Understanding Dementia and Neurologic Disorders: Interview, Elyse Singer, M. D.
Of all the physical and emotional difficulties which HIVdisease can present, those involving the nervous system may be
the most troubling and least understood. Many neurologic
problems are broadly associated with opportunistic illnesses, or
with the side effects of certain drugs. However, HIV itself can
have a number of effects on the nervous system, ranging from
subtle disorders to serious ones. It is important to know that
many of these respond to treatment.
Direct HIV involvement can impair cognitive (thinking) or
motor (coordinated movement) abilities, but it should be
distinguished from neurologic symptoms of infections and
malignancies that can appear in the wake of immune suppression,
such as toxoplasmosis, CMV or herpes encephalitis, cryptococcal
meningitis, progressive multifocal leukoencephalopathy (PML),
neurosyphilis and lymphoma. A fairly reliable diagnosis and
treatment "pathway" has been established for most of these.
Other problems of the nervous system can be "iatrogenic" in
nature, meaning they are the unintentional and sometimes
unavoidable effects of medical treatment. Examples are the
peripheral neuropathy that can result from the use of ddI, ddC or
vincristine, or myopathy (muscle damage) that can follow the
long-term use of AZT, or delirium sometimes associated with ddI
or ganciclovir.
Some neurologic symptoms are easy to confuse with depression
and sleep disorders, which can be a natural response to the
stresses of living with HIV. But chronic, immobilizing
depression or sleeplessness warrant treatment with appropriate
therapy or drugs.
Since opportunistic illnesses, drug toxicities, or
depression are often either urgent or easy to treat, they are
likely to be considered first when someone goes to their doctor
with a neurologic symptom. In contrast, cognitive or motor
disorders caused directly by HIV may be the least urgent,
clinically speaking, and the last treated of nervous system
diseases.
HIV may colonize the brain, nerves, and muscles early in the
infection, but this process is clinically "silent" in most people
until they are immune suppressed. Fortunately, the virus does
not directly infect neurons, which are the circuits of
consciousness and memory. Nevertheless, for reasons explored
below, even non-neuronal HIV neurologic activity can lead to
serious deficits in cognitive and motor functions in some people.
At one time, all neurologic deficits caused directly by HIV
were ominously described as "AIDS dementia complex." That has
given way to the more accurate, if more clumsy, "HIV-associated
cognitive and motor complex." Dementia can be part of this
complex, but it is only a late development in a spectrum of
cognitive or motor deficits. Limited research so far suggests
that these deficits can respond to treatment.
In other words, HIV can impair the way people think and
move, but that impairment may be reversible given the
preservation of neurons and intervention with effective
therapies.
We asked HIV neurologist Elyse Singer, MD, to share her
experience and expertise with HIV neurologic disease. Dr. Singer
is an Assistant Professor of Neurology at the University of
California Los Angeles Medical School, and a research physician
at West Los Angeles Veterans Administration Medical Center.
[Editor's note: This article, published for both patients
and medical professionals, includes some medical terminology
which would usually be avoided or explained in AIDS TREATMENT
NEWS. In some cases, especially when words are used only as
examples and are not necessary for understanding the main points
of the article, we felt that a definition or explanation would be
an unnecessary distraction. Readers should realize that they do
not need to know every word in order to understand this
interview.]
* * *
DS: How extensive are nervous system problems in HIV
disease, and what is their relationship to HIV dementia?
ES: The new classification, of course, for these is HIV-
associated cognitive and motor complex. This includes what we
once called AIDS dementia, AIDS encephalopathy (brain disorder),
and AIDS myelopathy (spinal cord disorder). In the past, there
was a tendency to lump together all HIV-associated involvement
of the central nervous system as dementia. But in fact, many of
these people did not meet the criteria for dementia that would be
applied to other diseases, such as Alzheimer's. Dementia is a
persistent, disabling loss of cognitive function, and may be
caused by damage to the brain from a number of diseases. Some
people with HIV neurologic impairment have mostly motor symptoms,
and some patients have minor, rather than major, cognitive
problems. So it is inappropriate to call them demented. Minor
involvement means that someone is slightly below their baseline
in terms of their ability to think or use their motor skills.
Dementia would involve a persistent cognitive deficit that
disables a person from doing their work or activities of daily
living. If people are so disabled, they may be given a diagnosis
of dementia. In perhaps one-third to two-thirds of people with
dementia, there is an associated problem with the spinal cord
called vacuolar myelopathy. The symptoms of this are difficulty
walking and trouble with bowel and bladder control.
Infrequently, you might see this myelopathy without dementia.
Dementia is a term that has very important medical and legal
implications, and it carries a lot of social stigma for people.
It should not be applied indiscriminately.
DS: For those reasons and others, a lot of people are very
afraid of developing dementia.
ES: Yes. I think that along with the fear of pain, people
are really afraid of becoming demented. The term dementia has
been overused and sometimes misused in an insulting fashion. This
frightens some people from either admitting that they have
symptoms of cognitive disorders, or getting treatment for those
symptoms. I think it's important to impress upon people that
there are now treatment strategies available for many cognitive
problems, and that early treatment improves the chances for
recovery.
DS: Could you help with some definitions? I think a lot of
people are confused about the difference between myopathy and
myelopathy, and between the central and peripheral nervous
systems.
ES: Central nervous system refers to the brain and spinal
cord, and peripheral nervous system refers to nerves and muscles.
Meningitis, encephalitis, myelopathy, cognitive disorders and
infections like toxoplasmosis are diseases of the central nervous
system; neuropathy and myopathy are diseases of the peripheral
nervous system. It would be nice to have another word for
myelopathy, which is spinal cord disease involving myelin, to
distinguish it from myopathy, which is a disease of the muscles.
DS: To make matters more complicated, myelin is a component
of both the central and peripheral nervous systems, right?
ES: Precisely. It's a covering around the nerve cell. One
of the functions of myelin is to speed up transmission of nervous
impulses. Demyelination can cause these impulses to slow or even
stop.
DS: Deciphering all these possibilities reminds me of the
movie "Lorenzo's Oil." The medical and political dilemmas of
Lorenzo's parents are amazingly parallel to what is posed by HIV.
Some cognitive and motor lapses seem to be hard to
distinguish from simple tiredness or preoccupation. How do you
know when to be concerned? What are the clinical signs of HIV
neurologic disorders that physicians and their patients should
watch for?
ES: It can be very helpful to first assess the stage of an
individual's HIV disease. People with very high CD4 levels
rarely get severe cognitive problems. They may have other
neurologic problems, perhaps some unrelated to their HIV
infection. Among the possibilities early in HIV disease are
aseptic meningitis and some of the auto-immune neuropathies, like
Guillain-Barr type neuropathy. Less frequently, we see some of
the muscle diseases. Significant cognitive dysfunction is not
frequently seen before the appearance of other signs and symptoms
of AIDS, or before the CD4s (T-helper cell counts) fall
significantly. But everyone should be aware of the signs of
neurologic problems that prompt evaluation. Problems that
develop slowly but daily are those such as balance difficulties,
weakness or loss of feeling in the arms or legs, any loss of
vision or the ability to communicate, a persistent loss or change
in memory, concentration or attention. Someone having unexpected
difficulty balancing their checkbook or remembering a
frequently-dialed telephone number, or getting lost in familiar
places, are examples of deficits that should be evaluated.
Severe, persistent headaches should take you to an emergency room
fast, especially if they are associated with fever, stiff neck,
nausea or vomiting, or any visual symptoms.
DS: Are the more gradual symptoms something that the
affected person would notice?
ES: Generally, yes. But in the case of behavioral or
cognitive problems, it's often the affected individual's partner
or family that notices changes. These can be somewhat difficult
to differentiate from depression, or from some of the side
effects of drugs, either prescription or street drugs. When
people think of dementia, they may conjure up an image of someone
like "Dr. Demento," or they may think of their grandmother who
had Alzheimer's disease. People with AIDS dementia rarely look
like this, especially in the early stages. First of all, people
do not become demented overnight. It's a process that develops
over weeks, if not months or years, and often will begin very
subtly. Of course, early on is the best time to diagnose and
treat it.
The first thing many people start to notice is a persistent
problem with memory, like retrieving words or names or
associations. This suggests a subcortical problem, which
primarily affects the inner part of the brain. It is very
different from the situation with Alzheimer's, in which the
cerebral cortex, the outer part, is impaired. In subcortical
deficits, people can respond to cueing. In other words, if
someone offers the person a hint, they can retrieve what they
want to remember. Someone with Alzheimer's will not respond to
cueing.
HIV cognitive problems usually begin with a general slowing
down -- not so much being different from your normal self.
Reading, writing and understanding other people are not generally
affected, until late in the disease. I compare early HIV
cognitive problems to a record that's played at too few RPMs,
whereas Alzheimer's is more like a record that starts skipping
badly right at the beginning.
DS: So HIV is not associated with the erratic behavior that
people usually connect to the word "dementia?"
ES: For the most part, no. In fact, it might have been
easier to get funding for HIV neurologic research if people only
displayed erratic and frightening behavior. Usually, people
experience HIV-associated cognitive difficulties rather quietly.
In most cases, especially in early stages, people rarely display
grossly impaired judgment or odd behavior. It's really quite
subtle, and can be overlooked by everyone, including the
patient's doctor. It's very easy to attribute memory problems to
depression, or medication, or having a bad day.
There is a subset of patients who present with a more
psychiatric picture of AIDS dementia. I emphasize that this is a
relatively small group. We don't know what makes these
individuals different from those with the more common picture of
just slowing down. These people will present with psychiatric
symptoms like mania, or with a delirium, in which they become
acutely confused, wander around, do unusual and bizarre things.
These people get identified very fast because they are
troublesome to other people. But they hardly represent the
majority of people with AIDS-related central nervous system
disease. And of course, before you decided that this was
dementia, you would want to know if they were doing any
recreational drugs, or if they had an opportunistic brain
infection, or if they had a history of psychiatric disease that
was reactivated under stress.
DS: Does dementia ever overlap with mental illness
unrelated to HIV infection? I've known of people with a history
of bipolar disorder [manic-depressive illness] which seemed to be
exacerbated by HIV.
ES: Yes. Many times people with a history of depression
will have a new episode when they find out they're positive. And
there's some research from Johns Hopkins University suggesting
that bipolar patients are a bit overrepresented in AIDS clinics.
There may be two types of problems here. There are those people
with a history of bipolar illness, which then got a little more
out of control with HIV. These situations are pretty easily
controlled with medication. Then there are people with no
personal or family history of mania or bipolar disease, who have
very low CD4 cells, and who present with a manic-type picture.
Often the mania responds to drugs, but then an underlying
dementia reveals itself. This is usually seen in very sick
patients, and it is not as common as persons with a single
diagnosis of either manic-depressive illness or AIDS-related
dementia.
The average person with HIV cognitive problems does not
usually get identified until they are quite advanced because they
are not out there making problems for people. They are just
slowing down, doing more poorly as time goes on. Often they are
ill enough physically that they have already stopped working. I
see a lot of people who have a minor cognitive or motor disorder.
They are still working, often in professional jobs, often people
who are quite bright, who are very quick to pick up on their
cognitive dysfunction. They want to continue to participate in
the mainstream of life as long as possible; they want any
cognitive problems treated as early and aggressively as possible.
DS: I understand that some important cells of the nervous
system -- neurons in particular -- are not infected by HIV. So
where does neurologic damage originate?
ES: It would appear that in most adults HIV enters the
nervous system at the time of initial infection. Usually there
are no symptoms -- the virus is there but it doesn't do very
much. We don't know exactly how HIV penetrates the nervous
system, but we think one way it may get in is by hitching a ride
on cells called monocytes, or macrophages, which can pass through
the blood/brain barrier. Once inside, they infect other cells.
The cells eventually infected are those that are not actually
brain tissue. There are a lot of cells in your head that are not
brain cells, per se. The cells like neurons, that do your
thinking for you, and the oligodendrocytes, that make the myelin
that surrounds the axons of neurons and help them conduct
messages, do not appear to get infected with HIV, as far as we
know. However, a lot of the supporting cells and scavenger cells
in the brain -- macrophages, monocytes and microglia -- can be
infected with HIV, and can actually live a long time with this
infection. During this time, they can infect more cells, and can
serve as a reservoir for HIV production.
DS: If neurons and oligodendrocytes are saved from
infection, what is it that can impair cognition?
ES: We are still in the process of answering that question.
We do know of several ways that the virus can indirectly injure
those brain cells; in other words, affect them without infecting
them. This is a new idea in neurology, and holds broad
implications for treatment of other neurologic diseases.
First of all, some of the individual component proteins of
HIV, like gp120, appear to be toxic to neurons. These proteins
can damage the neurons in a variety of ways. One of these is by
opening up calcium channels, which neurons usually control to
maintain a very specific balance. As calcium pours in, a process
is initiated that, over a very long time, ends in cell death.
The tat protein produced by HIV can also act as a neurotoxin.
A second mechanism by which damage can occur is actually
initiated by your own defenses. Your body's immune system
responds to the presence of the virus by making cytokines. These
are chemicals that immunologically activate cells and cell
messengers, such as tumor necrosis factor, the interleukins and
interferons. In fact we sometimes use cytokines as treatments
for certain diseases. However, chronically high levels may cause
cell damage. Tumor necrosis factor, for example, has been
associated with damage to oligodendrocytes, the cells that make
myelin. So having too much tumor necrosis factor may initiate
demyelination.
A third pathway for indirect damage to brain cells arises
when the metabolism of normal compounds in the brain is disturbed
by HIV infection. An example can be found in the transfer of
amino acids from food digestion into the brain for the
manufacture of neurotransmitters. These are substances that
allow brain cells to communicate with one another. Without the
right kind of balance of neurotransmitters, you see disturbances
of mood, of thinking, of motor ability and sleep patterns, and so
on. In HIV infection, several cytokines, including gamma
interferon and tumor necrosis factor, can divert the metabolism
of amino acids like tryptophan to make toxins like quinolinic
acid.
So there are at least three routes through which HIV can
hurt neurons: toxic viral byproducts, excessive cytokine
production, and derailed metabolism. All of these, separately
and combined, can functionally damage neurons. In fact,
quinolinic acid is actually synergistic with gp120. And in
addition to all of that, there may be other substances that
result from the HIV infectious process, like nitric oxide,
prostaglandins, and leukotrienes -- basically the products of
immune inflammation -- that could cause cell damage.
DS: The next question, of course, is whether there are
treatments to counter this damage.
ES: Yes, the good side is that since neurons themselves are
not infected, we can look for drugs, some of which are already
available, to block some of the indirect injuries. There is even
an assay, a way of screening drugs, to see if they have some
potential to be effective in treating these problems. For
example, we can grow certain kinds of brain-cell cultures, and
add gp120, and add a drug, and see if the drug protects the
cells. One of these drugs is nimodipine, which is a calcium-
channel blocker, which blocks gp120-mediated calcium channel
damage. Another is pentoxifylline, which may suppress the
production of tumor necrosis factor. This may be a way of
suppressing demyelination in the brain. A third drug is
memantine, available now in Europe to treat Parkinson's disease.
In test-tube cultures, memantine blocks the effects of quinolinic
acid. Trials of nimodipine are already in process, and trials of
pentoxifylline are set to begin soon. Memantine studies are
still in the discussion stage.
DS: What you said about cytokines reminds me of something
Dr. Larry Waites has always maintained -- that AIDS is not an
immune deficiency so much as a dysfunction of immune responses.
ES: Correct -- I agree with that. I think that we had a
very oversimplified view of AIDS in the beginning. We thought
that HIV simply depleted the immune system, and if you could stop
that process, the war would be over. In point of fact, one of
the things that goes wrong in HIV disease is an overactivation,
an inappropriate activation, of certain immune responses. So you
have excess cytokines and inflammatory processes causing fevers,
exaggerated allergic reactions, disturbed sleep, and wasting.
DS: Would anti-inflammatory agents like aspirin be helpful?
What about some of the other drugs discussed as treatments for
cognitive disorders -- antiretrovirals, the amphetamines, the B
vitamins, the "smart drugs?"
ES: I'm not sure if anti-inflammatories are helpful.
Concerning the antiretrovirals, AZT and ddI may have a protective
effect against dementia. Two controlled studies, one of which
will be published this spring, demonstrate that high-dose AZT,
1000 mg a day or more, can reverse many of the neuropsychiatric
abnormalities in AIDS dementia patients. However, one problem is
that only a fraction of the current antiretroviral drugs can
cross the blood-brain barrier, and so very high doses must be
sent through the bloodstream to obtain a positive neurological
effect. You may end up bombing the village in order to save it,
to borrow an image from the Vietnam War.
Another avenue is to treat the symptoms. Some motor slowing
can be reversed temporarily by the use of ritalin and other
stimulant drugs. But this would be a poor choice of drug to give
someone who was already manic. And these drugs do not make you
smarter, they just make you faster and more functional. This is
OK for getting to the bathroom, but not so much for driving a
car. They will not improve your judgment.
DS: So there is no therapeutic activity from amphetamines
on the underlying problem, just improved function of the neurons
that are already functioning.
ES: Right. It's symptomatic treatment.
DS: Why are B vitamins relevant?
ES: In terms of B12, we clearly know that people with HIV
frequently develop B12 deficiencies. These deficiencies, and
others, may indeed play a role in demyelination. Unfortunately,
you may have normal blood levels of B12 and other nutrients but
not be getting enough to the brain because of a problem with the
transport protein responsible for getting it there.
DS: So it's possible that you could hammer someone with
high-dose B12, and still not address the neuro deficiency
because of this transport problem?
ES: That is possible; the studies just haven't been done to
prove or disprove it.
DS: Speaking of metabolic pathways, what about the
endocrine connection? It is known that certain hormones can
function as neurotransmitters. I've long thought that the
endocrine system and the nervous system were the great
understudied areas of HIV research; maybe in fact they are a
single area.
ES: Absolutely ...the message of psychoneuroimmunology.
It's very well-documented that in HIV infection, the
hypothalamic/pituitary/adrenal axis is disturbed, and this may
lead to very high levels of cortisol in the blood. We found that
these levels are also high in the brain, and we know from
research into other diseases that this may be bad for your brain
cells. Cortisol may also exacerbate the damage caused by other
neurotoxins. It's another instance of having too much of
something that is usually a good thing. We found that when
compared to people with HIV who were asymptomatic, people with
AIDS dementia and other neurologic symptoms have high levels of
cortisol and low levels of certain neurotransmitters in the
spinal fluid. Imbalances of the neurohormones and
neurotransmitters can be associated with dysfunctions of thought
and mood and memory.
This is an area that remains underexplored. In other
diseases, we may not fix the original problem, but we control the
symptoms. We don't know the precise cause of Parkinson's
disease, for example. But we do know that there is a loss of a
neurotransmitter, dopamine. So even though we can't cure
Parkinson's, we have improved the life of people who have the
disease by giving them drugs that will replace the dopamine in
various ways. It may be that if we can identify some of the
specific pathways or hormones or transmitters that are disturbed
by HIV, and that contribute to neurologic disease, we can target
drugs to relieve these symptoms. This could help people to
remain functional and comfortable.
DS: Can you identify an early cognitive deficit and treat
it before it becomes disabling?
ES: I have a patient who is ordinarily a very high
functioning individual, someone who uses his brain a lot in a
very productive job, and now he's having some cognitive problems.
He certainly does not have dementia, but he has the potential to
get there. At first the symptoms were controlled with high-dose
AZT, and he had a great year and a half. Then we had to slow
down the dose to 400 mg a day because he developed some medical
problems from so much AZT. As soon as we did that, his
neurological functions got worse again. We're going to try other
antiretrovirals, or nimodipine. But the point is, he is really
upset and feeling like he's the only person in the world in his
situation. I think there has been a lack of attention to the
needs of these people. Perhaps this stems from the social
misconceptualization of dementia, of drooling people rummaging
through garbage cans. But my patient is more representative of
people with cognitive disorders: people who are functioning
below their baseline, who are worried about getting worse because
they want very badly to keep working.
There hasn't been much of a push from the scientific
community or the activist community for practical, clinical
treatments for cognitive problems, except for peptide T. The ACTG
trials have run into a lot of red tape and trouble with funding.
And I think there is a lot of embarrassment and confusion in the
community about cognitive problems in HIV disease. This may be a
response to the reactionaries out there who suggest that everyone
with AIDS is demented, which is not true, or that all people with
cognitive difficulties cannot take charge of their own lives,
which is not true. So in reaction, you end up with other people
saying that the problem doesn't occur, or it doesn't occur very
much, or it only happens to people who are about to die. In the
middle of these extreme positions, meanwhile, are patients who
have cognitive symptoms but don't have much support from either
their community or the medical establishment. I feel very
frustrated that there are agents out there which might help my
patients, but have not been tested. The incidence of people
whose first AIDS diagnosis is dementia may be only 7%. But that
goes up another 7% a year in people who have had some other
AIDS-index diagnosis. So this is going to become a bigger issue
as people live longer. I'll put a question to you: why do you
think dementia has been an underserved and ignored area?
DS: Well, I think you're right about the "embarrassment" of
dementia, and about mental status problems generally. If you
address them, then you allow for their existence, which allows
for their potential to target you. I also think that the specter
of "losing your mind," however inflated, is really draining to
face for people who already face the loss of their physical
health, and who in the past have come perilously close to losing
legal and civil rights. I do know people in ACT UP New York and
ACT UP Golden Gate who have seriously tried to get more research
attention for dementia. [For coverage of activist efforts, see
AIDS TREATMENT NEWS issue number 156, August 7, 1992.] If more
people did make waves for HIV cognitive research, and if Hillary
Clinton gave you half a zillion dollars for this research, where
would you start?
ES: First of all, that kind of money should be distributed
to research for everyone at risk for dementia. People with money
and education usually tend to get better care, and poor people
tend to get neglected. Also, neurologic diseases are more common
at the extremes of life, which is also where people get ignored a
lot. You're more likely to experience neurologic disease if you
are very young, or older. I would like to see more money for
clinical trials of symptomatic treatment of neurologic disease --
not just dementia, but also neuropathy, pain, headaches,
depression and sleep disorders. I'd like to see a balance
between basic molecular biology and meeting the immediate needs
of my patients.
DS: But those interests should converge!
ES: They should, but right now they're not. I'd also like
to have some better methods of drug delivery -- how to get enough
drug into the brain without flooding the rest of the body.
DS: What about intrathecal administration [injecting drugs
directly into the cerebrospinal fluid], or liposomal preparations
[drugs encapsulated in liposomes]?
ES: The intrathecal route has been tried, but it's fraught
with medical complications, and it's expensive. It may be a
solution for a very few people, but this is not a problem that
applies to just a few people. I don't know enough about
liposomal drugs. It worked for amphotericin, so it's an
interesting question. We need to get the funding to answer those
kinds of questions.
DS: Or even to get the questions asked.
ES: Yes. And one of the most important questions concerns
the very direction of HIV drug research. You could come up with
the best antiretroviral for the body, but if it doesn't
effectively penetrate the blood/brain barrier, you're going to
end up with the brain as a safe reservoir for viral replication,
a constant source of reinfection. Also, we should ask why some
people with HIV develop neurologic problems, and not others. The
answers to these questions can't all be with the virus. So
source: AIDS Treatment News
