                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                        February 23, 1996

                Opportunistic Infections (Part XX)

        Progressive Multifocal Leukoencephalopathy (PML)

[Oportunistic Infections and Related Disorders; From AmFAR's
AIDS/HIV Treatment Directory, Vol. 7, No. 3, January, 1995]

     PATHOGEN: The JC virus (JCV).

     SITES OF INFECTION: JCV infects oligodendrocytes, the cells
in the brain which produce myelin. PML is a rare neurological
disease believed to be caused by either primary infection or
reactivation of latent JCV infection which results in demyelination
of the central nervous system. Initial brain lesions occur around
blood vessels, suggesting dissemination via the blood. PML occurs
at a much higher frequency in people with AIDS than it does in
patients with other immunosuppressive disorders, developing in 3
to 4% of AIDS patients. Approximately 70% of adults in the U.S.
have antibodies to JCV. PML does not appear to be contagious.

     SYMPTOMS: Mental status changes followed by speech or language
deficits, visual deficits, and generalized or focal weakness.
Neurologic signs include lack of coordination (weakness of one limb
or one side of the body), cranial nerve palsies, loss of vision on
one side, sensory loss in one limb or one side of the body,
language disturbance, and unsteadiness.

     DIAGNOSIS: JCV has been isolated from the brain and urine.
Definitive diagnosis of PML requires brain biopsy although
sensitivity ranges from 40% to 96%. Clinically, diagnosis is made
by detecting focal lesions and abnormalities of the white matter
on neuroimaging studies (CT or MRI). Recently, polymerase chain
reaction (PCR) of DNA of JCV from cerebrospinal fluid (CSF) has
been used in diagnosis.

     TREATMENT RESULTS: No effective treatment for PML has been
defined. The disorder is usually rapidly progressive and fatal,
although rare prolonged survival has been documented.
     Britton et al. treated 13 PML patients (mean CD4 count 106)
with intrathecal cytosine arabinoside (ara-C, cytarabine). 8/13
subjects stabilized and improved after treatment. Other
investigators (de Truchis et al., Nicoli et al., Urtizberea et al.
and Fong et al.) have reported that ara-C offered no prolonged
clinical improvement to  patients with PML.
     It has been reported by Allegre et al. that no improvement was
observed when intrathecal AZT was given for 3 months to 2 PML
patients.

REFERENCES: Allegre T et al. Intrathecal zidovudine (IT-AZT)
treatment of patients with HIV associated progressive multifocal
leukoencephalopathy (PML). Abstract PO-B16-1727, IX Intl Conf AIDS,
Berlin, 1993.

     Antinori et al. Failure of cytravine adn increased JC virus-
DNA in the cerebrospinal fluid of patients with AIDS-related
progressive multifocal leukoencehalopathy (PML). Abstract PO-B-
1727, IX Intl Conf AIDS, Berlin, 1993.

     Britton CB et al. Progressive multifocal leukoencephalopathy:
disease progression, stabilization and response to intrathecal
ARA-C in 26 patients. Abstract ThB3886, VIII Intl Conf AIDS,
Amsterdam, 1992.

     De Truchis P et al. Inefficacy of cytarabine in progressive
multifocal leucoencephalopathy in AIDS. Lancet 342: 622, 1993.

     Fong IW et al. The natural history of progressive multifocal
leucoencephalopathy (PML) Abstract PO-B01-0864, IX Intl Conf AIDS,
Berlin, 1993.

     Nicoli F. et al. Efficacy of cytarabine in progressive
multifocal leucoencephalopathy in AIDS. Lancet 339: 306, 1992.

     Urtizebera JA et al. Cytarabine for progressive multifocal
leucoencephalopathy (PML) in AIDS patients. Abstract PO-B16-1717,
IX Intl Conf AIDS, Berlin, 1993.

OTHER REPORTS: Berger J et al. Progressive multifocal
leukoencephalopathy in HIV-1-infected children. AIDS(6): 837-841,
1992.

     Iida T et al. Origin of JC polyomavirus variants associated
with progressive multifocal leucoencephalopathy. PNAS 90:
5062-5065, 1993.

     Karahalios D et al. Progressive multifocal leukoencephalopathy
in patients with HIV infection: lack of impact of early diagnosis
by stereotactic brain biopsy. J AIDS 5: 1030-1038, 1992.

     Portegies P et al. Response to cytarabine in progressive
multifocal leucoencephalopathy. Lancet 337: 680-1, 1991.

     Wegner M et al. Regulation of JC virus by the POU-domain
transcription factor Tst-1: implications for progressive multifocal 
leukoencephalopathy. PNAS 90: 4743-4747, 1993.

     Copyright (c) 1995 - American Foundation for AIDS Research
(AmFAR) - All Rights Reserved. Permission to reproduce for
non-profit use granted with the condition that the source and date
of the information be given, and that AmFAR be notified. Eric
Fretz, Treatment Information Services, AmFAR. DISTRIBUTED BY
GENA/aegis (714.248.2836 * 8N1/Full Duplex * v.34).


           Progressive Multifocal Leukoencephalopathy
                     by Sarah Huffbauer, MD

[BEING ALIVE; Published by BEING ALIVE / Los Angeles April 1995]

(Sarah Huffbauer, MD, is a family physician practicing in the
Seattle area. This article is reprinted from the Fall 1994 STEP
Perspective, a publication of the Seattle Treatment Exchange
Project. For subscription information, Call 1.800.869.STEP.)

     Progressive multifocal leukoencephalopathy (PML) is a
neurologic syndrome somewhat similar to multiple sclerosis (MS)
that is seen in almost 4% of people with AIDS whose CD4 counts have
fallen below 100. Although PML is relatively rare, up to 60% of
people with HIV experience neurologic problems at some point which
must be distinguished from PML for appropriate treatment and
prognosis.
     There are three main categories of central neurologic
(occurring in the brain) syndromes in HIV: a) AIDS Dementia
Complex, though to be caused by HIV itself, b) neoplasms (cancers),
and c) opportunistic infections. In approximate order of frequency,
neurologic opportunistic infections are caused by toxoplasmosis,
cryptococcus and other fungi, viruses such as CMV and herpes,
mycobacteria, and the virus which causes PML called papovavirus or
Jacob-Crutchfeld virus.
     Since up to 70-90% of healthy older adults have antibodies to
the papovavirus, PML is most likely a reactivation of the virus in
an immunocompromised person as opposed to a primary infection.
Papovavirus was identified as a slowvirus (one which causes latent
and usually benign infection) and as the cause of PML in 1958. PML
was even rarer then, occurring mostly in people with leukemia or
lymphoma. As the HIV epidemic has increased the incidence of PML,
so has more interest in research into early diagnosis and treatment 
increased in the last decade.
     As mentioned earlier, PML is similar to multiple sclerosis
(which is much more common). Like MS, it is a demyelinating disease
of the brain. Demyelination refers to destruction of the
insulation-like cells called oligodendrocytes around nerve fibers.
Like people with MS, people with PML often first experience subtle
weakness or the lack of coordination of an arm or leg. Unique to
PML, there is often some difficulty with thinking and/or speaking.
Visual disturbances, seizures, memory problems and headache can  
sometimes follow. With rare exception, PML has been true to      
its name in that it is devastatingly progressive with a mean
survival of 2-4 months after onset of symptoms and a survival range
of 2 weeks to 18 months. 
     Also in line with its name, the usual findings on CT scan or
MRI are multi-focal lesions within the brain. These lesions are
best seen with MRI and are usually of high-signal intensity without
enhancement. PML lesions must be distinguished from lymphoma which
is also non-enhancing but usually only one lesion (unifocal instead
of multifocal), and from toxoplasmosis which is usually quite
enhancing on the scans. Unique to PML, there is rarely any edema
(brain swelling) or mass effect (shifting of the brain to one
side).
     The location of the lesions is usually subcortical at the
junction between the gray and white matter, unlike MS which is
cortical (higher white matter).
     Other potential diagnostic tools, once imaging of the brain
has been performed, are lumbar puncture and brain biopsy. Usually
the cerebral spinal fluid from lumbar puncture is normal with
occasional increases in lymphocytes (a type of white blood cells).
A new test for papovavirus is the spinal fluid by PCR (polymerase
chain reaction) is being developed and may have sensitivity of up
to 80%. The clinical use of this test would allow diagnosis based
on lumbar puncture and imaging alone, avoiding the more invasive
brain biopsy. As it stands now, brain biopsy still provides the
only definitive diagnosis. Biopsies are fairly low risk (only 3%
serious complication rate) and can be done under local anesthetic 
with CT guidance.
     While there is currently no effective treatment for PML, many
antivirals have been tried. There are case reports of AZT alone
being helpful, but there is also a 10% spontaneous remission rate,
so it has been hard to draw useful conclusions. Dr. Christina Marra
is conducting a randomized three arm trial for people with biopsy
proven PML (ACTG243). The trial compares the best antiviral the
person can tolerate alone, with best antiviral plus intrathecal
(into the spinal fluid) Ara-C. Ara-C (cytosine arabinoside) is an
antiviral and also used in chemotherapy. It has multiple potential 
toxicities, and so people receiving it must be carefully monitored.
While PML is a grim diagnosis to receive or to make, the more we
know about it, the more we can differentiate it from other more
readily treatable central nervous system problems. Accurate
diagnosis for neurologic problems in HIV can help to provide
realistic prognoses and expectations. Ongoing research will, one
hopes, identify effective treatment for PML in the near future.

     Copyright (c) 1995 - BEING ALIVE/Los Angeles.  Distributed by
AEGIS, your online gateway to a world of people, information, and
resources.  714.248.2836 * 8N1/Full Duplex * v.34


           PML Treatment Update, Peptide T Possibility
                        by John S. James

[AIDS TREATMENT NEWS #201, June 17, 1994.]

     PML (progressive multifocal leukoencephalopathy) is a brain
infection caused by a virus, the JC virus. It is relatively rare,
diagnosed in only about one percent of people with AIDS. But many
cases are misdiagnosed, usually as toxoplasmosis or lymphoma. While
PML most often occurs in late-stage AIDS, it can also be found in
persons with a  relatively high T-helper count; and it can be the
first AIDS-related condition diagnosed.
     There is no cure for PML, and there are no FDA-approved
treatments; therefore, persons who are diagnosed are often told by
their doctors that there is no treatment, and that they will die
in weeks or months. In fact, there are experimental or possible
treatments; and a number of people with PML have stabilized or
improved, and have lived relatively healthy lives for years. The
treatments remain uncertain, however, because controlled trials
have not been done.
     The best single source of information on PML treatments is a
privately-published book, Progressive Multifocal Leukoencepha-
lopathy (PML): Case Studies and Potential Treatments, by Peter and
Lisa Brosnan; the latest edition was printed in July 1993 (see
below for how to obtain a copy). The authors are not physicians or
medical specialists. Lisa's brother was diagnosed with PML in 1988,
and the Brosnans started searching the medical literature for
possible treatments. Lisa's brother died in a month, however,
before treatment could be started; the Brosnans continued their 
work, to make the information available to others. Because the
disease can progress rapidly, it is important to start treatment
as soon as possible.
     The book includes a brief description of PML, discussion of
treatments which have been tried (ARA-C, or a combination of two
or more of: acyclovir, heparin, interferon, NAC, and
dexamethasone), and mention of possible treatments which apparently
have not yet been tried in people but have some theoretical or
laboratory rationale (foscarnet, ganciclovir, isoprinosine, and
camptothecin derivatives such as topotecan). Recent anecdotal
reports about peptide T arrived too late to be included in
thecurrent printing; they are discussed in the interview below.

The book also includes:

* Fifteen case studies, most from medical journals, but some
collected by the authors;

* A survey of 21 people with PML, compiled by the authors;

* A resource section, including contact information for leading PML
experts your physician can call;

* Over two dozen articles and abstracts from the medical
literature, AIDS newsletters, and elsewhere, and references to
other articles.

For the most recent information, AIDS TREATMENT NEWS interviewed
co-author Peter Brosnan.

Interview with Peter Brosnan:

AIDS TREATMENT NEWS: What is the most important message for  our
readers?

Brosnan: That there are treatments for PML. I continually hear from
people who have been diagnosed with PML and told that there are no
treatments. That makes me angry. There are treatments. There are
no cures, but there is a wide range of drugs now that have shown
themselves to be effective in at least some cases. They are readily
available. All the evidence indicates that if treatment is going
to be successful, it must be started early and aggressively. And 
there are a number of treatments to choose from.

ATN: ARA-C (or its relative, ARA-A) is the treatment with the most
mainstream medical support, but it also may be the most dangerous
-- and there have been no controlled trials. What does the current
information suggest?

Brosnan: The jury is still out on ARA-C. I understand that a trial
will be starting shortly, comparing intrathecal to intravenous
ARA-C. It does seem to help in many cases. In other cases, however,
especially intravenously, it can be very dangerous. In somebody who
did not have AIDS, it would probably be immediately recommended.
In somebody whose immune system or overall health is already
compromised, it should be considered very cautiously, I think. 

ATN: Do people without immune deficiencies get PML?

Brosnan: Very rarely. Before AIDS, it was usually seen in
chemotherapy patients, and those who needed to take immune-
suppressive drugs because they had organ transplants. Contagion is
not an issue, since almost everybody has the virus already; the
immune system keeps it in check.

ATN: You mentioned a number of possible PML treatments that have
been tried, alone or in combination: acyclovir, heparin,
interferon, dexamethasone, and NAC. What can you say about them?

Brosnan: Acyclovir was a surprise to us when we first began doing
this, six years ago. We began hearing more and more from people who
claimed that their PML was either stabilized or in remission
without any treatment at all. But when we questioned these people
carefully, we found out over and over again that they had herpes
and were being treated with acyclovir. I understand there are some
basic similarities between the JC virus and the herpes virus. And
we have seen many people now who seem to be responding to the
acyclovir, especially at high oral doses, 2000 to 4000 mg per day.
Heparin [a drug usually used to prevent blood clotting] was first
suggested by Dr. Sidney Houff, with the National Institutes of
Health and the Veterans Administration near Washington, D.C. His
theory was that the JC virus apparently has a receptor on the B
lymphocytes, and it is these cells that transport the virus across
the blood-brain barrier into the brain. Heparin seems to interfere
with that transport, keeping the PML out of the brain. We have
heard from a number of people who haven't gotten better, but their
PML seemed to stabilize. The drug has few side effects.

Most of the people I have heard of who are using alpha interferon
are combining it with something else, such as ddI or acyclovir.
There do seem to have been some positive responses, and there are
some instances in the medical literature in which either alpha or
beta interferon has had a positive effect on PML. Beta interferon
is in very short supply right now, after it has been approved for
multiple sclerosis.

Multiple sclerosis, like PML, is a disease that destroys myelin.
There is one encouraging case in the medical literature, from
Japan, in which intrathecal beta interferon seemed to be very
effective. As far as I know, that is the only time it has been used
for PML.

NAC [n-acetylcysteine, not approved in the U.S. in oral form, but
available in buyers' clubs and health-food stores] is listed
because, for three or four years now, we have seen improvement of
symptoms in people with PML who have taken NAC.

Dexamethasone is a steroid which decreases inflammation -- although
it also suppresses the immune response. It is not a primary
treatment, but may help with the symptoms in some cases.

The best results we've seen are from people using a combination of
these drugs. Whether there is synergy [meaning that the drugs work
unexpectedly well together], or whether these people just happened
to hit the drug that is right for them, we don't know.

Peptide T

ATN: You mentioned peptide T -- which has long been a popular
semi-underground treatment for some other AIDS-related neurological
complications. The information is too recent to be included in your
current book (third edition, July 1993), however. What are you
hearing about it?

Brosnan: Peptide T is something we've had an eye on, ever since
starting this in 1988, because it seemed very promising. But
because of all the problems peptide T has encountered [political
and commercial problems in its development, not problems with the
drug itself], there has been little information until recently.
Just in the last couple of months we have heard four or five
reports of its use against PML, with what seemed in some cases to
be promising results. I don't want to get too excited -- we have 
all seen these kinds of things come and go before. But it does seem
very promising. And certainly it is a non-toxic substance.

ATN: Do you think peptide T may be giving only symptomatic relief?

Brosnan: We don't  know if we are seeing treatment of symptoms, or
treatment of the underlying problem. I am aware of a couple of
people who seem to have been stabilized by it, for up to a year.
If it were just treating the symptoms, I don't think that would
have happened.

I've spoken to one neurologist who is familiar with both PML and
peptide T. He sees a couple possibilities. Peptide T may itself be
a neurotransmitter. It might also be a very strong anti-TNF factor.
And TNF might be involved in demyelination [loss of the myelin
sheath from nerve tissue, which happens in PML, and also in other
diseases such as multiple sclerosis]. If that is the case, it would
be an argument for peptide T directly affecting the PML, not only
relieving symptoms.

ATN: You mentioned people stabilizing on peptide T for up to a
year. Did they then get worse, or is there only one year's
experience at this time? 

Brosnan: A doctor in New York called me in March. She had a patient
who had completely stabilized for one year after taking peptide T;
but now he was beginning to show signs of progression, she was
looking for a newer treatment. I believe all he was taking was AZT
and peptide T. I have not been able to check up on what has
happened since then.

In another case from New York, a man developed PML in the fall of
1993. By December he was unable to walk, and losing a lot of
weight. He started taking peptide T, and by January he was fine.
Then in February he ran out of money and had to stop taking the
peptide T; he got worse. In March he started taking it again; he
got better, and he seems to have stabilized.

A week ago I talked to a woman in Louisiana, whose husband has had
PML for a year. He had not walked in a year; he had not been able
to speak for six months. Two days after starting peptide T he took
his first steps, and spoke his first complete sentence.

You don't want to get too excited. But I'd certainly like to see
peptide T used more frequently, because it's something we need to
look into.

ATN: We should point this out to community-based research groups.
This is a study that could be done quickly, to get some
more-than-anecdotal data, less affected by self-selection of the
group of people who called you. There would be ethical concerns
that would have to be addressed carefully in planning any trial.
Would a control group be ethical? You could not ask people to avoid
other PML treatments. Maybe the way to start would be to give
peptide T to all study volunteers, in addition to their other
treatments, and carefully collect uncontrolled data. 

Brosnan: We have only seen a handful of cases. But it may be the
most exciting development in several years, and I'd certainly like
to see more studies done.

LTR Inhibitors

ATN: You briefly mentioned the experimental cancer treatments
camptothecin and topotecan [the latter is a camptothecin
derivative, engineered to have better pharmacologic properties than
camptothecin]. AIDS TREATMENT NEWS has covered this class of drugs
as potential HIV treatments -- they are in human trials for cancer,
but as far as we know no one with HIV has ever taken any of them.
In the laboratory these drugs inhibit the LTR (long terminal
repeat) of HIV, forcing the virus to remain inactive. How did they
come up in relation to PML? 

Brosnan: Apparently there have been two separate, unpublished
studies that show that these drugs cut off replication of the JC
virus, when it is combined with ARA-C. We don't have details at
this time.

Diagnosis Problems

Brosnan: I suspect that PML is being greatly underdiagnosed. There
have been some consecutive autopsy studies from Europe, in which
PML has been seen in from 7 to 18 percent of the people they
autopsied. I suspect that some patients who are being
unsuccessfully treated for toxoplasmosis are suffering from PML.
About two thirds of the people I speak to who have PML were
originally misdiagnosed as having toxo -- or strokes, or inner ear
infections, but usually toxo. I wish more AIDS doctors would keep
PML in the back of their mind as a possibility.

For More Information

You can obtain a copy of Progressive Multifocal Leukoencephalopathy
(PML): Case Studies and Potential Treatments, from Peter Brosnan,
1709 N. Fuller Avenue, #25, Los Angeles, CA 90046. To cover his
costs, he asks physicians and institutions to send $30, people with
AIDS $20, and in cases of hardship he will send it free.

In an emergency, call Peter Brosnan at 213/874-7885, so he can send
the book immediately.

[AIDS TREATMENT NEWS subscription and editorial Office:  P.O. Box
411256, San Francisco, CA 94141.  800/TREAT-1-2 (toll-free U.S. and
Canada); 415/255-0588 regular office number; fax: 415/255-4659;
Internet: aidsnews.igc.apc.org.  Copyright 1994 by John S. James.
Permission granted for noncommercial reproduction, provided that
address and phone number are included if more than short quotations
are used.]
