukoencephalopathy, or degeneration
of the white matter of the brain.
Until recently, neurologists were discouraged by the rapid
course of PML disease; the average survival time from date
of diagnosis was only 4-6 months. Dawn McGuire, MD, at the
Western NeuroAIDS Program at Davies Medical Center in San
Francisco, now paints a very different picture. According
to McGuire, the immune restoration that frequently accompanies
highly active antiretroviral therapy (HAART) may prove to
have a significant impact on the incidence of PML. A retrospective
study from London found that patients who took AZT monotherapy
also had a reduced risk of PML. McGuire tells her patients
to “ignore the literature that says you’ll be
dead in 4 months.” The majority of her patients survive
much longer.
PML has been particularly difficult to study. As many as
two-thirds of American adults harbor the JC virus, but very
few develop PML disease; these individuals usually become
symptomatic only when they become severely immune suppressed.
Clinical evaluation of these individuals is difficult. No
drugs to combat JC virus infection have been approved by
the Food and Drug Administration (FDA) and there is no accepted
standard of care. In addition, diagnostic tools do not always
help distinguish PML from other possible brain deficits
or infections. By themselves, the results of routine cerebrospinal
fluid (CSF) tests do not conclusively diagnose PML, nor
do they easily exclude it.
Until recently, treatment for the disease was usually referred
to euphemistically as “unsatisfactory.” However,
effective antiretroviral therapy may prevent PML, and new
treatment drugs may hold promise. This article discusses
the diagnosis, clinical evaluation and treatment of PML.
Symptoms
The symptoms of PML are not unique to PML. The neurological
symptoms often associated with PML include disturbances
in movement and coordination, including walking and posture.
A limp or muscular weakness may be noticed on one side of
the body, suggesting a lesion on the opposite side of the
brain. (The neural wiring that connects one side of the
body to the brain almost completely crosses to the opposite
side.) The visual field of some individuals with PML is
smaller and contains “visual field cuts,” or missing
parts of the visual field on the left or right of the environment.
Other senses may also be affected.
PML lesions may affect higher cortical functions, causing
aphasia (speech disorders) and apraxia (the inability to
coordinate movements despite having the strength to do so).
Memory loss, headache, confusion, dementia and seizures
may also result from PML lesions.
The onset of PML disease varies. Mental and physical decline
can be sudden and rapid, and people may require significant
help with the tasks of daily living. Personality changes
may create new challenges for caregivers. Occasionally,
PML spontaneously goes into remission. Encouraging anecdotal
reports suggest that highly active antiretroviral therapy
including a protease inhibitor or the experimental use of
cidofovir (Vistide) may reverse the decline usually seen
with the disease. In some reported cases, the response to
therapy has been so impressive that patients return to normal.
McGuire reports that one patient’s lesions seemed to
disappear from radiologic studies. However, it is difficult
to evaluate individual case reports when up to 10% of people
with PML get better without any specific treatment.
What PML Does
The nerve fibers that convey messages to and from the brain
are insulated from one another for many of the same reasons
that telephone wires are insulated. Myelin, the fat and
protein coating that forms a living sheath for neural fibers,
helps to speed the transmission of information to and from
the brain and prevents “cross talk,” or garbled
messages. Like multiple sclerosis, PML is a disease that
breaks down myelin (demyelination) by killing the cells
that make this insulating material. PML lesions typically
begin at the junction between the grey matter and the underlying
white matter of the brain. Demyelination results in lesions.
The brain lesions that define PML can affect motor and sensory
neural networks in some cases and intellectual functions
in others, depending on where the lesions are.
A commonly held theory about JC virus infection is that it
is harbored in the kidneys until the host becomes immune
suppressed, then travels through the blood to the brain.
Once in the brain, it infects and kills oligodendrocytes,
specialized neural cells that form myelin in the brain.
The movement of JC virus to the brain may be mediated by
B-cells, and may require some structural changes in the
virus. Further study is required to unravel the pathogenesis
of PML.
Diagnosis
One difficulty in establishing a diagnosis of PML is the
similarity of symptoms among many neurologic diseases. The
symptoms described above do not unmistakably point to just
one neurologic disease. A person with PML may look and act
like one with toxoplasmosis or central nervous system (CNS)
lymphoma. Each disease has a different set of characteristic
neuroimaging and diagnostic findings.
Brain
Biopsy
Brain biopsy, which involves the physical removal and study
of a small sample of brain tissue, has been the “gold
standard” for diagnosing PML. A stereotactic biopsy
allows a cutting tool to be precisely guided to the area
of a lesion by use of 3-dimensional coordinates. McGuire
recommends that physicians and patients inquire about rates
of complications that accompany a brain biopsy at the hospital
or institution where a biopsy is planned. Armed with this
information, the physician and patient can together decide
whether the risks of the procedure outweigh the benefits
of knowing for sure if PML is the problem. Considerable
research has been devoted to finding a safe and reliable
alternative to biopsy.
Cerebrospinal
Fluid Analysis
The cerebrospinal fluid (CSF) that bathes the brain and spinal
cord contains increased proteins in general, myelin basic
protein in specific, and more immunoglobulin content in
a person with PML. However, none of these increases proves
that a person has PML. McGuire has developed a polymerase
chain reaction (PCR) test that is 92% sensitive and specific
for JC virus DNA. This level of sensitivity allows McGuire
to detect PML without resorting to radiologic studies in
92% of all cases. Several other widely available commercial
assays detect JC virus DNA with similar reliability. Some
clinicians consider radiologic studies combined with a positive
result from a CSF PCR test sufficient to establish a diagnosis
of PML, although a negative CSF PCR test result does not
mean that a person does not have PML.
There is a concern about the way in which lumbar punctures
or spinal taps are done to obtain CSF. Neurologist Christina
Marra, MD, Assistant Professor of Neurology and Medicine
at the University of Washington, is the primary investigator
of an AIDS Clinical Trials Group study (ACTG 363) of cidofovir
for the treatment of PML. Marra prefers to use “pencil-point”
needles that do not leave holes in the dura mater that surrounds
the CSF. When regular needles are used, holes in the dura
mater allow some CSF leakage after a lumbar puncture, leading
to headaches in about 1 in 10 patients. The rate of headache
following a puncture with a “pencil-point” needle
is quite small.
Blood
Studies
PCR tests for JC virus in the blood are not very helpful
in diagnosing PML. As many as one-third of all people with
HIV have antibodies to JC virus in their blood, while two-thirds
of the public have been exposed to JC virus at some point
in their life. It is unlikely that simple blood tests will
replace the combination of radiologic tests and analysis
of the CSF in the near future.
Radiologic
Studies
In a retrospective study by Berger and colleagues, computerized
tomography (CT scans, or serial x-ray images) revealed low
density white matter lesions that did not distort the shape
of the brain, usually in the back part of the brain hemispheres.
Not all patients later known to have PML showed abnormalities
on CT. Enhancement of CT with contrast agents also failed
to locate lesions in most of Berger’s subjects. Many
neurologists feel strongly that CT scans provide insufficient
information to diagnose PML and are very costly, and therefore
should not be done.
Magnetic resonance imaging (MRI, a technique to create detailed
pictures of the brain without using x-rays) appeared superior
to CT in Berger’s study because it located more lesions
in more subjects. MRI is a better way to see PML lesions
below the surface of the brain, in the white matter. MRI
is more expensive and takes longer to perform, requires
a large space to house the apparatus and can be trying for
individuals with claustrophobia. “Open” MRI scanners
are available in larger cities for those with claustrophobia.
McGuire and Marra agree that radiologic results that are
consistent with PML combined with PCR studies of the CSF
are sufficient to accurately diagnose PML most of the time.
McGuire is reluctant to base a PML diagnosis solely on radiologic
studies. She observes that radiologic studies that misdiagnose
PML are rarely published, while successes are almost invariably
reported. This provides a distorted picture of the value
of radiologic studies by themselves.
Autopsy
Researchers who study the incidence of PML have historically
relied on autopsy information to provide a real picture
of the number of people affected by PML. Because the number
of people who have brain lesions caused by JC virus at autopsy
is higher than the number of people definitively diagnosed
with PML, pathologists speculate that a significant number
of PML cases are missed during life. Efforts are underway
to accurately identify individuals with JC virus infection
and PML early.
Treatment
Recent interest has focused on treating PML indirectly with
highly active antiretroviral therapy, usually consisting
of 2 nucleoside analog drugs in combination with a protease
inhibitor drug. David Clifford, MD, at Washington University
in St. Louis has begun to collect a database of physicians’
anecdotal experiences with HAART in people with newly diagnosed
or progressing PML. By August 7, Clifford had natural history
data from 16 individuals. The goal of Clifford’s observational
database is to document HAART use in people with PML, and
to chart the course of HIV viral load and any complications
that may arise once individuals are on his registry. Clifford
recommends “pulling out the stops” with regard
to aggressive antiretroviral therapy, as well as closely
monitoring viral load. He informally observes that the people
who are now getting PML generally do not seem to have undetectable
HIV viral loads. He encourages physicians with patients
who have PML to work diligently to decrease HIV viral load
and to share their experiences with him and the NeuroAIDS
Research Consortium (NARC). A website has been established
for the PML registry at www.neuro.wustl.edu/narc.
Three case reports of people who stabilized or dramatically
improved while receiving HAART have recently appeared in
BETA (September 1996, page 40; March 1997, page 29; June
1997, page 52).
For several years, people with PML were treated with cytosine
arabinoside (Ara-C), either by intravenous administration
or by introduction of the drug directly into the CSF. Most
work with the drug was done by Caroline Britton, MD, at
Columbia-Presbyterian Hospital in New York City. Her positive
results created a general impression that Ara-C might be
an effective treatment.
A recent AIDS Clinical Trials Group study (ACTG 243) compared
the 2 routes of administration of Ara-C combined with the
best antiretroviral therapy for the individual to the best
antiretroviral therapy alone. (Because this study began
before any protease inhibitor drugs were approved, many
participants did not receive combination therapy including
a protease inhibitor.) The study was halted after 60 participants
were treated. No statistical difference in survival could
be found among the study arms, suggesting that either too
few people were studied to detect a small benefit to the
use of Ara-C, or that there was no effect at all. This was
an important study, because many physicians elected to treat
their patients with Ara-C based on scant clinical evidence
that the drug worked. There have also been isolated reports
that combinations or alternations of Ara-C and interferon-alpha
produced some clinical improvement, but these combination
strategies have not been subjected to rigorous clinical
evaluation.
Test-tube studies have suggested that cidofovir kills several
viruses related to the JC virus. Belgian researchers Andrei,
Snoeck, Vandeputte and DeClercq have published encouraging
findings that show that cidofovir kills viruses related
to JC virus, and Gary Blick, MD, of Blick Medical Associates
in Greenwich, CT, has submitted a case report for publication
detailing successful treatment with cidofovir of an AIDS
patient diagnosed with PML. The only way to be sure that
cidofovir is a useful treatment for PML is through clinical
study.
Other drugs that have been used as treatment for PML include
prednisone, acyclovir, vidarabine and adenine arabinoside.
Interferon-alpha and interferon-beta have been combined
with other drugs or given alone. At the Fourth Conference
on Retroviruses and Opportunistic Infections in Washingtion,
DC, in January, 1997, Justin McArthur, MD, and colleagues
from Johns Hopkins University reported the effect of interferon-alpha
on survival by examining the records of 104 people with
HIV and PML. They found that untreated patients lived an
average of 121 days compared to 325 for those treated with
interferon-alpha. They concluded that interferon-alpha use
may delay progression, improve survival and be associated
with remission in HIV-associated PML.
Clinical Studies
A pilot study of cidofovir (ACTG 363) has been designed by
researchers in the ACTG and the NARC and at Gilead Sciences.
Primary investigator Marra says that the dosing and schedule
of administration of cidofovir will be the same in the upcoming
PML study as they are for the treatment of cytomegalovirus
(CMV) retinitis. Participants will be given intravenous
cidofovir at 5 mg/kg once a week for 2 weeks, then once
every 2 weeks for a total of 13 doses. The study lasts 24
weeks. This study will recruit participants in whom PML
has been proven by a combination of positive CSF PCR and
typical clinical and MRI findings. Marra intends to monitor
changes in the quantity of JC virus DNA in the CSF to see
if changes reflect changes in clinical response. She will
also look for evidence of CMV in the CSF, since CMV is known
to cause inflammation of the brain (encephalitis) and cidofovir
may have a positive effect on encephalitis. People with
positive PCR tests for CMV in the CSF will not be included
in the PML study.
Marra is cautious about the use of cidofovir. She is wary
of side effects such as iritis (inflammation of the eye)
and hypotony (decreased pressure inside the eye), both of
which are potentially serious, sight-threatening complications
that occurred in 7.3% of participants in a clinical study
of cidofovir. Participants in Marra’s multicenter study
will be closely monitored for the development of these conditions.
She will also monitor participants for kidney toxicity (protein
in the urine occurred in 48% and serum creatinine was elevated
in 8% of participants in one clinical study) and low blood
cell counts (neutrophil counts less than 750 cells/mm3
occurred in 31% of participants in one clinical study).
For local study sites, call the AIDS Clinical Trials Information
Service (ACTIS) toll-free at 800-874-2572.
Pharmacia and Upjohn, Gilead Science’s marketing partners
outside the United States, are conducting a study of the
safety and efficacy of cidofovir in the treatment of PML
in HIV seropositive individuals in Europe. This will be
a randomized, double blind, placebo-controlled study with
an open-label extension phase. The study will compare 6
months of cidofovir or placebo given to participants at
the time of diagnosis or progression of PML. All participants
will be offered an additional 6 months of access to cidofovir
at the conclusion of the study.
McGuire is studying topotecan, a topoisomerase inhibitor,
for the treatment of PML at the Western NeuroAIDS Program.
Topotecan inhibits an enzyme that is involved with making
usable DNA. Topotecan was approved for treating metastatic
cancer of the ovary after another treatment has already
failed. The drug is administered intravenously by a central
catheter continuously for 21 days with 7-day breaks between
infusions. Topotecan has been shown to inhibit both JC virus
and HIV. Previous use of Ara-C is technically an exclusion
for participation in this study, although it has been shown
to be ineffective. Study sponsors have assured BETA that
a protocol exception will allow people who have been previously
treated with Ara-C to participate.
Topotecan has been shown to penetrate well into the brain,
and the long continuous exposure to it permits the drug
to work at the correct stage in the cell cycle. Side effects
include bone marrow suppression (81%), nausea (74.8%), vomiting
(55.5%), diarrhea (39.3%) and hair loss (59.3%). The drug
is also being studied as a treatment for AIDS-related Kaposi’s
sarcoma and non-Hodgkin’s lymphoma. For further information,
contact the Western NeuroAIDS Program at 415-565-6368.
NARC has preliminary plans to study a related topoisomerase
inhibitor called 9-amino-camptothecin. Neurooncologist John
Henson, MD, at Massachusetts General Hospital is now developing
a proof-of-concept study.
Conclusion and Future Directions
The current outlook for people diagnosed with PML is nowhere
near as bleak as it was only 2 years ago. Perhaps the greatest
gain has been a perceived decline in the number of individuals
who are diagnosed with PML, widely attributed to increased
use of HAART. Antiretroviral drugs may protect against PML.
Important strides have recently been made in the ability
to accurately and efficiently diagnose PML without resorting
to stereotactic brain biopsy. McGuire and Marra both speculate
that quantitative PCR tests for JCV DNA in the cerebrospinal
fluid will become very useful in monitoring the effectiveness
of treatments for PML. Although the unofficial standard
treatment for PML, Ara-C, was found to be ineffective when
carefully scrutinized, topoisomerase inhibitors such as
topotecan may prove effective, and clinical studies are
clearly needed. The anti-CMV drug cidofovir shows considerable
promise and has enthusiastic supporters. Both studies will
fill slowly, as the number of individuals being diagnosed
each month may be declining. This alone is reason enough
for celebration.
Special thanks to Christina Marra, MD, Dawn McGuire,
MD, Sally Nuessle, PharmD, and David Clifford, MD, for their
comments or for review of this article. Any errors of fact
or omission are solely the responsibility of the author.
Mark Bowers is Managing Editor of Treatment Publications
at the San Francisco AIDS Foundation.
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